Effect of exercise on the expression of nerve growth factor in the spinal cord of rats with induced osteoarthritis.
Park Soo-Jin,Yong Min-Sik,Na Sang-Su
Journal of physical therapy science
[Purpose] We examined the impact of exercise on the expression pattern of nerve growth factor in the spinal cord of rats with induced osteoarthritis of the knee joint. [Subjects and Methods] To produce monosodium iodoacetate-induced arthritis, rats were administered 3 mg/50 µL monosodium iodoacetate through the interarticular space of the right knee. The animals were randomly divided into four groups: rats sacrificed 3 weeks after 0.9% saline solution injection (shame group, n = 10), rats sacrificed 3 weeks after monosodium iodoacetate injection (control group, n = 10), rats with 4 weeks rest from 3 weeks after monosodium iodoacetate injection (no exercise group, n = 10), and rats with 4 weeks treadmill training from 3 weeks after monosodium iodoacetate injection (exercise group, n = 10). Serial coronal sections of the lumbar spine were cut and processed for immunohistochemistry. [Results] The expression of nerve growth factor was significantly increased in the EG compared with the SG, CG, and NEG. [Conclusion] Increased nerve growth factor expression in the spinal cord due to exercise-induced stimulation can be effective in treating chronic pain. Such treatment will contribute not only to improving the joint function of patients with chronic pain but also their quality of life.
10.1589/jpts.27.2551
Anterior knee pain caused by patellofemoral pain syndrome can be relieved by Botulinum toxin type A injection.
Chen John Tzu-Ning,Tang Alice Chu-Wen,Lin Shih-Cherng,Tang Simon Fuk-Tan
Clinical neurology and neurosurgery
OBJECTIVE:To investigate the therapeutic effects of Botulinum toxin type A (BTA) for anterior knee pain caused by patellofemoral pain syndrome (PFPS). DESIGN:Prospective case control study for intervention. SETTING:A tertiary hospital rehabilitation center. PARTICIPANTS:Twelve bilateral PFPS patients with anterior knee pain were recruited. The worse pain knee was selected for injection, and the counterpart was left untreated. INTERVENTION:Injection of BTA to vastus lateralis (VL) muscle. MAIN OUTCOME MEASURES:Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess pain, stiffness, and functional status of the knee, and CYBEX isokinetic dynamometer to assess isokinetic muscle force before and after BTA application to VL. RESULTS:Remarkable improvement after receiving BTA injection was obtained not only in the questionnaire of WOMAC (p<0.05), but also in knee flexion torque (p<0.05). No significant change of knee extension torque was noted (p=0.682). CONCLUSION:BTA injection is a good alternative treatment to improve anterior knee pain, knee function and isokinetic flexion torque.
10.1016/S0303-8467(15)30008-1
Knee osteoarthritis related pain: a narrative review of diagnosis and treatment.
International journal of health sciences
BACKGROUND:Osteoarthritis is a common progressive joint disease, involving not only the joint lining but also cartilage, ligaments, and bone. For the last ten years, majority of published review articles were not specific to osteoarthritis of the knee, and strength of evidence and clinical guidelines were not appropriately summarized. OBJECTIVES:To appraise the literature by summarizing the findings of current evidence and clinical guidelines on the diagnosis and treatment of knee osteoarthritis pain. METHODOLOGY:English journal articles that focused on knee osteoarthritis related pain were searched via PubMed (1 January 2002 - 26 August 2012) and Physiotherapy Evidence Database (PEDro) databases, using the terms 'knee', 'osteoarthritis' and 'pain'. In addition, reference lists from identified articles and related book chapters were included as comprehensive overviews. RESULTS:For knee osteoarthritis, the highest diagnostic accuracy can be achieved by presence of pain and five or more clinical or laboratory criteria plus osteophytes. Some inconsistencies in the recommendations and findings were found between the clinical guidelines and systematic reviews. Generally, paracetamol, oral and topical non-steroidal anti-inflammatory drugs, opioids, corticosteroid injections and physical therapy techniques, such as therapeutic exercises, joint manual therapy and transcutaneous electrical nerve stimulation, can help reduce pain and improve function. Patient education programs and weight reduction for overweight patients are important to be considered. CONCLUSIONS:Some inconsistencies in the recommendations and findings were found between the clinical guidelines and systematic reviews. However, it is likely that a combination of pharmacological and non-pharmacological treatments is most effective in treating patients with knee osteoarthritis.
10.12816/0006075
Extraction of neuropeptides from joint tissue for quantitation by radioimmunoassay. A study in the rat.
Ahmed M,Bjurholm A,Srinivasan G R,Theodorsson E,Kreicbergs A
Peptides
The feasibility of extracting neuropeptides from rat knee joints for quantitation by radioimmunoassay was tested. The investigation, based on 25 adult Lewis rats, focused on substance P, calcitonin gene-related peptide, neuropeptide Y, and vasoactive intestinal polypeptide. The relative recovery of the peptides in different extraction media was assessed Both knee joints including the articulating epiphysis were dissected and cut into small pieces. The series was divided into five subgroups, 10 joints in each, for extraction in five different media: 1) 1 M acetic acid in 4% EDTA, 2) 2 M acetic acid in 4% EDTA, 3) neutral water in 4% EDTA, 4) 2 M acetic acid in 4% EDTA and 95% alcohol, and 5) 2 M acetic acid without EDTA. Measureable concentrations of the four neuropeptides were reproducibly assessed by RIA. Although all extraction media provided measurable concentrations, 2 M acetic acid in 4% EDTA was found to give the highest overall yield of the four neuropeptides analyzed. Reverse-phase HPLC confirmed that the immunoreactivities assessed by RIA corresponded to the four neuropeptides of interest. Experimental and clinical evidence suggest a neurogenic involvement in the pathophysiology of inflammatory joint disease, e.g., rheumatoid arthritis. The extraction procedure described offers a means of determining neuropeptide concentrations in joint tissue under normal and pathologic conditions by RIA.
Cannabinoid receptor type 2 is upregulated in synovium following joint injury and mediates anti-inflammatory effects in synovial fibroblasts and macrophages.
Osteoarthritis and cartilage
OBJECTIVE:Joint injury-induced perturbations to the endocannabinoid system (ECS), a regulator of both inflammation and nociception, remain largely uncharacterized. We employed a mouse model of ACL rupture to assess alterations to nociception, inflammation, and the ECS while using in vitro models to determine whether CB2 agonism can mitigate inflammatory signaling in macrophages and fibroblast-like synoviocytes (FLS). DESIGN:Mice underwent noninvasive ACL rupture (ACLR) via tibial compression-based loading. Nociception was measured longitudinally using mechanical allodynia and knee hyperalgesia testing. Synovitis was assessed using histological scoring and histomorphometry. Gene and protein markers of inflammation were characterized in whole joints and synovium. Immunohistochemistry assessed injury-induced alterations to CB1+, CB2+, and F4/80+ cells in synovium. To assess whether CB2 agonism can inhibit pro-inflammatory macrophage polarization, murine bone marrow-derived macrophages (mBMDM) were stimulated with IL-1β or conditioned medium from IL-1β-treated FLS and treated with vehicle (DMSO), the CB2 agonist HU308, or cannabidiol (CBD). Macrophage polarization was assessed as the ratio of M1-associated (IL1b, MMP1b, and IL6) to M2-associated (IL10, IL4, and CD206) gene expression. Human FLS (hFLS) isolated from synovial tissue of OA patients were treated with vehicle (DMSO) or HU308 following TNF-α or IL-1β stimulation to assess inhibition of catabolic/inflammatory gene expression. RESULTS:ACLR induces synovitis, progressively-worsening PTOA severity, and an immediate and sustained increase in both mechanical allodynia and knee hyperalgesia, which persist beyond the resolution of molecular inflammation. Enrichment of CB2, but not CB1, was observed in ACLR synovium at 3d, 14d, and 28d, and CB2 was found to be associated with F4/80 (+) cells, which are increased in number in ACLR synovium at all time points. The CB2 agonist HU308 strongly inhibited mBMDM M1-type polarization following stimulation with either IL-1β or conditioned medium from IL-1β-treated mFLS, which was characterized by reductions in Il1b, Mmp1b, and Il6 and increases in Cd206 gene expression. Cannabidiol similarly inhibited IL-1β-induced mBMDM M1 polarization via a reduction in Il1b and an increase in Cd206 and Il4 gene expression. Lastly, in OA hFLS, HU308 treatment inhibited IL-1β-induced CCL2, MMP1, MMP3, and IL6 expression and further inhibited TNF-α-induced CCL2, MMP1, and GMCSF expression, demonstrating human OA-relevant anti-inflammatory effects by targeting CB2. CONCLUSIONS:Joint injury perturbs the intra-articular ECS, characterized by an increase in synovial F4/80(+) cells, which express CB2, but not CB1. Targeting CB2 in murine macrophages and human FLS induced potent anti-inflammatory and anti-catabolic effects, which indicates that the CB2 receptor plays a key role in regulating inflammatory signaling in the two primary effector cells in the synovium. The intraarticular ECS is therefore a potential therapeutic target for blocking pathological inflammation in future disease-modifying PTOA treatments.
10.1016/j.joca.2021.09.003
Norepinephrine inhibition of mesenchymal stem cell and chondrogenic progenitor cell chondrogenesis and acceleration of chondrogenic hypertrophy.
Jenei-Lanzl Zsuzsa,Grässel Susanne,Pongratz Georg,Kees Frieder,Miosge Nicolai,Angele Peter,Straub Rainer H
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)-dependent and cartilage progenitor cell (CPC)-dependent chondrogenesis. METHODS:Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific β-adrenergic receptor (β-AR) agonist isoproterenol, and the specific β-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation. RESULTS:TH+ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, β-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy. CONCLUSION:Our findings demonstrate NE-dependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options.
10.1002/art.38695
Long-term repetitive mechanical loading of the knee joint by in vivo muscle stimulation accelerates cartilage degeneration and increases chondrocyte death in a rabbit model.
Horisberger Monika,Fortuna Rafael,Valderrabano Victor,Herzog Walter
Clinical biomechanics (Bristol, Avon)
BACKGROUND:Excessive chronic loading is thought to be one factor responsible for the onset of osteoarthritis. For example, studies using treadmill running have shown an increased risk for osteoarthritis, thereby suggesting that muscle-induced joint loading may play a role in osteoarthritis onset and progression. However, in these studies, muscle-induced loading was not carefully quantified. Here, we present a model of controlled muscular loading which allows for the accurate quantification of joint loading. The aim of this study was to evaluate the effects of long-term, cyclic, isometric and dynamic, muscle-induced joint loading of physiologic magnitude but excessive intensity on cartilage integrity and cell viability in the rabbit knee. METHODS:24 rabbits were divided into an (i) eccentric, (ii) concentric, or (iii) isometric knee extensor contraction group (50 min of cyclic, submaximal stimulation 3 times/week for four weeks=19,500 cycles) controlled by the stimulation of a femoral nerve cuff electrode on the right hind limb. The contralateral knee was used as a non-loaded control. The knee articular cartilages were analysed by confocal microscopy for chondrocyte death, and histologically for Mankin Score, cartilage thickness and cell density. FINDINGS:All loaded knees had significantly increased cell death rates and Mankin Scores compared to the non-loaded joints. Cartilage thicknesses did not systematically differ between loaded and control joints. INTERPRETATION:Chondrocyte death and Mankin Scores were significantly increased in the loaded joints, thereby linking muscular exercise of physiologic magnitude but excessive intensity to cartilage degeneration and cell death in the rabbit knee.
10.1016/j.clinbiomech.2013.04.009
Delayed neutrophil apoptosis induced by synovial fluid in rheumatoid arthritis: role of cytokines, estrogens, and adenosine.
Ottonello Luciano,Frumento Guido,Arduino Nicoletta,Bertolotto Maria,Mancini Marina,Sottofattori Enzo,Dallegri Franco,Cutolo Maurizio
Annals of the New York Academy of Sciences
The fate of neutrophils at sites of inflammation, where these cells are likely exposed to both anti- and proapoptotic influences, needs to be clarified. To investigate this issue, we studied the survival of neutrophils in the presence of articular fluids from RA joints before and after immune complex activation. Eight of eleven samples of RA synovial fluid studied were found to inhibit spontaneous and immune complex-stimulated neutrophil apoptosis. No relationships were found between GM-CSF and TNF-alpha concentrations measured on each sample of synovial fluid studied and the levels of neutrophil apoptosis detectable in the presence of the same synovial fluid. Furthermore, no activity on neutrophil survival was observed at either physiologic or pharmacologic concentrations of estradiol. On the contrary, the synovial fluid anti-apoptotic activity correlates (r(2) = 0.8818, p < 0.0001) with the adenosine detected at concentrations in each sample ranging from 18.7 to 52.4 microM. Finally, synovial fluids were incapable of interfering with neutrophil activation evaluated as superoxide anion production. Our results suggest that the microenvironment of rheumatoid synovial fluid is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils.
10.1111/j.1749-6632.2002.tb04219.x
Innervation of bone from healthy and arthritic rats by substance P and calcitonin gene related peptide containing sensory fibers.
Hukkanen M,Konttinen Y T,Rees R G,Gibson S J,Santavirta S,Polak J M
The Journal of rheumatology
Mechanical stress causes remodelling of bone, a transformation of bone structure by physical forces through an unknown mechanism. Inflammation also affects bone structure, through altered use and the production of various inflammatory mediators. The peripheral nervous system may play both a sensory and an efferent role in the mechanical and inflammatory influences on bone structure. We studied the occurrence of substance P and calcitonin gene related peptide (CGRP) containing nerves in periosteal tissue, bone marrow, diaphysis and epiphysis of the ankle and knee joints of healthy and adjuvant arthritic rats. In arthritic animals, only ankle joints were affected by the inflammation. The periosteum was richly innervated both in healthy and arthritic animals. In arthritic rats few nerve fibers penetrated the woven, callous bone underlying the periosteum. Also bone marrow contained substance P and CGRP immunoreactive nerves in normal bone, whereas the hypercellular bone marrow of arthritic rats showed a decrease in the density of substance P and CGRP containing fibers. Epiphysis had a dense innervation compared to diaphysis. In contrast to large erosions, small peripheral erosions contained some CGRP immunoreactive fibers, perhaps as a sign of attempts of reactive repair. Our results suggest a local delivery system of potent peptide regulatory factors in bone, a system also affected by the pathophysiology of arthritis.
Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist, LY5454694 tosylate, in 2 chronic pain conditions.
Chappell Amy S,Iyengar Smriti,Lobo Evelyn D,Prucka William R
Pain
This article reports results of 2 studies investigating LY545694 in pain due to osteoarthritis (OA) of the knee and diabetic peripheral neuropathic pain (DPNP). Study I randomized patients to either of 2 doses of LY545694 or to placebo, and study II randomized patients to either of 3 doses of LY545694, to pregabalin, or to placebo. No significant differences between LY545694 groups and placebo were observed on the primary (average pain severity) or secondary efficacy measures in either study. Notably, study I lacked an active control, and, in study II, pregabalin, did not separate from placebo. Treatment-emergent nausea, vomiting, and dizziness were significantly more frequent in the LY545694 groups in both trials (P⩽.05), and significantly more LY545694-treated patients discontinued because of adverse events (P<.001). Steady-state concentrations of LY545694 were comparable in patients in both studies but were lower than exposures required for efficacy in animal models of pain behavior. Because the active control did not separate from placebo in the DPNP study, the study was potentially failed, rather than negative. Without an active control, it is unknown whether the OA study was negative or failed. Consequently, efficacy of selective ionotropic glutamate receptor antagonism in chronic pain conditions may warrant further investigation. Future trials should consider different pain conditions, contain a positive control with larger patient numbers per arm, and be conducted within a single region.
10.1016/j.pain.2014.02.023
Surgical synovectomy decreases density of sensory nerve fibers in synovial tissue of non-inflamed controls and rheumatoid arthritis patients.
Ossyssek B,Anders S,Grifka J,Straub R H
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Surgical synovectomy is a technique to treat synovitis and pain in patients with rheumatoid arthritis (RA) resistant to DMARDs or therapy with biologics. Indication to synovectomy is subject to tight cooperation of orthopaedic surgeons and rheumatologists. It was thought that synovectomy leads to a reduction of sensory nerve fibers, called sensory denervation. Since sensory denervation after synovectomy has never been histologically tested, we aimed to investigate sensory and sympathetic innervation in synovial tissue before and after synovectomy. Eight non-inflamed control subjects and eight patients with RA were included in this study with a two-stage synovectomy approach (interval 40–50 days). Nerve fibers and cells in synovial tissue were detected and counted using immunofluorescence. Density of sympathetic nerve fibers did not change after synovectomy, whereas density of sensory nerve fibers decreased in all control subjects and seven of eight patients with RA. In parallel, the density of synovial cells increased after synovectomy in all control subjects and six of eight RA patients, which is indicative of a wound healing response. In one female RA patient, density of sensory nerve fibers increased and a very marked rise of cellular density was observed, too. This indicates that probably not all patients profit from surgical synovectomy. The majority of patients (94%) demonstrated sensory denervation after surgical synovectomy accompanied by a wound healing cell response. This study can help to explain the positive effects of surgical synovectomy which usually leads to pain reduction and improved mobility.
10.1002/jor.21233
Citral-induced analgesia is associated with increased spinal serotonin, reduced spinal nociceptive signaling, and reduced systemic oxidative stress in arthritis.
Mota Clarissa M D,Rodrigues-Santos Caroline,Carolino Ruither O G,Anselmo-Franci Janete A,Branco Luiz G S
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Arthritic pain is the main unpleasant component of rheumatoid arthritis. The pharmacological approaches used to treat arthritic pain are often accompanied by adjuvant drugs or non-pharmacological treatments, showing a constant need in identifying new efficient analgesic drugs. AIM OF THE STUDY:To test the hypothesis that citral, which is a monoterpenoid compound with therapeutic properties, reduces nociception, spinal pro-nociceptive and pro-inflammatory signaling, and systemic oxidative stress in arthritic rats. MATERIALS AND METHODS:Complete Freund's adjuvant (CFA) was administrated in the left knee joint of rats. Oral treatment with citral was performed during eight days and mechanical allodynia was monitored during the period of treatment to evaluate the analgesic effect of citral. We assessed the levels of serotonin (5-hydroxytryptamine, 5-HT) in the lumbar dorsal horn of the spinal cord (DHSC) and the profiles of expression of the glycogen synthase kinase-3β (GSK3β), which is a 5-HT-regulated intracellular protein, and of the stress-activated protein kinase (SAPK)/jun N-terminal kinase (JNK) in the DHSC. Plasma levels of superoxide dismutase (SOD) were assessed as an indicator of oxidative stress. RESULTS:Administration of CFA induced mechanical allodynia associated with reduced spinal GSK3β phosphorylation, increased spinal SAPK/JNK phosphorylation, and increased plasma SOD levels. Oral administration of citral reversed mechanical allodynia, increased endogenous spinal 5-HT levels, reduced spinal SAPK/JNK phosphorylation, and reduced plasma SOD levels. CONCLUSION:Citral shows anti-nociceptive effects in an animal model of arthritic pain by modulating spinal nociceptive signaling.
10.1016/j.jep.2019.112486
Peripheral Nerve Stimulation of the Saphenous and Superior Lateral Genicular Nerves for Chronic Pain After Knee Surgery.
Chitneni Ahish,Berger Amnon A,Orhurhu Vwaire,Kaye Alan D,Hasoon Jamal
Orthopedic reviews
Total knee arthroplasty (TKA) is one of the most commonly conducted surgeries in the United States. Typically, TKA is conducted to relieve pain from patients with long-standing osteoarthritis. Postoperative knee pain is a common issue after TKA. For some patients, postoperative knee pain exceeds the normal 3-6-month phase and becomes chronic. Pain is typically managed with the use of medications and physical therapy. In this case, we describe the use of peripheral nerve stimulation (PNS) of the saphenous and superior lateral genicular nerves for a patient experiencing chronic postoperative knee pain utilizing SPRINT PNS technology.
10.52965/001c.24435
(E)-3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one ameliorates the collagen-arthritis via blocking ERK/JNK and NF-κB signaling pathway.
Li Xiuxia,Peng Fei,Xie Caifeng,Wu Wenshuang,Han Xiaolei,Chen Lijuan
International immunopharmacology
Our previous report has shown a natural pyranochalcones-derived compound, (E)-3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one (5b), that exerted protection against carrageenan-induced hind paw edema and adjuvant-induced arthritis. In this study, collagen-induced arthritis (CIA) model was used to further examine the anti-arthritic effects of 5b in vivo; the underlying molecular mechanisms of action were also investigated using a murine monocytic cell line, RAW264.7 cells. Here we showed that oral administration of 5b (20mg/kg) significantly suppressed the progression of arthritis. Improvement in disease severity was accompanied by inhibition of CD68-positive cells in knee joint and reduced pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in serum. In vitro, 5b suppressed expressions of iNOS, cyclooxygenase-2 (COX-2), TNF-α, IL-6 and IL-1β as well as productions of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated macrophages. This compound also significantly suppressed LPS-induced NF-κB activation, including phosphorylation of I-κB, degradation of I-κB, and nuclear translocation of p65 and p50. Treatment with 5b also blocked LPS-induced expression of TLR4 remarkably, suppressed degradation of IRAKs and phosphorylations of JNK and ERK, but had little effect to p38 kinase activation. These findings indicated that 5b might be a therapeutic agent for rheumatoid arthritis, and exerted an anti-inflammatory effect mainly through mediating TLR4, NF-κB and ERK/JNK signaling pathways in monocytes.
10.1016/j.intimp.2013.10.001
RhoA/ROCK-dependent pathway is required for TLR2-mediated IL-23 production in human synovial macrophages: suppression by cilostazol.
Park So Youn,Lee Sung Won,Lee Won Suk,Rhim Byung Yong,Lee Seung Jin,Kwon Sang Mo,Hong Ki Whan,Kim Chi Dae
Biochemical pharmacology
IL-23 is produced by antigen presenting cells and plays critical roles in immune response in rheumatoid arthritis. In this study, we investigated whether the RhoA/Rho-kinase pathway is required to elevate TLR2-mediated IL-23 production in synovial macrophages from patients with rheumatoid arthritis (RA), and then examined the suppressive effect of cilostazol on these pathways. IL-23 production was elevated by lipoteichoic acid (LTA), a TLR2 ligand, and this elevation was more prominent in RA macrophages than in those from peripheral blood of normal control. LTA increased the activation of RhoA in association with increased the nuclear translocation of NF-κB and its DNA-binding activity. Pretreatment of RA macrophages with the pharmacological inhibitors exoenzyme C3 (RhoA), Y27632 (Rho-kinase) or BAY11-7082 (NF-κB) inhibited IL-23 production by LTA. Inhibition of the RhoA/Rho-kinase pathway by these drugs attenuated NF-κB activation. Cilostazol suppressed the TLR2-mediated activation of RhoA, decreased NF-κB activity with down-regulated IL-23 production, and these effects were reversed by Rp-cAMPS, as an inhibitor of cAMP-dependent protein kinase. The expression of IL-23, which colocalized with CD68⁺ cells in knee joint of CIA mice, was significantly attenuated by cilostazol along with the decreased severity of arthritis. Taken together, the RhoA/Rho-kinase pathway signals TLR2-stimulated IL-23 production in synovial fluid macrophages via activation of NF-κB. Thus it is summarized that cilostazol suppresses TLR2-mediated IL-23 production by suppressing RhoA pathway via cAMP-dependent protein kinase activation.
10.1016/j.bcp.2013.08.017
Chronic inflammation and pain in a tumor necrosis factor receptor (TNFR) (p55/p75-/-) dual deficient murine model.
Westlund Karin N,Zhang Liping,Ma Fei,Oz Helieh S
Translational research : the journal of laboratory and clinical medicine
Many aspects of tissue damage after acute or chronic inflammatory reactions can be attributed directly to the concomitant biosynthesis and release of inducible early proinflammatory cytokine tumor necrosis factor alpha (TNFα). Conversely, systemic inflammation is impacted by the consequences of tissue damage. Dysregulated TNFα contributes to numerous pathophysiologic conditions including inflammatory bowel disease (IBD) and arthritis. Inflammatory stimuli trigger proteolytic cleavage and shedding of extracellular domains of TNFα receptors giving rise to 2 soluble fragments (p55 soluble tumor necrosis factor receptor 1 (sTNFR1) and p75 sTNFR2) that block the additional binding, activity, and synthesis of TNFα. We hypothesized that absence of sTNFR inhibitory feedback control would result in accumulated high levels of TNFα and other inflammatory factors promoting the cardinal signs of chronic inflammation and pain. The current study reports a translational murine model of chronic arthritis precipitated by 2 consecutive inflammatory insults. The "double hit" procedures provoke a chronic inflammatory response and pain-related behaviors in mice that are dually deficient in p55 (TNFR1) and p75 (TNFR2). The inflammation- and pain-related behaviors are transient in similarly treated wild-type (WT) mice. The complete Freund's adjuvant (CFA) method was used initially to induce knee joint inflammation, tactile mechanical and heat hypersensitivity, and gait disturbance. After these transient effects of the insult were resolved, a recrudescence persisting at least through 23 weeks was promoted by gastrointestinal (GI) insult with dilute intracolonic mustard oil (MO) only in the mutant mice and was reversed by a P2X7 antagonist. A serum proteome profiling analysis revealed high levels of serum inflammatory factors TNFα, regulated upon activation normally T-cell expressed and secreted (RANTES), chemokine (C-X-C motif) ligand 9 [CXCL9 (MIG)], chemokine (C-X-C motif) ligand 10 [CXCL10 (IP-10)], and chemokine (C-C motif) ligand 2 [CCL2 (MCP-1)]. These data suggest that impaired signaling of TNFα as a result of the deficit of the 2 protective soluble p55 and p75 sTNFR inhibitory factors plays a pivotal role in the reactivation of the immune response to GI insult that can produce recrudescence of inflammatory injury and a chronic pain state through promotion of high levels of serum inflammatory factors.
10.1016/j.trsl.2011.10.003
Impaired chronic pain-like behaviour and altered opioidergic system in the TASTPM mouse model of Alzheimer's disease.
Aman Y,Pitcher T,Ballard C,Malcangio M
European journal of pain (London, England)
BACKGROUND:Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD. METHODS:Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue. RESULTS:MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β-endorphin post-MIA which correlated with impaired allodynia. CONCLUSIONS:These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD. SIGNIFICANCE:This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.
10.1002/ejp.1288
Neutrophils-derived peroxynitrite contributes to acute hyperalgesia and cell influx in zymosan arthritis.
Bezerra Mirna M,Brain Susan D,Girão Virgínia C C,Greenacre Stan,Keeble Julie,Rocha Francisco A C
Naunyn-Schmiedeberg's archives of pharmacology
We investigated the contribution of neutrophils to joint hyperalgesia and peroxynitrite formation in zymosan arthritis. Rats received 1 mg zymosan intra-articular, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. After 6 h, joint exudates were collected by aspiration for the assessment of cell influx, myeloperoxidase activity, and nitrite (as an index of nitric oxide formation) levels. Nitrotyrosine content, used as an index of peroxynitrite formation, was measured in joint exudates, using enzyme-linked immunosorbent assay. A group of rats was rendered neutropenic through the administration of a rabbit anti-rat neutrophil antibody (2 ml kg(-1), i.p.) 30 min before injection of 1 mg zymosan intra-articular. Other groups received uric acid (100 or 250 mg kg(-1), i.p.), the peroxynitrite scavenger, 30 min before 1 mg zymosan intra-articular. Controls received the vehicle. The significant inhibition of joint hyperalgesia in neutropenic animals was associated to significantly decreased cell influx, myeloperoxidase activity, nitric oxide, and nitrotyrosine levels in the joint exudates, as compared to naive rats. Uric acid administration inhibited both hyperalgesia and cell influx, as compared to controls. Neutrophils are involved in both nitric oxide and peroxynitrite formation in zymosan arthritis, thereby contributing to acute joint hyperalgesia. Scavenging of reactive nitrogen species (e.g. peroxynitrite) inhibits neutrophil migration and joint hyperalgesia in the acute phase of zymosan arthritis in rats.
10.1007/s00210-006-0123-9
Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines.
Ottonello L,Cutolo M,Frumento G,Arduino N,Bertolotto M,Mancini M,Sottofattori E,Dallegri F
Rheumatology (Oxford, England)
OBJECTIVE:In synovial fluid (SF) from patients with rheumatoid arthritis (RA), neutrophils are exposed to proinflammatory mediators endowed with either anti-apoptotic or pro-apoptotic properties. We investigated neutrophil apoptosis in the presence of SF from 11 RA patients. METHODS:SF was obtained from affected knees of 11 patients with RA. Human neutrophil apoptosis was evaluated by light microscopic examination and flow-cytometric analysis of annexin V binding. Immune complex-induced neutrophil activation was evaluated as superoxide anion production. Adenosine levels in SF were detected by chromatographic analysis and cytokine levels were studied by enzyme-linked immunosorbent assay. RESULTS:Spontaneous and immune complex-triggered neutrophil apoptosis was reduced by SF from eight out of 11 patients. Immune complex-induced neutrophil activation was unaffected by SF. The cytokines tested had no role in promoting the anti-apoptotic activity of SF. On the contrary, the anti-apoptotic activity of SF was found to depend on the presence of adenosine. Adenosine levels detected in the various samples of SF correlated significantly with the anti-apoptotic activity of the fluids and with the number of apoptotic neutrophils detected in the articular exudate. CONCLUSION:The microenvironment of rheumatoid SF is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon, which is related to anti-apoptotic activity.
10.1093/rheumatology/41.11.1249
Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis.
Sung J Y,Hong J H,Kang H S,Choi I,Lim S D,Lee J K,Seok J H,Lee J H,Hur G M
Immunopharmacology
Various cytokines and reactive oxygen species (ROS) play a fundamental role in the inflammatory and immunologic processes of rheumatoid arthritis (RA). Methotrexate (MTX) is one of the disease-modifying anti-rheumatic drugs and its effect may be partly due to the modulation of immunologic or inflammatory reactions by some cytokines. In the present study, we investigated the effects of MTX on the gene expression and synthesis of interleukin-6 (IL-6), and the proliferative activity and the production of ROS in the fibroblast-like synoviocytes (FLSs) obtained from the patient of RA. The expression or production of IL-6 was induced spontaneously, and augmented by the addition of recombinant human IL-6 or recombinant human IL-1 beta and TNF-alpha in FLSs. These spontaneous and augmented IL-6 expressions or productions were suppressed by treatment with low-concentration of MTX (1 microg/ml). Also, IL-6 stimulated the proliferation of FLSs, and this IL-6 driven proliferation was inhibited with the treatment of MTX or N-acetylcysteine (NAC, 1 mM). Furthermore, ROS production in FLSs was increased significantly by IL-6, and its effect was also abrogated in the presence of MTX or NAC. These results suggest that inflammatory reaction in the synovium of RA patients could be augmented by the autocrine or other cytokine-induced production of IL-6 with subsequent generation of ROS in the synoviocytes, and the modulations of IL-6 synthesis and ROS production may contribute to the therapeutic effects of MTX for RA.
COOH-terminal heparin-binding fibronectin fragment induces nitric oxide production in rheumatoid cartilage through CD44.
Yasuda T,Kakinuma T,Julovi S M,Yoshida M,Hiramitsu T,Akiyoshi M,Nakamura T
Rheumatology (Oxford, England)
OBJECTIVES:To examine the mechanism of nitric oxide (NO) production by a COOH-terminal heparin-binding fibronectin fragment (HBFN-f) in rheumatoid arthritis (RA) cartilage. METHODS:Articular cartilage slices from RA knee joints and normal hip joints were cultured with HBFN-f. Secreted NO levels in conditioned media were determined. Cultures were pretreated with anti-CD44 antibody or HBFN-f-derived synthetic peptide (peptide V; WQPPRARI) to evaluate the role of CD44 in HBFN-f action. Immunofluorescence histochemistry was performed using fluorescein isothiocyanate-conjugated anti-CD44 antibody. RESULTS:HBFN-f stimulated NO production in a dose-dependent manner. Whereas CD44 expression was up-regulated in RA cartilage, anti-CD44 antibody blocked HBFN-f-stimulated NO production. Peptide V with heparin-binding ability significantly reduced NO levels elevated by HBFN-f. Compared with normal cartilage, cartilage response to HBFN-f and the blocking effects of anti-CD44 antibody on HBFN-f action were stronger in RA cartilage. CONCLUSIONS:The present study clearly demonstrated that HBFN-f stimulated NO production through CD44 in RA cartilage. Increased expression of CD44 in RA cartilage may play a pathological role in joint destruction through enhanced NO production by binding to fibronectin fragments such as HBFN-f.
10.1093/rheumatology/keh274
Microvascular substance P binding to normal and inflamed rat and human synovium.
Walsh D A,Salmon M,Mapp P I,Wharton J,Garrett N,Blake D R,Polak J M
The Journal of pharmacology and experimental therapeutics
The regulatory peptide substance P has been implicated in the development and persistence of inflammatory synovitis. The authors used quantitative in vitro receptor autoradiography to compare synovial binding of 125Iodine-Bolton Hunter-labeled substance P ([125I]BH-SP) in rats and humans and between uniflamed and persistently inflamed synovium. [125I]BH-SP binding to microvascular endothelium paralleled the distribution of substance P-immunoreactive nerves and had characteristics of the neurokinin (NK) 1 class of tachykinin receptor. Specific binding was inhibited by the selective NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist FK224, with Hill coefficients near unity. FK888 was > 1000 times and FK224 > 10 times more potent at inhibiting binding in human compared with rat synovium. Synovium from patients and rats with chronic arthritis contained heterogeneously distributed inflammatory cell infiltrates. For the 10 microvessels with the densest [125I]BH-SP binding in each section, no significant differences in binding density, affinity, or Ki values for substance P, FK888 or FK224 were found between synovium from naive and monoarthritic rats, nor between that from patients with rheumatoid arthritis or osteoarthritis. However, in both rat and human specimens, microscopic examination suggested that microvascular [125I]BH-SP binding in intensely infiltrated regions of synovium was less dense than in adjacent, less infiltrated areas. It was concluded that NK1 receptors are similarly distributed in rat and human synovium but show major differences in selectivity for antagonists such as FK888. NK1 receptors in synovium may mediate proinflammatory actions of locally released substance P; defective neurovascular regulation may contribute to the persistence of chronic arthritis.
The potential anti-inflammatory and anti-nociceptive effects of rat hemopressin (PVNFKFLSH) in experimental arthritis.
European journal of pharmacology
Inflammatory arthritis, such as rheumatoid arthritis (RA), stands out as one of the main sources of pain and impairment to the quality of life. The use of hemopressin (PVNFKFLSH; Hp), an inverse agonist of type 1 cannabinoid receptor, has proven to be effective in producing analgesia in pain models, but its effect on neuro-inflammatory aspects of RA is limited. In this study, antigen-induced arthritis (AIA) was evoked by the intraarticular (i.art.) injection of methylated bovine serum albumin (mBSA) in male Sprague Dawley rats. Phosphate buffered saline (PBS)-injected ipsilateral knee joints or AIA contralateral were used as control. Nociceptive and inflammatory parameters such as knee joint oedema and leukocyte influx and histopathological changes were carried out in addition to the local measurement of interleukins (IL) IL-6, IL-1β, tumor necrosis factor-α and the immunoreactivity of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal cord (lumbar L3-5 segments) of AIA rats. For 4 days, AIA rats were treated daily with a single administration of saline, Hp injected (10 or 20 μg/day, i.art.), Hp given orally (20 μg/Kg, p.o.) or indomethacin (Indo; 5 mg/Kg, i.p.). In comparison to the PBS control group, the induction of AIA produced a significant and progressive mono-arthritis condition. The degree of AIA severity progressively compromised the normal walking pattern and impaired mobility over the next four days in relation to PBS-injected rats or contralateral knee joints. In AIA rats, the reduction of the distance between footprints and disturbances of gait evidenced signs of nociception. This response worsened at day 4, and a loss of footprint from the ipsilateral hind paw was evident. Daily treatment of the animals with Hp either i.art. (10 and 20 μg/knee) or p.o. (20 μg/Kg) as well as Indo (5 mg/Kg, i.p.) ameliorated the impaired mobility in a time-dependent manner (P < 0.05). In parallel, the AIA-injected ipsilateral knee joints reach a peak of swelling 24 h after AIA induction, which persisted over the next four days in relation to PBS-injected rats or contralateral knee joints. There was a significant but not dose-dependent inhibitory effect produced by all dosages and routes of Hp treatments on AIA-induced knee joint swelling (P < 0.05). In addition, the increased synovial levels of MPO activity, total leukocytes number and IL-6, but not IL-1β, were significantly reduced by the lower i.art. dose of Hp. In conclusion, these results successfully demonstrate that Hp may represent a novel therapeutic strategy to treat RA, an effect which is unrelated to the proinflammatory actions of the neuropeptides CGRP and SP.
10.1016/j.ejphar.2020.173636
The clinically available NMDA receptor antagonist memantine is antinociceptive on rat spinal neurones.
Neugebauer V,Kornhuber J,Lücke T,Schaible H G
Neuroreport
In anaesthetized rats antinociceptive effects of the clinically available drug memantine, an NMDA (N-methyl-D-aspartate) antagonist in vitro, were evaluated using extracellular recordings from spinal neurones with knee joint input. Memantine (1-12 mg kg-1) was applied intravenously before (control animals) or after induction of an acute knee joint inflammation which rendered spinal neurones hyperexcitable. Memantine (2 mg kg-1, i.v.) selectively reduced the responses to ionophoretic application of NMDA close to the neurone but not those to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid). In control animals memantine reduced the neurones' responses to noxious but not to innocuous pressure on to the knee. In rats with acute arthritis memantine reduced the responses to noxious and innocuous pressure. Thus memantine may be useful for the treatment of pain states.
10.1097/00001756-199309000-00012
Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis.
Murphy E P,McEvoy A,Conneely O M,Bresnihan B,FitzGerald O
Arthritis and rheumatism
OBJECTIVE:To examine the regulation and mode of action of peripheral corticotropin-releasing hormone (CRH) in human inflammatory arthritis. METHODS:CRH messenger RNA (mRNA) levels were measured in normal and inflamed synovial tissue and in primary synoviocytes prior to and following cytokine stimulation. Primary synoviocytes were transiently transfected with CRH promoter/reporter constructs, and promoter activity in response to cytokines was assessed. Immunohistochemical staining established CRH receptor expression, and Northern blot analysis confirmed that the nuclear transcription factors NUR77 and NURR1 contributed to synovial CRH receptor-mediated signaling. Primary synoviocytes were treated with pro- and antiinflammatory mediators, and the time course of NURR1 and NUR77 modulation was examined. Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer. RESULTS:CRH mRNA was up-regulated in the synovial tissue in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and sarcoid arthritis, but not in normal synovium. Inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor alpha, enhanced the transcriptional activity of the human CRH promoter and increased levels of CRH mRNA in primary synoviocytes. Synovial CRH functioned in a paracrine manner to induce NURR1 and NUR77. NURR1 was abundantly expressed in the inflammatory cells of both RA and PsA synovium. NURR1 and NUR77 were differentially regulated, and NURR1 was the major cytokine-regulated member of the NURR subfamily as well as the mediator of cytokine- and CRH-dependent inflammatory responses in synovium. Furthermore, glucocorticoids dramatically suppressed cytokine- and CRH-induced synovial NURR1 mRNA. CONCLUSION:These data demonstrate the involvement of the transcription factor NURR1 in the regulation of CRH expression and activity in human inflammatory arthritis.
10.1002/1529-0131(200104)44:4<782::AID-ANR134>3.0.CO;2-H
Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice.
Lopes Fernando,Graepel Rabea,Reyes Jose Luis,Wang Arthur,Petri Björn,McDougall Jason J,Sharkey Keith A,McKay Derek M
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Activation of antiinflammatory cholinergic (vagal) pathways can reduce inflammation, and in vitro studies support a pivotal role of α7 nicotinic acetylcholine receptors (α7-nAChR), macrophages, and T cells in these events. The aim of this study was to assess α7-nAChR agonists as an antiinflammatory treatment for Freund's complete adjuvant (CFA)-induced monoarthritis. METHODS:Arthritis was induced by intraarticular injection of CFA unilaterally into the knee joints of mice. Animals were treated with α7-nAChR agonists (AR-R17779 or A844606), with or without antagonists (COG133 or methyllycaconitine), and joint inflammation and pain were assessed. Experiments were repeated in c-Kit(W-sh) mast cell-deficient mice, and the effects of an α7-nAChR agonist on mast cell proliferation, migration, and activation by lipopolysaccharide (LPS) were tested. RESULTS:Treatment with α7-nAChR agonists significantly exacerbated CFA-induced arthritis and pain, as gauged by all indices of assessment, the specificity of which was confirmed by coadministration of an nAChR antagonist that attenuated the increase in disease severity. Toluidine blue-positive mast cells were increased in the joint capsule of CFA plus AR-R17779-treated mice, and AR-R17779 enhanced LPS-induced TNF proliferation and migration of a human mast cell line. The AR-R17779-driven increase in severity of CFA-induced arthritis was significantly reduced in mast cell-deficient mice. CONCLUSION:Using CFA to elicit a local inflammatory response, we found that pharmacologic activation of α7-nAChR exacerbated joint inflammation and pain, in part via mast cells, which illustrates the organ- and disease-specific nature of regulatory neuroimmune mechanisms. Thus, α7-nAChR activation may not be uniformly antiinflammatory in all types of inflammatory joint disease.
10.1002/art.39411
Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints.
Tonussi Carlos R,Ferreira Sérgio H
Pain
Tumour necrosis factor-alpha (TNF alpha) was studied in the carrageenin (CG) induced knee-joint incapacitation, and also in mediating recurrent incapacitation response in knee-joints previously exposed to an inflammatory attack. CG or TNF alpha intra-articular injection into CG-primed knee-joints induced an intense and long-lasting (>8 h) peaking incapacitation response. TNF alpha injected in naive joints did not elicit incapacitation. Anti-TNF alpha serum in situ treatment specifically inhibited CG-induced incapacitation in naive joints, and also TNF alpha-induced incapacitation in primed joints. Hoe-140 (D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin, a bradykinin B2 receptor antagonist, given before CG, abolished incapacitation, but was without effect when injected 3 h after. Hoe-140 given before or after the CG injection in primed joints was without effect, but it produced a partial inhibitory effect in the early phase (1 h) of TNF alpha-induced incapacitation. Des-Arg9[Leu3]-bradykinin, a bradykinin B1 receptor antagonist, given intra-articularly after CG or TNF alpha, reversed incapacitation either in naive or primed joints. Indomethacin abolished the incapacitation induced by CG in naive joints, but only the 5-lipoxygenase inhibitor MK-886 plus indomethacin blocked the response in primed joints. MK-886 did not modify CG-induced incapacitation in naive joints, but lately reversed CG-induced incapacitation in primed joints, and blocked TNF alpha-induced response. Substance P or prostaglandin E2 did not induce incapacitation in either naive or primed joints. Our results support the conclusion that TNF alpha is a mediator of CG-induced inflammatory incapacitation, and is able to induce the further release of kinins and leukotrienes, which is suggested to have an important role in the maintenance of long-lasting nociceptive response.
10.1016/S0304-3959(99)00035-4
Δ -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB receptors.
Palomares Belén,Garrido-Rodriguez Martín,Gonzalo-Consuegra Claudia,Gómez-Cañas María,Saen-Oon Suwipa,Soliva Robert,Collado Juan A,Fernández-Ruiz Javier,Morello Gaetano,Calzado Marco A,Appendino Giovanni,Muñoz Eduardo
British journal of pharmacology
BACKGROUND AND PURPOSE:Δ -Tetrahydrocannabinolic acid (Δ -THCA-A), the precursor of Δ -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ -THCA-A to modulate the classic cannabinoid CB and CB receptors and evaluated its anti-arthritis activity in vitro and in vivo. EXPERIMENTAL APPROACH:Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti-arthritis properties of Δ -THCA-A were studied in human chondrocytes and in the murine model of collagen-induced arthritis (CIA). Plasma disease biomarkers were identified by LC-MS/MS based on proteomic and elisa assays. KEY RESULTS:Functional and docking analyses showed that Δ -THCA-A can act as an orthosteric CB receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Δ -THCA-A seemed to be an inverse agonist for CB receptors. In vivo, Δ -THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ -THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ -THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Δ -THCA-A mediated its activity mainly through PPARγ and CB receptor pathways. CONCLUSION AND IMPLICATIONS:Δ -THCA-A modulates CB receptors through the orthosteric and allosteric binding sites. In addition, Δ -THCA-A exerts anti-arthritis activity through CB receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.
10.1111/bph.15155
Losartan protects endothelium-dependent relaxation in vivo in a murine model of rheumatoid arthritis.
European journal of pharmacology
Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.
10.1016/j.ejphar.2021.174133
Characterization of the acute and persistent pain state present in K/BxN serum transfer arthritis.
Christianson Christina A,Corr Maripat,Firestein Gary S,Mobargha Anahita,Yaksh Tony L,Svensson Camilla I
Pain
Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects approximately 1% of the population. Synovial inflammation cannot fully explain the level of pain reported by patients and facilitation of pain processing at the spinal level has been implicated. We characterized the K/BxN serum transfer arthritis model as a model of joint inflammation-induced pain and examined pharmacologic responsiveness and spinal glia activation. Mechanical allodynia developed congruently with joint swelling. Surprisingly, allodynia persisted after resolution of inflammation. At the peak of joint inflammation (days 4-10), hypersensitivity was attenuated with i.p. etanercept, gabapentin, and ketorolac. Following resolution of synovial inflammation (days 19-23), only gabapentin relieved allodynia. The superficial dorsal horn of arthritic mice displayed increased staining of microglia at early and late time points, but astrocyte staining increased only during the inflammatory phase. ATF3, a marker of nerve injury, was significantly increased in the lumbar dorsal root ganglia during the late phase (day 28). Hence, serum transfer in the K/BxN serum transfer arthritis model produces a persistent pain state, where the allodynia during the inflammatory state is attenuated by TNF and prostaglandin inhibitors, and the pharmacology and histochemistry data suggest a transition from an inflammatory state to a state that resembles a neuropathic condition over time. Therefore, the K/BxN serum transfer model represents a multifaceted model for studies exploring pain mechanisms in conditions of joint inflammation and may serve as a platform for exploring novel treatment strategies for pain in human arthritic conditions.
10.1016/j.pain.2010.07.030
Substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity (-LI) in rat knee joint synovial fluid during acute monoarthritis is not correlated with concentrations of neuropeptide-LI in cerebrospinal fluid and plasma.
Bileviciute I,Lundeberg T,Ekblom A,Theodorsson E
Neuroscience letters
In a recent study we have shown a bilateral release of substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) in rat synovial fluid during acute monoarthritis. In order to elucidate the mechanisms underlying these phenomena, we examined the correlation between neuropeptide-LI in rat cerebrospinal fluid (CSF) and synovial fluid and between plasma and synovial fluid following the intra-articular injection of equal volumes (0.05 ml) of either Freund's adjuvans, carrageenan 2%, substance P 10(-5) M or human recombinant interleukin-1 alpha. Control rats were given saline intra-articularly. CSF, plasma and synovial fluid from the knee joints were obtained at 2, 6 and 24 h after injection and were analysed by specific radioimmunoassays. The intra-articular injection of pro-inflammatory substances induced changes in neuropeptide-LI in synovial fluid, CSF and plasma. However, there was no correlation between neuropeptide-LI in synovial fluid and plasma or between synovial fluid and CSF. The results of the present study does not support the hypothesis that the bilateral changes in neuropeptide-LI in synovial fluid were due to a release of neuropeptides from the inflamed joint into the systemic circulation. However, in carrageenan induced inflammation there was a tendency towards a correlation in SP-LI between CSF and synovial fluid suggesting that central neurogenic mechanisms should be studied in order to explain the bilateral changes seen.
10.1016/0304-3940(94)91048-0
Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis.
Baddack-Werncke Uta,Busch-Dienstfertig Melanie,González-Rodríguez Sara,Maddila Santhosh Chandar,Grobe Jenny,Lipp Martin,Stein Christoph,Müller Gerd
Journal of neuroinflammation
BACKGROUND:This study examined the development of chronic pain, a cardinal symptom of rheumatoid arthritis (RA), in mice with antigen- and collagen-induced arthritis (ACIA). Since the role of CD8 T cells in arthritis is controversial, we investigated the consequences of CD8-depletion on arthritis development and opioid modulation of pain in this novel model of chronic autoimmune arthritis. METHODS:Disease severity in control and CD8-depleted animals was determined by histological assessment of knee-joint sections and measurement of autoantibody formation. Pain was evaluated by measuring mechanical allodynia and thermal hyperalgesia in von Frey and Hargreaves tests, respectively. The production and release of endogenous opioids and inflammatory cytokines was assessed in immunoassays. RESULTS:In ACIA, mice display persistent mechanical allodynia and thermal hyperalgesia for more than 2 months after induction of arthritis. The blockade of peripheral opioid receptors with naloxone-methiodide (NLXM) transiently increased thermal hyperalgesia, indicating that endogenous opioid peptides were released in the arthritic joint to inhibit pain. CD8 T cell depletion did not affect autoantibody formation or severity of joint inflammation, but serum levels of the pro-inflammatory cytokines TNFα and IL-17 were increased. The release of opioid peptides from explanted arthritic knee cells and the NLXM effect were significantly reduced in the absence of CD8 T cells. CONCLUSIONS:We have successfully modeled the development of chronic pain, a hallmark of RA, in ACIA. Furthermore, we detected a yet unknown protective role of CD8 T cells in chronic ACIA since pro-inflammatory cytokines rose and opioid peptide release decreased in the absence of these cells.
10.1186/s12974-017-0804-y
Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction.
Lubberts E,Joosten L A,van Den Bersselaar L,Helsen M M,Bakker A C,van Meurs J B,Graham F L,Richards C D,van Den Berg W B
Journal of immunology (Baltimore, Md. : 1950)
Rheumatoid arthritis is a chronic inflammatory joint disease, leading to cartilage and bone destruction. In this study, we investigated the effects of local IL-4 application, introduced by a recombinant human type 5 adenovirus vector, in the knee joint of mice with collagen-induced arthritis. One intraarticular injection with an IL-4-expressing virus caused overexpression of IL-4 in the mouse knee joint. Enhanced onset and aggravation of the synovial inflammation were found in the IL-4 group. However, despite ongoing inflammation, histologic analysis showed impressive prevention of chondrocyte death and cartilage erosion. In line with this, chondrocyte proteoglycan synthesis was enhanced in the articular cartilage. This was quantified with ex vivo 35S-sulfate incorporation in patellar cartilage and confirmed by autoradiography on whole knee joint sections. Reduction of cartilage erosion was further substantiated by lack of expression of the stromelysin-dependent cartilage proteoglycan breakdown neoepitope VDIPEN in the Ad5E1 mIL-4-treated knee joint. Reduced metalloproteinase activity was also supported by markedly diminished mRNA expression of stromelysin-3 in the synovial tissue. Histologic analysis revealed marked reduction of polymorphonuclear cells in the synovial joint space in the IL-4-treated joints. This was confirmed by immunolocalization studies on knee joint sections using NIMP-R14 staining and diminished mRNA expression of macrophage-inflammatory protein-2 in the synovium tissue. mRNA levels of TNF-alpha and IL-1beta were suppressed as well, and IL-1beta and nitric oxide production by arthritic synovial tissue were strongly reduced. Our data show an impressive cartilage-protective effect of local IL-4 and underline the feasibility of local gene therapy with this cytokine in arthritis.
The neuropathic phenotype of the K/BxN transgenic mouse with spontaneous arthritis: pain, nerve sprouting and joint remodeling.
Gonçalves Dos Santos Gilson,Jimenéz-Andrade Juan Miguel,Woller Sarah A,Muñoz-Islas Enriqueta,Ramírez-Rosas Martha Beatriz,Ohashi Nobuko,Ferreira Catroli Glaucilene,Fujita Yuya,Yaksh Tony L,Corr Maripat
Scientific reports
The adult K/BxN transgenic mouse develops spontaneous autoimmune arthritis with joint remodeling and profound bone loss. We report that both males and females display a severe sustained tactile allodynia which is reduced by gabapentin but not the potent cyclooxygenase inhibitor ketorolac. In dorsal horn, males and females show increased GFAP astrocytic cells; however, only males demonstrate an increase in Iba1 microglia. In dorsal root ganglia (DRG), there is an increase in CGRP, TH, and Iba1 (macrophage) labeling, but no increase in ATF3 cells. At the ankle there is increased CGRP, TH, and GAP-43 fiber synovial innervation. Thus, based on the changes in dorsal horn, DRG and peripheral innervation, we suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, an assertion consistent with the analgesic pharmacology seen in this animal. These results indicate the relevance of this model to our understanding of the nociceptive processing which underlies the chronic pain state that evolves secondary to persistent joint inflammation.
10.1038/s41598-020-72441-5
Kynurenic acid, an endogenous constituent of rheumatoid arthritis synovial fluid, inhibits proliferation of synoviocytes in vitro.
Parada-Turska Jolanta,Rzeski Wojciech,Zgrajka Wojciech,Majdan Maria,Kandefer-Szerszeń Martyna,Turski Waldemar
Rheumatology international
Kynurenic acid is an antagonist of ionotropic glutamate receptors. It has been found that glutamate antagonists inhibit proliferation of different human tumor cells. Since the hyperplasia of synovial fibroblasts is one of the most striking features of inflammatory arthritis, the main goals of this study were detection and quantification of kynurenic acid in synovial fluid obtained from patients with rheumatoid arthritis, and determination of its effect on proliferation of synoviocytes in vitro. Presence of kynurenic acid was determined by HPLC in all 58 samples of synovial fluid. The mean concentration was 15.89 pmol/ml. Kynurenic acid inhibited synoviocyte proliferation with the IC50 value of 5.9 mM. In subthreshold concentration of 0.3 mM it enhanced antiproliferative action of celecoxib and nimesulide. In conclusion, the presence of kynurenic acid in synovial fluid was documented in patients with rheumatoid arthritis. Its potential role as an endogenous substance, controlling synoviocyte proliferation can be suggested.
10.1007/s00296-005-0057-4
Pain hypersensitivity in juvenile idiopathic arthritis: a quantitative sensory testing study.
Cornelissen Laura,Donado Carolina,Kim Joseph,Chiel Laura,Zurakowski David,Logan Deirdre E,Meier Petra,Sethna Navil F,Blankenburg Markus,Zernikow Boris,Sundel Robert P,Berde Charles B
Pediatric rheumatology online journal
BACKGROUND:Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children. Synovial inflammation results in pain, swelling and stiffness. Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity. The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission. Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children. METHODS:60 children aged 7-17 years with JIA participated. QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence. Joint site included finger, wrist, knee and ankle. Clinical status was measured using objective and subjective markers of disease severity. Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue. QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92). Statistical analyses were performed using Kruskal-Wallis with Dunn's post-hoc comparison, Mann-Whitney or Fisher's exact test, where appropriate. RESULTS:Overall, children with JIA reported low pain scores and low degrees of functional disability. Sensory detection thresholds and pain thresholds were similar in "active" compared to "inactive" joints. Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs. EU p < 0.001), light touch (vs. EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001). CONCLUSIONS:JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity. Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes.
10.1186/1546-0096-12-39
Joint capsule treatment with enkephalin-encoding HSV-1 recombinant vector reduces inflammatory damage and behavioural sequelae in rat CFA monoarthritis.
Lu Ying,McNearney Terry A,Wilson Steven P,Yeomans David C,Westlund Karin N
The European journal of neuroscience
This study assessed enkephalin expression induced by intra-articular application of recombinant, enkephalin-encoding herpes virus (HSV-1) and the impact of expression on nociceptive behaviours and synovial lining inflammation in arthritic rats. Replication-conditional HSV-1 recombinant vectors with cDNA encoding preproenkephalin (HSV-ENK), or control transgene beta-galactosidase cDNA (HSV-beta-gal; control) were injected into knee joints with complete Freund's adjuvant (CFA). Joint temperatures, circumferences and nociceptive behaviours were monitored on days 0, 7, 14 and 21 post CFA and vector treatments. Lumbar (L4-6) dorsal root ganglia (DRG) and spinal cords were immunostained for met-enkephalin (met-ENK), beta-gal, HSV-1 proteins and Fos. Joint tissues were immunostained for met-ENK, HSV-1 proteins, and inflammatory mediators Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and cyclo-oxygenase-2, or stained with haematoxylin and eosin for histopathology. Compared to exuberant synovial hypertrophy and inflammatory cell infiltration seen in arthritic rats treated with CFA only or CFA and HSV-beta-gal, the CFA- and HSV-ENK-treated arthritic rats had: (i) striking preservation of synovial membrane cytoarchitecture with minimal inflammatory cell infiltrates; (ii) significantly improved nociceptive behavioural responses to mechanical and thermal stimuli; (iii) normalized Fos staining in lumbar dorsal horn; and (iv) significantly increased met-ENK staining in ipsilateral synovial tissue, lumbar DRG and spinal cord. The HSV-1 and transgene product expression were confined to ipsilateral lumbar DRG (HSV-1, met-ENK, beta-gal). Only transgene product (met-ENK and beta-gal) was seen in lumbar spinal cord sections. Targeted delivery of enkephalin-encoding HSV-1 vector generated safe, sustained opioid-induced analgesia with protective anti-inflammatory blunting in rat inflammatory arthritis.
10.1111/j.1460-9568.2008.06076.x
Antioxidant effects of Genkwa flos flavonoids on Freund׳s adjuvant-induced rheumatoid arthritis in rats.
Zhang Chun-Feng,Zhang Su-Li,He Xin,Yang Xiao-Lin,Wu Hai-Tao,Lin Bao-Qin,Jiang Cui-Ping,Wang Jun,Yu Chun-Hao,Yang Zhong-Lin,Wang Chong-Zhi,Li Ping,Yuan Chun-Su
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Genkwa flos (Daphne genkwa Sieb. et Zucc.), a Chinese herbal medicine, has been traditionally used for over two thousand years in China for inflammation related symptoms, including joint pain. To evaluate the antioxidative effects of flavonoid aglycones (FA) isolated from Genkwa flos on adjuvant arthritis in rats and to identify the relationship between antioxidant potential and whole blood viscosity (WBV). MATERIALS AND METHODS:FA compounds were identified using LC-MS and the content was assayed by HPLC. Arthritis was induced by an intradermal injection of Freund׳s complete adjuvant in the footpad. The effects of FA on paw volumes, secondary arthritis scores, histopathology of joints, and body and organ weights were measured. The antioxidant effects of FA and WBV were determined. RESULTS:LC-MS analysis showed that the FA contained four major compounds: luteolin, apigenin, hydroxygenkwanin and genkwanin. FA significantly decreased paw edema, arthritis scores, and weight loss. These observations were consistent with the reduction of oxidative stress and the improvement of the WBV. CONCLUSION:FA significantly decreased arthritis in a rat model through antioxidant and hemorheological modulatory mechanisms. The Genkwa flos flavonoids may have clinical potential for the treatment of rheumatoid arthritis.
10.1016/j.jep.2014.03.046
Interleukin-1 immunoreactive nerve fibres in rat joint synovium.
Bjurholm A,Ahmed M,Svenson S B,Kreicbergs A,Schultzberg M
Clinical and experimental rheumatology
The occurrence of interleukin-1 immunoreactive nerves in the synovial membrane of rat knee joints was investigated by immunohistochemistry. Synovial tissue sections from 11 rats consistently showed interleukin-1 positive nerve fibres. The majority of the fibres appeared in blood vessel walls. However, varicose interleukin-1 positive fibres were also seen to terminate amidst synoviocytes. The overall distribution resembled that of autonomic fibres previously identified in synovium. Further investigation by double staining disclosed the co-existence of interleukin-1 and neuropeptide Y in the synovial nerve fibres. It has been suggested that the nervous system is implicated in the pathogenesis of arthritis. Considering the role of the cytokine interleukin-1 in various immunogenic and inflammatory conditions, it may prove that neuronal interleukin-1 in the synovial membrane represents a pathway for mediating such effects in joint tissue.
AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain.
Murai Nobuhito,Takeshita Nobuaki,Nishigaki Fusako,Irie Megumi,Tamura Seiji,Aoki Toshiaki,Matsuoka Nobuya
Neurological research
OBJECTIVES:The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the analgesic effects of AS1069562 in rat models of inflammatory and noninflammatory nociceptive pain. METHODS:Adjuvant-induced arthritis (AIA) and bradykinin-induced knee joint pain were used as rat models of inflammatory pain. The chronic phase of monoiodoacetate-induced arthritis (MIA) was used as a rat model of noninflammatory pain. Analgesic effects were evaluated by weight-bearing deficit in the AIA and MIA models and by pain response in the bradykinin-induced knee joint pain model. RESULTS:In the AIA model and the bradykinin-induced knee joint pain model, AS1069562 significantly ameliorated the pain-related behavior of weight-bearing deficit and the pain response, respectively. AS1069562 also significantly improved the pain-related behavior of weight-bearing deficit in the chronic phase of the MIA model. Further, following monoiodoacetate injection, repeated administration of AS1069562 or duloxetine significantly improved weight-bearing deficit in the MIA model. Interestingly, the analgesic effect of AS1069562 was sustained for 24 hours after the last administration, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the analgesic effect of duloxetine did not continue after treatment discontinuation. DISCUSSION:AS1069562 exerts analgesic effects on inflammatory and noninflammatory nociceptive pain in rat models of arthritis pain, and repeated administration of AS1069562 exerts a more persistent analgesic effect on arthritis pain than duloxetine. These findings suggest that AS1069562 has an attractive analgesic profile for the treatment of nociceptive pain.
10.1179/1743132815Y.0000000007
Nitric oxide synthase inhibitor influences prostaglandin and interleukin-1 production in experimental arthritic joints.
de Mello S B,Novaes G S,Laurindo I M,Muscará M N,Maciel F M,Cossermelli W
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
OBJECTIVE:To assess involvement of nitric oxide (NO) in the increase in eicosanoid and interleukin- 1 (IL-1) levels in the synovial fluid during antigen-induced arthritis (AIA) in rabbits treated with a competitive inhibitor of NO synthesis. SUBJECTS:Thirteen New Zealand White rabbits were sensitized with 5 mg of methylated bovine serum albumin (mBSA). Arthritis was induced in the knee joint by injecting 0.5 ml of a sterile solution of mBSA (2 mg/ml) into the intra-articular cavity. TREATMENT:Prior to the induction of arthritis, the animals received N-Omega-Nitro-L-Arginine Methyl Ester (LNAME) or N-Omega-Nitro-D-Arginine Methyl Ester (DNAME) for 2 weeks, both at a dose of 20 mg/kg/day mixed with drinking water. METHODS:Leukocyte efflux (total and differential white cell count), vascular permeability (Evans's blue method), synovial PMN cell infiltrate, and total nitrite (NO2.)/nitrate (NO3.) (HPLC), PGE2, TxB2, LTB4 (radioimmunoassay), and IL-1 beta (ELISA) levels were quantified in the synovial fluid. RESULTS:LNAME but not DNAME significantly suppressed leukocyte efflux and protein leakage into the articular cavity as well as synovial PMN cell infiltrate. Total NO2./NO3., PGE2 and IL-1 beta levels were significantly reduced in the synovial fluid of LNAME treated animals. TxB2 and LTB4 were not affected by LNAME treatment. CONCLUSION:These data clearly show NO involvement in the IL-1-induced PGE2 production in the synovial fluid of antigen-induced arthritis in rabbits.
10.1007/s000110050086
Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits.
Matsukawa A,Ohkawara S,Maeda T,Takagi K,Yoshinaga M
Clinical and experimental immunology
Injection of lipopolysaccharide (LPS) into rabbit knee joints provoked leucocyte infiltration and loss of proteoglycan (PG) from the cartilage. We investigated the role of IL-1 and IL-1 receptor antagonist (IL-1Ra) and its significance in the pathogenesis of LPS-arthritis. Production of IL-1 beta peaked at 6 h (196.7 +/- 89.4 pg/joint) after injection of 10 ng of LPS, while IL-1Ra peaked at 9 h (34.5 +/- 13.4 ng/joint). The amount of IL-1Ra was 180-200-fold molar excess of IL-1, and a large amount of IL-1Ra was sustained for 1 week. Both IL-1 beta and IL-1Ra were mainly produced by synovial exudate cells. Arthritis was reproduced by rabbit IL-1 beta. LPS-induced leucocyte infiltration was inhibited 70-75% by rabbit IL-1Ra. Loss of PG in LPS-arthritis was prevented by IL-1Ra and also by neutrophil elastase inhibitor, and superoxide dismutase. In leucopenic rabbits, injection of LPS induced neither production of IL-1 beta nor loss of PG. Direct injection of inflammatory exudated cells in leucopenic rabbits reproduced loss of PG, and there was only a partial recovery by IL-1Ra. These results suggest that LPS-initiated IL-1 acts as a key mediator in LPS-arthritis and that endogenous IL-1Ra may suppress a part of IL-1 activity at the site, but its amount was too low for suppression of the produced IL-1. Loss of PG is a sequela of infiltrated leucocytes and leucocyte-derived elastase, and superoxide anion may play a pivotal role in the destruction of cartilage.
10.1111/j.1365-2249.1993.tb07967.x
Regulation by reactive oxygen species of interleukin-1beta, nitric oxide and prostaglandin E(2) production by human chondrocytes.
Mathy-Hartert M,Deby-Dupont G P,Reginster J-Y L,Ayache N,Pujol J-P,Henrotin Y E
Osteoarthritis and cartilage
OBJECTIVES:To determine the effects of two drugs, N-monomethyl-L-arginine (L-NMMA) and N-acetylcysteine (NAC), on interleukin-1beta (IL-1beta), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production by human chondrocytes. The effect of aceclofenac (ACECLO), a non-steroidal antiinflammatory drug (NSAID), was also examined. METHODS:Human chondrocytes were enzymatically isolated from osteoarthritic knee cartilage and then maintained in culture in suspension for 48h in the absence or in the presence of lipopolysaccharide (LPS) (10 microg/ml), L-NMMA (0.5mM), NAC (1mM) or ACECLO (6.10(-6)M). IL-1beta and PGE(2) productions were quantified by specific immunoassays. Nitrite was measured in the culture supernatants by a spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS) and IL-1beta gene expressions were quantified by transcription of mRNA followed by real time and quantitative polymerase chain reaction. COX-2 protein expression was analysed by Western blot. RESULTS:LPS markedly increased the expression of IL-1beta, iNOS and COX-2 genes. In parallel, NO(2) and PGE(2) amounts found in the culture supernatants were significantly enhanced whereas IL-1beta was immunologically undetectable. The addition of L-NMMA (0.5mM) fully blocked LPS-induced NO production but greatly increased PGE(2) production, suggesting a negative effect of NO on PGE(2) synthesis. Inversely, NO production was stimulated by NAC while PGE(2) production was not affected. Interestingly, NAC increased the IL-1beta and iNOS mRNA levels but did not significantly modify COX-2 mRNA expression. L-NMMA did not significantly affect the expression of IL-1beta, iNOS and COX-2. The amount of COX-2 protein did not change in the presence of the antioxidants. Finally, ACECLO fully blocked the production of PGE(2) by chondrocytes without affecting the levels of COX-2 mRNA. CONCLUSIONS:The stimulation of IL-1beta, NO and PGE(2) production by LPS is differentially controlled by reactive oxygen species (ROS). In fact, L-NMMA and NAC have different mechanisms of action on the regulation of NO and PGE(2) productions. L-NMMA fully inhibits NO but increases PGE(2) production whereas NAC up-regulates NO but does not modify PGE(2) synthesis. The stimulating effect of L-NMMA on PGE(2) production is not controlled at the transcriptional level. These findings suggest that antioxidant therapy could have different effects according to the oxygen radical species targeted.
10.1053/joca.2002.0789
Increased content of bombesin/GRP in human synovial fluid in early arthritis: different pattern compared with substance P.
Westermark T,Rantapää-Dahlqvist S,Wållberg-Jonsson S,Kjörell U,Forsgren S
Clinical and experimental rheumatology
OBJECTIVE:Bombesin (BN) and the mammalian homologue gastrin-releasing peptide (GRP) are known trophic factors, neurotransmitters and paracrine hormones. BN/GRP has not previously been demonstrated in synovial fluid. In this study, the amounts of BN/GRP and substance P (SP) present in synovial fluid from the knee joints of patients with rheumatoid arthritis (RA) and of healthy controls were measured. METHODS:Synovial fluid from the knee joint was collected from patients with either longstanding RA (n = 32) or early arthritis (symptoms for < 12 months; n = 9) and from control subjects, i.e., individuals without known joint disease (n = 10). These samples were analyzed using radioimmunoassays. RESULTS:Levels of BN/GRP-like peptide were below the assay detection limits in synovial fluid from controls. Detectable levels of immunoreactive BN/GRP were present in the majority of patients with either longstanding RA or early arthritis. The levels were significantly higher in the synovial fluid from patients classified as having early arthritis compared with those with longstanding RA (p < 0.05). There was a strong correlation between BN/GRP levels and the number of leukocytes in the synovial fluid in the patients with early arthritis. The levels of SP-like peptide in the patients, whether with early arthritis or longstanding RA, were significantly elevated compared with controls. However, there was no difference in the levels between these two patient groups. CONCLUSIONS:These observations show that BN/GRP-like peptide is present in the synovial fluid of joints affected by arthritis and that the pattern of BN/GRP increase differs from that of SP. It appears as if the presence of BN/GRP is particularly related to the early processes of joint involvement. These observations are of interest because BN/GRP has well-known trophic and paracrine effects and chondrocytes have recently been shown to produce neuropeptides such as BN/GRP.
Opiates inhibit the discharges of fine afferent units from inflamed knee joint of the cat.
Russell N J,Schaible H G,Schmidt R F
Neuroscience letters
The spontaneous discharges in 15 out of 19 small-diameter afferent units from inflamed knee joints of anaesthetized cats were significantly inhibited by one or several opiates (morphine in the dose range 1.0-5.0 mg/kg; gly-ol 0.5-5.0 mg/kg; U50488 1.0-10.0 mg/kg; ethylketocyclazacine 0.5-4.0 mg/kg administered by close arterial injection into the joint). In the majority of cases a subsequent injection of naloxone (1 mg/kg i.a.) significantly reversed this effect. These data provide an electrophysiological demonstration that opiates may act on opiate receptors located at peripheral sites of primary afferent fibres and hence exert a peripheral 'analgesic' effect.
10.1016/0304-3940(87)90201-1
Distribution of neuropeptide-containing nerve fibers in the synovium and adjacent bone of the rat knee joint.
Iwasaki A,Inoue K,Hukuda S
Clinical and experimental rheumatology
OBJECTIVE:The innervation of normal rat synovium and adjacent bone, especially the communicatory nerve fibers between them, were investigated. METHODS:Nerve fibers were visualized using immunohistochemistry. Antisera to substance P(SP) and antisera to calcitonin gene-related peptide (CGRP) were employed to identify sensory nerves, while antisera to neuropeptide Y (NPY) were used to identify sympathetic nerves. RESULTS:In the synovium, SP-positive nerve fibers were found in the lining cell layer, with some fibers branching toward the joint space. In the sublining layer of the synovium, SP-positive and CGRP-positive fibers were observed mainly near the blood vessels. NPY-positive fibers were predominantly seen as a network around the blood vessels in the sublining layer. A large number of SP-positive and CGRP-positive fibers were seen near the attachment of the meniscus to the synovium. Toluidine blue positive mast cells were detected in close proximity to all three types of fibers, especially near the blood vessels. In bones forming the knee joint, nerve fibers immunoreactive to SP, CGRP and NPY were present in the bone marrow and some of these fibers communicated with the synovium through the synovium-bone junction located in the bare area. CONCLUSION:The role of nerves, especially the role of the communicatory nerves between the synovium and the bone marrow, should be considered in the pathophysiolosy of erosive arthritis.
Intraarticular variability of synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis.
Kirkham B,Portek I,Lee C S,Stavros B,Lenarczyk A,Lassere M,Edmonds J
The Journal of rheumatology
OBJECTIVE:To assess the variability of synovial histology, immunohistology, and cytokine mRNA expression at different sites within the knee joints of subjects with rheumatoid arthritis receiving slow acting antirheumatic drugs. The effects of intraarticular bupivacaine and adrenaline, and a comparison of synovial fluid cell and synovial membrane cytokine expression, were also investigated. METHODS:Arthroscopically directed synovial biopsies were taken at 3 or 4 predetermined sites from the knee joints of 11 patients. Histology for synovial lining layer, sublining cellularity and vascularity, and immunohistology for T cells, T cell subsets, and macrophages were assessed. Messenger RNA expression of interleukins 1beta, 2, 4, 6, 8, 10, granulocyte-monocyte colony stimulating factor, tumor necrosis factor-alpha, and interferon-gamma was detected using the reverse transcription/polymerase chain reaction technique. RESULTS:Synovial histology, immunohistology, and cytokine mRNA expression did not vary significantly. CD8 cell immunohistology was variable. Intraarticular bupivacaine and adrenaline did not change synovial characteristics. Synovial fluid cell and membrane cytokine expression did not match in 35% of comparisons. CONCLUSION:Biopsies from the suprapatellar pouch, medial gutter, and cartilage-pannus junction will provide a representative sample of synovial membrane pathology in patients with rheumatoid arthritis.
[In vitro inhibitive effects of Tripterygium wilforii on NO production, iNOS activity, and iNOS-mRNA expression in chondrocyrtes of patients with rheumatoid arthritis].
Guo W,Ma L,Tao X
Zhonghua yi xue za zhi
OBJECTIVE:To study the mechanism of treatment of rheumatoid arthritis with Tripterygium wilfordii Hook. f. (TWHF). METHODS:Chondrocytes from the resected knee joint cartilage of patients with rheumatoid and TWHF, dexamethasone, or (arthritis were isolated and cultured. IL-1 indomethacin of different concentrations were added into the culture solution overnight. Griess reagent was added to the supernatant to detect the content of NO. Chondrocytes were collected to examine the iNOS activity by detecting the conversion of L-14C-arginine into L-14C-citruline. The total RNA of chondrocyte was extracted and the iNOS-mRNA was examined by Northern blotting. RESULTS:The inhibitory rates of NO production by TWHF of concentrations of 2 mg/L, 4 mg/L, 8 mg/L, and 16 mg/L were 10.8%, 25.48%, 55.17%, and 80.45% respectively. The inhibitory rates of iNOS activity by TWHF of concentrations of 2 mg/L, 4 mg/L, 8 mg/L, and 16 mg/L were 12.29%, 27.67%, 59.04%, and 85.06% respectively. Such inhibitory effects were dosage-dependent. TWHF ffectively inhibited the expression of iNOS-mRNA induced by IL-1 in chondrocyte (r = 0.976 and 0.974). Dexamethasone inhibited NO production, iNOS activity, and expression of iNOS-mRNA significantly but not dosage-dependently. Indomethcin only had weak inhibitory effect. CONCLUSION:TWHF inhibits NO production in chondrocytes by limiting the transcription of iNOS gene, which may be one of the mechanisms of treatment of RA with TWHF.
The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.
Li Ling,Fox Bridget,Keeble Julie,Salto-Tellez Manuel,Winyard Paul G,Wood Mark E,Moore Philip K,Whiteman Matthew
Journal of cellular and molecular medicine
The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.
10.1111/jcmm.12016
Microtopography of the autonomic nerves in the rat knee: a fluorescence microscopic study.
Schwab W,Bilgiçyildirim A,Funk R H
The Anatomical record
BACKGROUND:The autonomic innervation of the joint is involved in different functions, such as sensory inputs, modulation of the function of immune cells, and trophic actions. To have a basis for further studies of the arthritic knee joint we have investigated the topographical distribution of different neuropeptides in knees of newborn and adult rats and in adult rats after arthritis induction. METHODS:The distribution of the neuropeptides calcitonin gene-related peptide (CGRP), neurokinin A (NKA), substance P (SP), and neuropeptide Y (NPY) was analyzed using fluorescence immunohistochemistry. Samples were investigated after fixation by perfusion and decalcification by a special method which allows studies in bone tissue. Vascular structures were analyzed by scanning electron microscopy (SEM) of vascular resin casts. RESULTS:In all tissues of the joint (synovial membrane, vessels, fibrous structures, bone, and cartilagineous tissues) CGRP and NKA are the most frequent neuropeptides. They are localized in free or perivascular fibers predominantly around arteries and arterioles. The NPY-ergic perivascular fibers even enter the vessel wall. Generally, SP-ergic fibers occur rarely. Free NKA- and CGRP-ergic nerve fibers spread out in the synovial lining layer reaching the synovial cavity and the outer layers of the articular and metaphyseal cartilage. In the cartilagineous tissue these nerves contact the chondrocytes. The density of NKA- and CGRP-immunoreactive fibers is lower in newborn rats than in adult rats. Six hours after arthritis induction SP-, NKA-, and CGRP-immunoreactivity is enhanced especially in perivascular fibers. The related vessels are dilated substantially. CONCLUSIONS:The distribution pattern of the autonomic nerves found in this study might reflect the functions of these nerves: control of the microcirculation, sensory and even trophic functions. The new finding of CGRP- and NKA-ergic fibers in the outer layer of the cartilage can also have implications for the pathogenesis of rheumatoid arthritis.
10.1002/(SICI)1097-0185(199701)247:1<109::AID-AR13>3.0.CO;2-T
Perioperative Inpatient Use of Selective Serotonin Reuptake Inhibitors Is Associated With a Reduced Risk of THA and TKA Revision.
Yao Jie J,Maradit Kremers Hilal,Kremers Walter K,Lewallen David G,Berry Daniel J
Clinical orthopaedics and related research
BACKGROUND:Depression is common in the general population, and so it is likewise common among patients undergoing THA and TKA. Depression is associated with lower perioperative patient-reported outcomes and an increased risk of postoperative complications. Antidepressants are effective in managing symptoms of depression and may potentially contribute to better functional status and better clinical outcomes after THA and TKA. QUESTIONS/PURPOSES:We examined (1) whether perioperative depression is associated with all-cause revisions, revisions for aseptic loosening, revisions without infection, and periprosthetic joint infections (PJIs) in patients undergoing THA and TKA; and (2) whether perioperative antidepressant use reduces the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs in patients undergoing THA and TKA. METHODS:This was a retrospective study of adult patients (≥ 18 years) who underwent 20,112 primary and revision THAs and TKAs from January 1, 2002, through December 31, 2009, at a large US tertiary care hospital. Data on patient and surgery characteristics and outcomes (dates and types of revisions, death) were ascertained through the institutional joint registry. Perioperative antidepressant use was assessed by searching the daily medication administration records beginning at admission and ending at discharge. A diagnosis of depression was present in 4466 (22%), and antidepressants were administered at the time of 5077 (25%) surgical procedures. Multivariable Cox proportional hazard models were used to estimate associations between antidepressant use and the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs. RESULTS:Depression was associated with an increased risk of all-cause revisions (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.42-2.02; p < 0.001) and PJIs (HR, 2.23; 95% CI, 1.53-3.17; p < 0.001). Overall, perioperative antidepressant use was not associated with the risk of revision or PJI, but selective serotonin reuptake inhibitor (SSRI) users had a lower risk of all-cause revisions (HR, 0.77; 95% CI, 0.61-0.96; p = 0.001) and aseptic revisions (HR, 0.72; 95% CI, 0.56-0.93; p = 0.013). CONCLUSIONS:The presence of a depression diagnosis confers an increased risk of revision and PJI among patients undergoing THA and TKA, yet the risk is lower within the subset of patients who received SSRIs during the perioperative period. Future longitudinal studies with detailed antidepressant medication histories are warranted to better understand the potential biologic effects of SSRI on the risk of revision in patients undergoing THA and TKA. LEVEL OF EVIDENCE:Level III, therapeutic study.
10.1007/s11999.0000000000000098
Assessment of zymosan-induced leukocyte influx in a rat model using sulfated polysaccharides.
Planta medica
Fucoidan, a sulfated polysaccharide from the brown algae Fucus vesiculosus, has diverse biological properties, including anti-inflammatory, anticoagulant and antithrombotic activity. This study analyzed the therapeutic activity of total fucoidan (TF) from F. vesiculosus and that of purified fractions (F1 and F2) on zymosan-induced arthritis. Arthritis was induced by injecting zymosan into the knee joint. Thus, three fucoidan fractions were obtained by acetone fractionation. Due to the yield obtained from F3, we used only fucoidans F1 and F2 in the induced inflammation tests. Chemical analyses and electrophoretic characterization of these fractions demonstrated that they contain polysaccharides, sulfate ester and very low protein levels. The fucoidans obtained from TF showed only an electrophoretic band in agarose gel with much lower polydispersion. The F2 fraction showed a migration between fucoidans F1 and F3. We administered TF (15, 30, 50 mg/kg I. P.), F1 or F2 (10, 25 and 50 mg/kg I. P.), diclofenac sodium (10 mg/kg I. P.), lumiracoxib (5 mg/kg O. A.) or L-NAME (30 mg/kg I. P.), 1 hour after induction of articular inflammation. We analyzed cell influx and nitrite levels in addition to performing histopathological analysis. TF (total fucoidan) at 15, 30, 50 mg/kg I. P. and its fractions (F1 and F2 at concentrations of 25 and 50 mg/kg I. P.) significantly reduced cellular influx and nitric oxide concentration. Moreover, the articular inflammation in zymosan-induced arthritis caused a progressive loss in glycosaminoglycan content. This loss decreased when TF (30 mg/kg) was administered. These data suggest that fucoidan exerts anti-inflammatory action in a zymosan-induced model of acute inflammation in rats. Taken together with the fact that these natural compounds have minimal toxicity, this may have important therapeutic implications.
10.1055/s-0029-1186003
Histamine excites groups III and IV afferents from the cat knee joint depending on their resting activity.
Herbert M K,Just H,Schmidt R F
Neuroscience letters
The effect of histamine on the sensory activity of primary afferents was studied in normal and acutely inflamed cat knee joints. A subpopulation of groups III and IV articular afferents could be activated by close-arterial bolus injections of histamine: units with a high resting activity (about 100/min) were particular sensitive to histamine and were excited even by 3.3 fg histamine. The lower the resting discharges of groups III and IV units both from normal and acutely inflamed joints, the higher the dose of histamine (up to 3.3 or 33 microg) necessary to excite the nerve fibres. Thirty-seven of 39 units without any resting activity were completely insensitive to histamine. In contrast to its clear excitatory effect, histamine caused only minor changes in the responses to joint movements. Movement-evoked activity remained unchanged in 22 of 28 units, 1 unit was sensitized and 5 units showed reduced activity after histamine (3.3 microg). The present results support the notion that histamine may participate in the mediation of pain from injured or inflamed tissue. It is remarkable that histamine has a profound excitatory action on a proportion of both groups III and IV articular afferents without changing their sensitivity to joint movements.
10.1016/s0304-3940(01)01817-1
Effects of leflunomide on human cartilage.
Panico Annamaria,Cardile Venera,Gentile Barbara,Garufi Floriana,Fama' Paolo,Bonfiglio Giuseppe,Ronsisvalle Giuseppe
Farmaco (Societa chimica italiana : 1989)
Modern therapeutic approach in rheumatoid arthritis (RA) includes early use of disease-modifying anti-rheumatic drugs (DMARDs). DMARDs may influence the course of disease progression, and their introduction in early RA is recommended to limit irreversible joint damage. Among DMARDs, leflunomide and methotrexate are more utilised in pharmacological therapy. In the present work, we considered the effects of leflunomide, in comparison with those of methotrexate and to those of leflunomide-methotrexate combination on human cartilage to verify its effectiveness in arthritic disease, simulated by our experimental model. We measured in vitro the amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) released into the culture medium of human articular cartilage treated with interleukin-1beta (IL-1beta), which promotes the cartilage destruction during articular disease. Leflunomide, in the presence of IL-1beta decreased NO production and GAGs release respect IL-1beta alone treated samples, in dose-related manner. Our results suggest that leflunomide is able to protect cartilage matrix from degradative factors induced by IL-1beta with respect to methotrexate and leflunomide-methotrexate combination.
10.1016/S0014-827X(03)00109-5
Centrally administered non-NMDA but not NMDA receptor antagonists block peripheral knee joint inflammation.
Sluka K A,Westlund K N
Pain
An experimental arthritis of the knee joint resulted in limping, guarding, and an increased response to heat stimuli (heat hyperalgesia). Spinal administration of the non-N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), significantly reduced the degree of peripheral inflammation, thermal and behavioral manifestations of arthritis. NMDA antagonists had no effect on the inflammation but did prevent the development of the heat hyperalgesia. Thus, central non-NMDA receptors play a major role in the development of peripheral inflammation while both non-NMDA and NMDA receptors are involved in the development of heat hyperalgesia.
10.1016/0304-3959(93)90150-N
Two novel α7 nicotinic acetylcholine receptor ligands: in vitro properties and their efficacy in collagen-induced arthritis in mice.
van Maanen Marjolein A,Papke Roger L,Koopman Frieda A,Koepke Jessica,Bevaart Lisette,Clark Roger,Lamppu Diana,Elbaum Daniel,LaRosa Gregory J,Tak Paul P,Vervoordeldonk Margriet J
PloS one
INTRODUCTION:The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by the vagus nerve. This neurotransmitter binds to the α7 subunit of nicotinic acetylcholine receptors (α7nAChR), expressed on macrophages and other immune cells. We tested the pharmacological and functional profile of two novel compounds, PMP-311 and PMP-072 and investigated their role in modulating collagen-induced arthritis (CIA) in mice. METHODS:Both compounds were characterized with binding, electrophysiological, and pharmacokinetic studies. For in vivo efficacy studies in the CIA model the compounds were administered daily by oral gavage from day 20 till sacrifice at day 34. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. RESULTS:Treatment with PMP-311 was effective in preventing disease onset, reducing clinical signs of arthritis, and reducing synovial inflammation and bone destruction. PMP-072 also showed a trend in arthritis reduction at all concentrations tested. The data showed that while both compounds bind to α7nAChR with high affinity, PMP-311 acts like a classical agonist of ion channel activity, and PMP-072 can actually act as an ion channel antagonist. Moreover, PMP-072 was clearly distinct from typical competitive antagonists, since it was able to act as a silent agonist. It synergizes with the allosteric modulator PNU-120596, and subsequently activates desensitized α7nAChR. However, PMP-072 was less efficacious than PMP-311 at both channel activation and desensitization, suggesting that both conducting and non-conducting states maybe of importance in driving an anti-inflammatory response. Finally, we found that the anti-arthritic effect can be observed despite limited penetration of the central nervous system. CONCLUSIONS:These data provide direct evidence that the α7nAChR in immune cells does not require typical ion channel activation to exert its antiinflammatory effects.
10.1371/journal.pone.0116227
Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids.
Telleria-Diaz Alejandro,Schmidt Martin,Kreusch Stefan,Neubert Anne-Kathrin,Schache Florian,Vazquez Enrique,Vanegas Horacio,Schaible Hans-Georg,Ebersberger Andrea
Pain
Both cyclooxygenase-1 and -2 are expressed in the spinal cord, and the spinal COX product prostaglandin E(2) (PGE(2)) contributes to the generation of central sensitization upon peripheral inflammation. Vice versa spinal COX inhibition is considered an important mechanism of antihyperalgesic pain treatment. Recently, however, COX-2 was shown to be also involved in the metabolism of endocannabinoids. Because endocannabinoids can have analgesic actions it is conceivable that inhibition of spinal COX produces analgesia not only by inhibition of PG synthesis but also by inhibition of endocannabinoid breakdown. In the present study, we recorded from spinal cord neurons with input from the inflamed knee joint and we measured the spinal release of PGE(2) and the endocannabinoid 2-arachidonoyl glycerol (2-AG) in vivo, using the same stimulation procedures. COX inhibitors were applied spinally. Selective COX-1, selective COX-2 and non-selective COX inhibitors attenuated the generation of spinal hyperexcitability when applied before and during development of inflammation but, when inflammation and spinal hyperexcitability were established, only selective COX-2 inhibitors reversed spinal hyperexcitability. During established inflammation all COX inhibitors reduced release of spinal PGE(2) almost equally but only the COX-2 inhibitor prevented breakdown of 2-AG. The reversal of spinal hyperexcitability by COX-2 inhibitors was prevented or partially reversed by AM-251, an antagonist at the cannabinoid-1 receptor. We conclude that inhibition of spinal COX-2 not only reduces PG production but also endocannabinoid breakdown and provide evidence that reversal of inflammation-evoked spinal hyperexcitability by COX-2 inhibitors is more related to endocannabinoidergic mechanisms than to inhibition of spinal PG synthesis.
10.1016/j.pain.2009.08.013
Cloricromene, a coumarine derivative, protects against collagen-induced arthritis in Lewis rats.
British journal of pharmacology
1. The aim of the present study was to investigate the effects of cloricromene, a coumarine derivative, in rats subjected to collagen-induced arthritis. 2. Collagen-induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 microl of the emulsion (containing 100 microg of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. 3. Lewis rats developed an erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri-articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 27 in the CII challenged rats and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling. 4. The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of rats with cloricromene (10 mg kg(-1) i.p. daily) starting at the onset of arthritis (day 23), delayed the development of the clinical signs at days 24 - 35 and improved histological status in the knee and paw. 5. Immunohistochemical analysis for iNOS, COX-2, nitrotyrosine and for poly (ADP-ribose) synthetase (PARS) revealed a positive staining in inflamed joints from collagen-treated rats. The degree of staining for iNOS, COX-2, nitrotyrosine and PARS were markedly reduced in tissue sections obtained from collagen-treated rats, which had received cloricromene. 6. Radiographic signs of protection against bone resorption and osteophyte formation were present in the joints of cloricromene-treated rat. 7. This study provides the first evidence that cloricromene, a coumarine derivative, attenuates the degree of chronic inflammation and tissue damage associated with collagen-induced arthritis in the rat.
10.1038/sj.bjp.0703695
Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior.
Driscoll Clare,Chanalaris Anastasios,Knights Chancie,Ismail Heba,Sacitharan Pradeep K,Gentry Clive,Bevan Stuart,Vincent Tonia L
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Pain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain-sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA-related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation. METHODS:Ten-week-old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain-related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription-polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild-type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme-linked immunosorbent assay. RESULTS:Mice developed pain-related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain-related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor β-activated kinase 1-, fibroblast growth factor 2-, and Src kinase-dependent manner. CONCLUSION:Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA.
10.1002/art.39523
S-(+)-3-isobutylgaba and its stereoisomer reduces the amount of inflammation and hyperalgesia in an acute arthritis model in the rat.
Houghton A K,Lu Y,Westlund K N
The Journal of pharmacology and experimental therapeutics
The present study investigated whether spinal administration of S-(+)-3-isobutylgaba (S-(+)-3-IBG) or its stereoisomer, R-(-)-3-isobutylgaba (R-(-)-3-IBG), are effective in reducing the hyperalgesia and swelling observed after injection of kaolin and carrageenan into the knee joint of the rat. The effects of pretreatment and post-treatment of S-(+)-3-IBG, R-(-)-3-IBG and artificial cerebrospinal fluid (aCSF) on the swelling, pain-related behavior scores and the heat hyperalgesia induced by knee joint inflammation were compared. Infusion of either S-(+)-3-IBG or R-(-)-3-IBG through a microdialysis fiber, implanted in the dorsal horn of the spinal cord, for 1.5 h before injection of kaolin and carrageenan resulted in a 20 to 30% reduction in joint swelling compared with aCSF-treated controls, and prevented the development of heat hyperalgesia and spontaneous pain. In contrast, infusion of either stereoisomer after the development of inflammation reduced the hyperalgesia but did not reduce the amount of joint swelling compared with aCSF-treated animals. In summary, S-(+)-3-IBG and R-(-)-3-IBG are effective antihyperalgesic agents when administered both before and after joint inflammation. In addition, if administered before injection of kaolin and carrageenan into the knee joint this drug can attenuate joint inflammation. Both the antihyperalgesic and anti-inflammatory properties of this drug probably are mediated through a central neurogenic mechanism.
Streptozotocin-induced diabetes decreases substance P levels in experimental arthritis in the rat knee.
Garrett N E,Kidd B L,Cruwys S C,Tomlinson D R
Neuroscience letters
Diabetic patients with sensory neuropathy are predisposed to disorders of the musculoskeletal system. It has been postulated that altered neurogenic inflammation, involving the neuropeptide substance P, may play a part in this phenomenon. We investigated the effect of streptozotocin-induced (STZ) diabetes on the development of an antigenic (mBSA) monoarthritis in the rat with particular reference to changes in substance P levels in dorsal root ganglia (DRG) and knee joint synovium. We found that STZ-induced diabetes of 24 weeks duration reduced the substance P content of L4/L5 DRG and knee joint synovial tissue. Induction of mBSA arthritis in diabetic rats resulted in diminished increases in synovial substance P and knee joint swelling compared to non-diabetic arthritic controls. The results show that chronic STZ diabetes reduces neurogenic inflammatory responses in the rat knee which may render the joint more susceptible to arthritic attack.
10.1016/0304-3940(95)11376-8
Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats.
Umar Sadiq,Zargan Jamil,Umar Khalid,Ahmad Sayeed,Katiyar Chandra Kant,Khan Haider A
Chemico-biological interactions
Thymoquinone (TQ) is the major active compound derived from Nigella sativa. Our aim of this work was to evaluate the antioxidant and antiarthritic activity of TQ in Wistar rat by collagen induced arthritis (CIA). TQ was administered at a dose of 5mgkg(-1) body weight once daily for 21days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE(2)) and histological studies in joints. TQ was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of TQ resulted in significantly reduced the levels of pro-inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE(2)) and increased level of IL-10. The protective effects of TQ against RA were also evident from the decrease in arthritis scoring and bone histology. In conclusion, the fact that TQ abolished a number of factors known to be involved in RA pathogenesis indicates that the administration of thymoquinone may have potential value in the treatment of inflammatory disease.
10.1016/j.cbi.2012.03.003
Beta-endorphin ameliorates synovial cell hyperfunction in the collagen-induced arthritis rat model by specific downregulation of NF-kappa B activity.
Yin Hongen,Zhang Fengchun,Yu Mengxue,Cheng Hong,Lin Jiayou,Gao Yang,Han Bing,Zhu Liping
Neuroendocrinology
OBJECTIVES:To observe the multiple immunoregulating effects of beta-endorphin (beta-END) on synovium cells of collagen-induced arthritis (CIA) in rats and to determine whether the regulation involves the transcriptional factor-kappaB (NF-kappaB) signal pathway. METHODS:CIA was induced in female Wistar rats by immunization with native bovine type-II collagen emulsified with complete Freund's adjuvant. Synovial cells in the knees of the CIA rats were cultivated, and the effects of beta-END, beta-END receptor inhibitor (naloxone, Nal) in proliferation and apoptosis of the synovial cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, flow cytometry, and DNA integrity, respectively. The effects of beta-END and Nal on mRNA expression of several cytokines in the synovial cells, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, regulated upon activation normal T-cell expressed and secreted (RANTES), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2) and MMP-9 were estimated by quantitative reverse transcription-polymerase chain reaction. Effects of beta-END and Nal on NF-kappaB activity were analyzed using luciferase gene reporter assays. The effects of beta-END and Nal on p65NF-kappaB expression of the synovial cells were examined using Western blot. RESULTS:75% of the rats were demonstrated to have established the CIA model successfully. beta-END was shown to exert multiple effects on synovial cells of CIA rats including decreased proliferation, induced apoptosis, and downregulation of TNF-alpha, IL-1beta, IL-6, RANTES, iNOS, MMP-2 and MMP-9 mRNA expression. beta-END seemed to play an immunoregulating role by downregulating the activity and expression of NF-kappaB. It was found that the beta-END receptor blockage could counteract all the effects. CONCLUSIONS:beta-END ameliorates synovial cell functions of CIA rats through binding with receptors and downregulating the NF-kappaB signal pathway. This suggests that beta-END, by blocking the activity and expression of NF-kappaB, is a potential anti-inflammatory and anti-rheumatic agent against CIA.
10.1159/000084828
IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses.
Olee T,Hashimoto S,Quach J,Lotz M
Journal of immunology (Baltimore, Md. : 1950)
IL-18, a cytokine originally identified as IFN-gamma-inducing factor, is a member of the IL-1 family of proteins. Because IL-1alpha and IL-1beta are important mediators in the pathogenesis of arthritis, the present study addresses the expression of IL-18 and its role in regulating in articular chondrocytes. IL-18 mRNA was induced by IL-1beta in chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on chondrocytes showed that it inhibits TGF-beta-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human articular chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identify IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.
Mechanism of joint sparing in a patient with unilateral psoriatic arthritis and a longstanding hemiplegia.
Veale D,Farrell M,Fitzgerald O
British journal of rheumatology
The case of a 59-year-old female with a longstanding hemiplegia who developed unilateral psoriatic arthritis and unilateral psoriasis on the non-hemiplegic side only is reported. Investigations showed an erythrocyte sedimentation rate of 58 mm/h, with all classes of rheumatoid factor negative in serum and synovial fluid (SF). An inflammatory infiltrate was demonstrated in both knee joints despite the absence of clinical involvement on the hemiplegic side. In addition, while neurofilament and substance P (SP) immunoreactivity was demonstrated in both synovial specimens, conspicuously less SP was present in the clinically involved synovial membrane. Finally, SF levels of SP and IL1 beta were raised in the clinically involved knee only.
Effects of anti-glaucoma drugs timolol and GLC756, a novel mixed dopamine D2 receptor agonist and D1 receptor antagonist, on endotoxin-induced-uveitis and -arthritis in rats.
Laengle U W,Court M,Markstein R,Germann P G,Nogues V,Roman D
Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie
Anti-glaucoma drugs exhibiting anti-inflammatory properties are desirable for the long-term treatment of glaucoma since they may reduce the risk for treatment-related inflammatory processes in outer compartments of the eye. The purpose of this study was to evaluate potential anti-inflammatory effects of two topically and systemically applied anti-glaucoma drugs i.e. GLC 756, a novel mixed dopamine D2 receptor agonist and D1 receptor antagonist, and timolol a beta-adrenoceptor antagonist using endotoxin-induced uveitis (EIU) and arthritis in rats as an in vivo model. For EIU, 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone, as a positive control, were either topically (0.4%, 0.5%, and 0.1%, respectively, 16-times 20 microL eye drops during 48 h) or systemically (1mg/kg subcutaneous for 5 days) administered. Cell infiltration in tissue of the eye and knee joint were assessed histopathologically and in special compartments of the eye by confocal microscopy 48 h after LPS-induction. Numerous infiltrating cells were detected in the eyes after LPS-induction and half of the animals showed arthritis. Topical and systemic pre-treatment with GLC756 and timolol resulted in reduced cell infiltration in the eye. In addition, GLC756 reduced, whereas timolol increased the incidence of arthritis. Betamethasone suppressed almost completely the cell infiltration in the eye and the incidence of arthritis. In conclusion, the observations that GLC756 reduced cell infiltration in the eye and the incidence of arthritis after LPS-induction is compatible with anti-inflammatory properties of this drug. By contrast, timolol produced no consistent anti-inflammatory effect since both inhibitory as well as stimulatory effects on inflammatory processes were seen.
10.1016/j.etp.2005.02.008
Tenuigenin Prevents IL-1β-induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing PI3K/AKT/NF-κB Signaling Pathway.
Wang Chunlei,Zeng Lihong,Zhang Tao,Liu Jiakun,Wang Wenbo
Inflammation
Tenuigenin (TEN), the main active component of Polygala tenuifolia, has been reported to have anti-inflammatory effects. However, the effects of TEN on IL-1β-stimulated osteoarthritis chondrocytes have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and mechanism of TEN on IL-1β-stimulated human osteoarthritis chondrocytes. Human osteoarthritis chondrocytes were pretreated with or without TEN for 1 h and then stimulated with IL-1β. The production of NO and PGE2 were detected by the Griess reagent and ELISA. The expression of NF-κB and MAPKs (p38, JNK, ERK) were measured by Western blot analysis. The production of MMP-1, MMP3, and MMP13 were measured by ELISA. The results showed that treatment of TEN significantly inhibited IL-1β-induced NO and PGE2 production. TEN also suppressed IL-1β-induced MMP-1, MMP3, and MMP13 expression. Furthermore, TEN was found to inhibit IL-1β-induced NF-κB activation, PI3K, and AKT phosphorylation. In conclusion, these results suggest that TEN inhibits IL-1β-induced inflammation in human osteoarthritis chondrocytes by inhibiting PI3K/AKT/NF-κB signaling pathway.
10.1007/s10753-016-0309-3
Differences in nitric oxide production by superficial and deep human articular chondrocytes: implications for proteoglycan turnover in inflammatory joint diseases.
Häuselmann H J,Stefanovic-Racic M,Michel B A,Evans C H
Journal of immunology (Baltimore, Md. : 1950)
During inflammatory joint diseases, chondrocytes are exposed to cytokines such as IL-1 that induce the synthesis of nitric oxide (NO). Chondrocytes from different zones of the articular cartilage are known to have different metabolic properties. In the present study, we have demonstrated that chondrocytes recovered from the superficial zone of normal, human, articular cartilage synthesize approximately 2 to 3 times as much NO in response to IL-1 as chondrocytes recovered from the deep zone of the same cartilage. Production of NO by normal cartilage in response to IL-1 was also found to decrease with age. Addition of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMA, 1 mM) blocked NO production by cells of both zones. L-NMA completely reversed the suppression of proteoglycan synthesis imposed by IL-1 in deep chondrocytes, but produced only partial reversal in superficial cells. As noted previously, IL-1 failed to elicit a strong catabolic response in cultures of human cartilage. In the presence of L-NMA, however, IL-1 reduced the metabolic t(1/2) of proteoglycans by approximately 50% in both the superficial and deep zones. This suggests that NO has, directly or indirectly, an anticatabolic effect in human cartilage. These data confirm the metabolic heterogeneity of human chondrocytes, and suggest that NO may be involved to different degrees as an endogenous modulator of the turnover of the cartilaginous matrix in different zones of articular cartilage.
Comparison of periarticular multidrug infiltration and epidural catheter use in total knee arthroplasty: A prospective randomized controlled study.
Ukai Taku,Kosuke Hamahashi,Ebihara Goro,Watanabe Masahiko
Journal of orthopaedic surgery (Hong Kong)
PURPOSE:The purpose of this study was to assess the effectiveness of periarticular multidrug infiltration (PMDI) and compare it with that of epidural catheter use. METHODS:Fifty-eight patients (58 joints) who underwent total knee arthroplasty were included in this single-center, prospective, parallel, randomized, controlled trial. Preoperatively, patients were randomly categorized into the PMDI and epidural catheter groups. We evaluated postoperative pain (visual analog scale (VAS) and narcotic consumption), functional outcomes (range of motion (ROM) of knee flexion, the day patients could perform the straight-leg raising (SLR) test, and day of starting cane use), and laboratory data (white blood cell (WBC) and C-reactive protein (CRP)). RESULTS:There was no significant difference in the VAS score, ROM of knee flexion, the day patients could do SLR, and the day of starting cane use between the PMDI and epidural catheter groups. However, the PMDI group could perform SLR on a postoperative day (POD) 1 ( < 0.05). WBC level on POD 1 was significantly higher in the PMDI group ( < 0.05), whereas the CRP levels on POD 1 ( < 0.01), 3 ( < 0.01), and 5 ( < 0.01) were significantly lower in the PMDI group than in the epidural catheter group. The frequency of side effects was not significantly different between the groups. CONCLUSION:PMDI was as effective as epidural catheter use for pain control. A higher percentage of patients who underwent PMDI could perform SLR on POD 1; therefore, the functional recovery was earlier in the PMDI group than in the epidural catheter group. PMDI may suppress inflammation in the whole body because of steroids.
10.1177/2309499020910663
Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats.
Sluka K A,Deacon M,Stibal A,Strissel S,Terpstra A
The Journal of pharmacology and experimental therapeutics
Transcutaneous electrical nerve stimulation (TENS) is commonly used for relief of pain. The literature on the clinical application of TENS is extensive. However, surprisingly few reports have addressed the neurophysiological basis for the actions of TENS. The gate control theory of pain is typically used to explain the actions of high-frequency TENS, whereas, low-frequency TENS is typically explained by release of endogenous opioids. The current study investigated the role of mu, delta, and kappa opioid receptors in antihyperalgesia produced by low- and high-frequency TENS by using an animal model of inflammation. Antagonists to mu (naloxone), delta (naltrinodole), or kappa (nor-binaltorphimine) opioid receptors were delivered to the spinal cord by microdialysis. Joint inflammation was induced by injection of kaolin and carrageenan into the knee-joint cavity. Withdrawal latency to heat was assessed before inflammation, during inflammation, after drug (or artificial cerebral spinal fluid as a control) administration, and after drug (or artificial cerebral spinal fluid) administration + TENS. Either high- (100 Hz) or low- frequency (4 Hz) TENS produced approximately 100% inhibition of hyperalgesia. Low doses of naloxone, selective for mu opioid receptors, blocked the antihyperalgesia produced by low-frequency TENS. High doses of naloxone, which also block delta and kappa opioid receptors, prevented the antihyperalgesia produced by high-frequency TENS. Spinal blockade of delta opioid receptors dose-dependently prevented the antihyperalgesia produced by high-frequency TENS. In contrast, blockade of kappa opioid receptors had no effect on the antihyperalgesia produced by either low- or high-frequency TENS. Thus, low-frequency TENS produces antihyperalgesia through mu opioid receptors and high-frequency TENS produces antihyperalgesia through delta opioid receptors in the spinal cord.
Is intra-articular multimodal drug injection effective in pain management after total knee arthroplasty? A randomized, double-blinded, prospective study.
Joo Jong-Hwan,Park Jang-Won,Kim Jun-Shik,Kim Young-Hoo
The Journal of arthroplasty
We performed a prospective, double-blinded, randomized, and controlled study to assess the clinical efficacy and safety of intra-articular multimodal drug injection after total knee arthroplasty. Two hundred eighty-six patients undergoing simultaneous bilateral total knee arthroplasty were randomized to receive the injection of multimodal drugs in one knee and normal saline solution as a placebo in the contralateral knee. All patients received patient-controlled analgesia for 48 hours after surgery, followed by standard analgesia. Visual analog scores for pain during activity and rest and for patient satisfaction were recorded. The range of motion and blood loss were also recorded. Intraoperative intra-articular injection of multimodal drugs into the knee did not improve patient pain and satisfaction, range of motion, or blood loss compared with the placebo control.
10.1016/j.arth.2011.03.052
Role of capsaicin-sensitive nerves and tachykinins in mast cell tryptase-induced inflammation of murine knees.
Borbély Éva,Sándor Katalin,Markovics Adrienn,Kemény Ágnes,Pintér Erika,Szolcsányi János,Quinn John P,McDougall Jason J,Helyes Zsuzsanna
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
OBJECTIVE, DESIGN:Mast cell tryptase (MCT) is elevated in arthritic joints, but its direct effects are not known. Here, we investigated MCT-evoked acute inflammatory and nociceptive mechanisms with behavioural, in vivo imaging and immunological techniques. MATERIAL AND SUBJECTS:Neurogenic inflammation involving capsaicin-sensitive afferents, transient receptor potential vanilloid 1 receptor (TRPV1), substance P (SP), neurokinin A (NKA) and their NK1 tachykinin receptor were studied using gene-deleted mice compared to C57Bl/6 wildtypes (n = 5-8/group). TREATMENT:MCT was administered intraarticularly or topically (20 μl, 12 μg/ml). Capsaicin-sensitive afferents were defunctionalized with the TRPV1 agonist resiniferatoxin (RTX; 30-70-100 μg/kg s.c. pretreatment). METHODS:Knee diameter was measured with a caliper, synovial perfusion with laser Doppler imaging, mechanonociception with aesthesiometry and weight distribution with incapacitance tester over 6 h. Cytokines and neuropeptides were determined with immunoassays. RESULTS:MCT induced synovial vasodilatation, oedema, impaired weight distribution and mechanical hyperalgesia, but cytokine or neuropeptide levels were not altered at the 6-h timepoint. Hyperaemia was reduced in RTX-treated and TRPV1-deleted animals, and oedema was absent in NK1-deficient mice. Hyperalgesia was decreased in SP/NKA- and NK1-deficient mice, weight bearing impairment in RTX-pretreated, TRPV1- and NK1-deficient animals. CONCLUSIONS:MCT evokes synovial hyperaemia, oedema, hyperalgesia and spontaneous pain. Capsaicin-sensitive afferents and TRPV1 receptors are essential for vasodilatation, while tachykinins mediate oedema and pain.
10.1007/s00011-016-0954-x
Sensitisation of articular afferents in normal and inflamed knee joints by substance P in the rat.
Heppelmann B,Pawlak M
Neuroscience letters
To examine whether substance P (SP) influences the response properties of fine articular afferents in normal and acutely inflamed joints, single units were recorded from the rat knee during normal and noxious joint rotations. Only three of 39 units were activated by a single bolus injection of 0.1 mM SP. However, 35% (7/20) of the nerve fibres from the normal joint and 21% (4/19) of the units from the inflamed joint significantly increased their responses to movements after the SP injection. This was most prominent during noxious movements in normal joints, whereas in inflamed joints increase of responses occurred mainly during normal movements. These data indicate that SP may also be involved in the process of sensitisation of primary afferents during an inflammation.
10.1016/s0304-3940(97)13408-5
Role of kinins and nitric oxide on the rabbit arthritis induced by Bothrops jararaca venom.
Guzzo M L,Farsky S H,De Nucci G,Antunes E,Silva M A,Mello S B
Toxicon : official journal of the International Society on Toxinology
The effects of the nitric oxide synthase inhibitor N(omega)Nitro-L-arginine-methyl ester (L-NAME) and of the bradykinin B(2) receptor antagonist HOE 140 were evaluated in the inflammatory reaction induced by Bothrops jararaca venom (BjV) in New Zealand White rabbits. Arthritis was induced by injecting 0.5 ml of a sterile solution of BjV (1-64 microg/ml) into the knee intraarticular cavity. The contralateral joint was injected with bovine serum albumin (BSA) diluted in sterile saline. At selected times thereafter (4, 24 and 48 h), the vascular permeability and the leukocyte influx in both the synovial fluid and synovium were evaluated. BjV caused a dose-dependent increase in both leukocyte influx and protein extravasation which reached a maximal response at 16 microg. Bothrops jararaca venom also induced the increase in the leukocyte accumulation in the synovium and in the concentration of both NO(2)/NO(3) in the synovial fluid. Chronic administration of L-NAME (20 mg/kg/day in the drinking water for 2 weeks) markedly reduced the leukocyte accumulation (90%), protein leakage (44%), and NO(2)/NO(3) (50%) levels in the synovial fluid, measured at the 4th h. Hoe 140, given i.v. (0.3 mg/kg, 30 min before) also reduced leukocyte accumulation (75%), protein leakage (48%), and NO(2)/NO(3) (79%) levels in the synovial fluid, measured at the 4th h. Similar results were obtained with acute administration of L-NAME (30 mg/kg, i.v., 30 min before). These results indicate that arthritis induced by BjV is triggered by kinin formation and that the increase in both vascular permeability and leukocyte accumulation is modulated by NO release.
Differential effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on spinal release of amino acids after development of acute arthritis in rats.
Sluka K A,Jordan H H,Willis W D,Westlund K N
Brain research
Following induction of acute knee joint arthritis in rats, an increase in the release of amino acids in the spinal dorsal horn occurs in two phases: (1) at the time of injection for all amino acids tested; and (2) a late prolonged phase for aspartate (Asp) and glutamate (Glu) (3.5-8 h). In the present study, the increased late phase release of Glu was reversed by posttreatment of the spinal cord with the N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, but not with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Asp late phase release in arthritic animals was unaffected by posttreatment of the spinal cord with either AP7 or CNQX. Arthritic animals became hyperalgesic to radiant heat stimuli by 4 h and this hyperalgesia was reversed by both CNQX and AP7. During the paw withdrawal latency (PWL) test for heat hyperalgesia, there was an increase in the glycine (Gly) and serine (Ser) concentrations in the dorsal horn. This increase in Gly and Ser was blocked by both CNQX and AP7. Indications of inflammation in arthritic animals posttreated with AP7, including increased joint circumference and temperature, were similar to animals that did not receive antagonists. Arthritic animals posttreated with CNQX, however, showed a reduction in the degree of joint swelling. Thus, both non-NMDA and NMDA receptors appear to play a role in the processing of the information evoked by stimuli in the periphery. The arthritis-induced release of Gly and Ser during the PWL test for heat hyperalgesia appears to be dependent on activation of both non-NMDA and NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
10.1016/0006-8993(94)91956-9
The role of proinflammatory cytokines in the generation and maintenance of joint pain.
Schaible H-G,von Banchet G Segond,Boettger M K,Bräuer R,Gajda M,Richter F,Hensellek S,Brenn D,Natura G
Annals of the New York Academy of Sciences
The proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) not only promote and maintain inflammation, they also contribute to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. A large proportion of dorsal root ganglion (DRG) neurons express TNF receptors and receptor units for stimulation with IL-6. In the rat model of antigen-induced arthritis (AIA), neutralization of TNF-alpha by etanercept and infliximab reduced inflammation-evoked mechanical hyperalgesia at the inflamed knee joint. This treatment also attenuated the infiltration of macrophages into the DRGs usually observed during the acute phase of AIA. Intra-articular application of etanercept reduced the responses of C-fibers to mechanical stimulation of the inflamed joint but did not influence responses to stimulation of the normal joint. Finally, in cultured DRG neurons TNF-alpha increased the proportion of neurons that express the TRPV1 receptor and may thus contribute to the generation of inflammation-evoked thermal hyperalgesia.
10.1111/j.1749-6632.2009.05301.x
Efficacy of duloxetine compared with opioid for postoperative pain control following total knee arthroplasty.
Kim Man Soo,Koh In Jun,Choi Keun Young,Yang Sung Cheol,In Yong
PloS one
BACKGROUND:The purpose of this study was to assess the efficacy of duloxetine as an alternative to opioid treatment for postoperative pain management following total knee arthroplasty (TKA). METHODS:Among 944 patients, 290 (30.7%) of patients received opioid or duloxetine for pain control for 6 weeks when the pain Visual Analogue Scale (VAS) score was greater than 4 out of 10 at the time of discharge. 121 patients in the Opioid group and 118 in the Duloxetine group were followed up for more than one year. Preoperative and postoperative patient reported outcome measures (pain VAS score, Western Ontario and McMaster Universities OA Index (WOMAC) score were compared. The rate of further drug prescription (opioid or duloxetine) after 6 weeks of first prescription, 30-day readmission rate, and side effects were also investigated. RESULTS:There was no significant difference in pain VAS score, WOMAC Pain and Function score, at each time point between before and after surgery (all p>0.05). Fifteen (9.8%) patients in the opioid group and six (4.4%) patients in the duloxetine group were prescribed additional medication after first 6 weeks, showing no significant (p>0.05) difference in proportion. The 30-day readmission rate and the incidence of side effects were also similar (all p>0.05). There was no difference in the incidence of side effects between the two groups (p>0.05). CONCLUSION:Duloxetine and opioid did not show any difference in pain control, function, and side effects for up to one year after TKA. Although large-scale randomized controlled trials are still required to further confirm the side effects of duloxetine, it can be considered as an alternative to opioid for postoperative pain control following TKA.
10.1371/journal.pone.0253641
Intra-articular Botulinum Toxin Type A: a new approach to treat arthritis joint pain.
Mahowald Maren Lawson,Krug Hollis E,Singh Jasvinder A,Dykstra Dennis
Toxicon : official journal of the International Society on Toxinology
There is a growing need for novel treatments of refractory arthritis joint pain as the aging population is expanding with many patients who are unable to undergo joint replacement surgery. We are studying the efficacy and safety of intra-articular injection of Botulinum Toxin Type A (IA-BoNT/A) into joints with arthritis pain. In several small open label studies, initial effects for IA-BoNT/A were encouraging because two thirds of the patients had more than 50% reduction in joint pain severity that was associated with a significant improvement in function. Importantly no serious adverse effects of IA-BoN/A were noted. Based on these initial results, we have completed two pilot randomized controlled trials in painful shoulder joints and painful knee joints. In the shoulder study, IA-BoNT/A produced a significant decrease in shoulder pain severity at one month (6.8-4.4 on VAS, p=.002) that was also significantly better than the non-significant change after IA-Saline placebo (1.6 unit difference favoring IA-BoNT/A, p=.014). In the knee study IA-BoNT/A produced a significant 48% decrease in McGill Total Pain Score at one month (p=.01 1) that was still significant at 3 mo after injection (p=.002). There was a strong placebo response in one third of those but the decrease in pain severity was not significant. We are currently conducting a RCT of IA-BoNT/A for painful prosthetic knee joints. Based on these initial studies of IA-BoNT/A we have gone 'back to the bench' to standardize a menu of pain behaviors for mice with acute inflammatory arthritis pain and chronic inflammatory arthritis pain. IA-BoNT/A significantly reduced arthritis joint tenderness (evoked pain score) in acute and chronic inflammatory arthritis and normalized impaired spontaneous wheel running in mice with chronic inflammatory arthritis but not in those with acute inflammatory arthritis. With these models of arthritis and pain behavior methods we will be able to screen potential intra-articular analgesics, define dose response curves and injection schedule, and study the relationships of articular pain and loss of function.
10.1016/j.toxicon.2009.03.028
New sustained-release intraarticular gel formulations based on monolein for local treatment of arthritic diseases.
Réeff Jonathan,Gaignaux Amelie,Goole Jonathan,De Vriese Carine,Amighi Karim
Drug development and industrial pharmacy
Inflammatory osteoarthritis (OA) is characterized by painful and destructive inflammatory flares of a single joint, mainly in the back, the knees, the wrists or the hips. Monoarthritis is generally treated by intraarticular (IA) injections of corticosteroids or hyaluronic acid (HA). However, due to their toxicity, the chronic use of corticosteroids should be avoided. The aim of this work was to develop a new slow-release formulation for a parenteral route of administration (e.g., IA). The development's strategy was based on the use of amphiphilic ingredients such as glyceryl monooleate (GMO), which is able to generate viscous crystalline phase structures upon contact with an aqueous fluid (e.g., synovial fluid) to sustain the drug activity over weeks. Clonidine (CLO) was suggested as a small and hydrophilic model drug and HA as a hydrophilic viscoelastic scaffold. Thermal analyses showed that the stability of GMO, HA, and CLO in mixtures with a ratio of 1:1 (wt/wt) was not affected in comparison with the raw materials. In order to obtain a formulation presenting suitable syringeability and containing GMO, CLO, and HA, two elements were found to be essential: a minimum of about 15% (wt/wt) water content and the use of co-solvents such as ethanol (ET) and propylene glycol (PG), approved by the FDA for parenteral use. Several developed gels presented pseudoplastic flow behavior. Moreover, the best composition provided an in vitro release of CLO for about 1 week that was similar to a cubic reference formulation, described by many authors as presenting poor syringeability but the best sustained-release capacity.
10.3109/03639045.2012.730529
Glatiramer acetate (GA), the immunomodulatory drug, inhibits inflammatory mediators and collagen degradation in osteoarthritis (OA) cartilage.
Attur M,Millman J S,Dave M N,Al-Mussawir H E,Patel J,Palmer G,Abramson S B
Osteoarthritis and cartilage
OBJECTIVE:Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes. DESIGN:Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes. RESULTS:GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100 μg) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1β-induced inflammatory mediators such as nitric oxide (NO) [mean NO (μM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004). CONCLUSIONS:These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies.
10.1016/j.joca.2011.06.006
Nitric oxide synthase isoforms and NF-kappaB activity in normal and osteoarthritic human chondrocytes: regulation by inducible nitric oxide.
Rosa S C,Judas F,Lopes M C,Mendes A F
Nitric oxide : biology and chemistry
To elucidate the role of endogenous inducible nitric oxide (NO) on the regulation of NF-kappaB activity in human chondrocytes, we evaluated (i) the pattern of expression of the neuronal (nNOS) and inducible (iNOS) NO synthase isoforms and the basal NF-kappaB activity in normal and osteoarthritic (OA) human chondrocytes, (ii) the role of cytokines and growth factors in modulating the protein levels of the two NOS isoforms, and (iii) the effect of inhibiting endogenous inducible NO production on the ability of interleukin-1beta (IL-1) to induce NF-kappaB activation. nNOS was more frequently expressed in normal than in OA chondrocytes, whereas the opposite was found for iNOS. IL-1 induced the degradation of both enzymes, but iNOS disappeared more rapidly. Although IkappaB-alpha was present in all the normal samples and in the majority of the OA samples, NF-kappaB-DNA binding activity in OA chondrocytes was increased approximately twofold relatively to normal cells. Addition of a NOS inhibitor, after induction of iNOS expression, induced IkappaB-alpha degradation and potenciated the effect of IL-1, indicating that endogenous inducible NO inhibits NF-kappaB activation. Taken together, these findings favor an inhibitory role of high NO levels on the regulation of NF-kappaB activation in chondrocytes, indicating that NF-kappaB activity is regulated, at least in part, by the balanced production of NO resulting from a dynamic process that, at any given moment, determines the availability of the constitutive and inducible NOS isoforms. Moreover, the down-regulatory role of NO on NF-kappaB activation warrants caution as to the possible utilization of NO inhibitors in the therapy of OA.
10.1016/j.niox.2008.07.005
Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production.
Manacu Christina Alexandra,Martel-Pelletier Johanne,Roy-Beaudry Marjolaine,Pelletier Jean-Pierre,Fernandes Julio C,Shipkolye Fazool S,Mitrovic Dragoslav R,Moldovan Florina
Arthritis research & therapy
The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.
10.1186/ar1489
Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes.
Roman-Blas Jorge A,Contreras-Blasco María A,Largo Raquel,Alvarez-Soria María A,Castañeda Santos,Herrero-Beaumont Gabriel
European journal of pharmacology
Oxidative stress may play a relevant role in synovial inflammation and subsequently on cartilage damage during osteoarthritis development. We have assessed how the antioxidant N-acetylcysteine (NAC) affects the expression of different proinflammatory and structural mediators in human stimulated osteoarthritic synoviocytes and chondrocytes. Synovial membrane and articular cartilage were obtained from the osteoarthritis knees of patients who underwent joint replacement surgery. In cells stimulated with IL-1beta (10U/mL), the effects of NAC (2mmol/L) were tested at the mean peak plasma level following oral administration of therapeutic doses and its influence on prostaglandin E2 (PGE(2)) production, cyclooxigenase-2 (COX-2) expression, nitric oxide (NO) synthesis, nuclear factor kappa B (NF-kappaB) activation, and metalloproteinase-1 (MMP-1) and metalloproteinase-13 (MMP-13) expression were evaluated. While NAC significantly diminished PGE(2) release and the expression of both COX-2 and MMP-13 protein in IL-1beta-stimulated synoviocytes, it failed to modify their production in stimulated chondrocytes. Likewise, NAC only inhibited IL-1beta-stimulated NF-kappaB activation in synoviocytes. No inhibition of IL-1beta-induced NO synthesis by chondrocytes was observed following NAC incubation, while synoviocytes did not release detectable levels of NO. NAC did not induce changes in MMP-1 protein expression in either IL-1beta-stimulated synoviocytes or chondrocytes. Thus, NAC decreases the synthesis of several catabolic mediators by osteoarthritic synoviocytes, whereas, it failed to produce the same effects in osteoarthritic chondrocytes. Our results suggest that NAC inhibits some oxygen-dependent mechanisms in synoviocytes but not in chondrocytes during osteoarthritis. Therefore, NAC might have a symptomatic effect on the synovium rather than a structural effect on the cartilage in osteoarthritis.
10.1016/j.ejphar.2009.09.016
Levels of metalloproteinase (MMP-3, MMP-9), NF-kappaB ligand (RANKL), and nitric oxide (NO) in peripheral blood of osteoarthritis (OA) patients.
Li Heng,Li Liqin,Min Jikang,Yang Honghang,Xu Xuchun,Yuan Yongjian,Wang Dan
Clinical laboratory
BACKGROUND:The aim of this study was to judge whether there is a correlation between some biochemical features of knee osteoarthritic blood and clinical characteristics and to evaluate the potential relationship between osteoarthitis (OA) severity and putative biomarkers for the disease. METHODS:105 patients suffering from knee OA were analyzed clinically (Lequesne's index) and radiographically (Kellgren and Lawrence, K&L). Plasma and peripheral blood mononuclear cells (PBMC) were harvested separately. Specimens were analyzed for concentrations of nitric oxide (NO), matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-9 (MMP-9). Transcript levels of the receptor activator of NF-kB ligand (RANKL) mRNA, MMP-3mRNA, and MMP-9mRNA were measured using real-time quantitative RT-PCR. RESULTS:Data certified significantly increasing concentrations of plasma MMP-3, MMP-9, and NO as well as transcript levels of RANKL mRNA and MMP-9 mRNA in early OA (at grade I). There was a positive correlation of MMP-3 and MMP-9 content in plasma and MMP-9 mRNA expression levels in PBMC with the severity of clinical symptoms (total Lequesne's scores) in early OA. NO content in plasma correlated with total Lequesne's scores, pain scores in response to pressure, and swelling scores of early OA patients (atgGrade I). Analogously, there were positive correlations of RANKL mRNA expression with total Lequesne's scores, pain scores in response to pressure, and swelling scores in OA patients at Grade I. CONCLUSIONS:[corrected] Some biochemical factors, including content of NO, MMP-3, MMP-9, and transcript levels of some genes, including MMP-9 mRNA and RANKL mRNA, may be specific and sensitive enough to diagnose OA diseases at an early stage in the pathological process of OA when radiological features do not reflect degradation of articular cartilage. Therefore, proper regulation of these factors may be a promising and realistic new target for the treatment of degenerative osteoarticular diseases.
Histamine in rheumatoid arthritis.
Adlesic M,Verdrengh M,Bokarewa M,Dahlberg L,Foster S J,Tarkowski A
Scandinavian journal of immunology
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent inflammation of the synovium, leading to the erosion of articular cartilage and bone. Synovial mast cells and their effector molecule, histamine, receive increased attention as mediators of joint inflammation. The aim of our study was to analyse levels of free histamine in serum and joint fluid of RA patients and to evaluate the potential inflammatogenic properties of histamine in vivo and in vitro. Histamine levels were measured by an ELISA in synovial fluid and sera of RA patients and of healthy controls. Histamine levels were also assessed in plasma of RA patients undergoing anti-TNF-alpha treatment. In the murine part of the study, histamine was injected intra-articularly in the knee joint of mice and the joints were subsequently analysed with respect to induction of inflammation. RA patients displayed significantly lower levels of histamine in circulation (0.93 +/- 0.16 ng/ml) compared with the healthy controls (1.89 +/- 0.45 ng/ml, P < 0.001). Locally, in synovial fluid the levels of histamine were even lower (0.37 +/- 0.16 ng/ml, P < 0.0006). Long-term anti-TNF-alpha treatment significantly increased circulating levels of histamine in RA patients. Our experiments on animals show that histamine on its own neither induces inflammation in the joint cavity nor influences the course of HMGB1 and peptidoglycan-induced joint inflammation. Based on our experimental and clinical studies we suggest that histamine lacks harmful properties in RA.
10.1111/j.1365-3083.2007.01938.x
Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis.
Adán Norma,Guzmán-Morales Jessica,Ledesma-Colunga Maria G,Perales-Canales Sonia I,Quintanar-Stéphano Andrés,López-Barrera Fernando,Méndez Isabel,Moreno-Carranza Bibiana,Triebel Jakob,Binart Nadine,Martínez de la Escalera Gonzalo,Thebault Stéphanie,Clapp Carmen
The Journal of clinical investigation
Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3-dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor-null (Prlr(-/-)) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA.
10.1172/JCI69485
Methylprednisolone reduces pain and decreases knee swelling in the first 24 h after fast-track unicompartmental knee arthroplasty.
Rytter Søren,Stilling Maiken,Munk Stig,Hansen Torben Bæk
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA
PURPOSE:Unicompartmental knee arthroplasty (UKA) results in less operative trauma and faster patient recovery than after a conventional total knee arthroplasty. Despite an increased focus on multimodal analgesic strategies, there is still a substantial level of patient-reported pain in the early postsurgical period after UKA. The purpose of the study was to evaluate the effect of a single preoperative dose of systemic methylprednisolone on postsurgical pain after fast-track UKA. METHODS:Seventy-two patients in two consecutive series undergoing unilateral UKA were included in a prospective cohort study. The patients (n = 35) in the treatment group received a single preoperative dose of systemic methylprednisolone 125 mg, whereas the control group (n = 37) did not. Outcome measures were postsurgical pain at rest and during walking, consumption of opioids for pain rescue, knee swelling and knee range of motion, and complications. RESULTS:In the first 24 h after surgery, the treatment group had less pain at rest (p < 0.001) and during walking (p < 0.001) and less consumption of opioids (p = 0.01) in comparison with the control group. Furthermore, the treatment group had 2.2 cm less knee swelling (p = 0.02) in the first post-operative day, and better knee extension (p = 0.004), whereas knee flexion was similar (n.s.) between groups. No serious complications were associated with the treatment. CONCLUSION:Addition of a single preoperative dose of 125 mg systemic methylprednisolone to a multimodal analgesic regime significantly reduced postsurgical pain and opioid consumption and decreased knee swelling in the first 24 h after fast-track UKA. LEVEL OF EVIDENCE:Therapeutic study, Level II.
10.1007/s00167-014-3501-8
Peripheral Stimulation of the Saphenous and Superior Lateral Genicular Nerves for Chronic Knee Pain.
Hasoon Jamal,Chitneni Ahish,Urits Ivan,Viswanath Omar,Kaye Alan D
Cureus
Chronic knee pain continues to cause increasing levels of functional deficits, mobility issues, and decreased quality of life in the United States. Initial treatment for knee pain consists of physical therapy, weight loss, medication management, injections, and radiofrequency ablation (RFA). Definitive treatment usually requires surgical management. Peripheral nerve stimulation (PNS) has been effective in the treatment of a variety of chronic pain conditions including the treatment of postoperative pain related to knee surgery. We describe the case of a patient who refused operative management as well as RFA of the genicular nerves and obtained significant pain relief from PNS of the superior lateral genicular nerve and the saphenous nerve for severe knee pain caused by osteoarthritis.
10.7759/cureus.14753
Effects of an experimental arthritis on the sensory properties of fine articular afferent units.
Schaible H G,Schmidt R F
Journal of neurophysiology
An acute experimental arthritis was induced in the right knee joint of adult cats anesthetized with chloralose, and the activity of single fine afferent units of the medial articular nerve was recorded from filaments of the saphenous nerve. All units included in this study were sensitive to local mechanical probing of the medial and anteromedial aspects of the knee joint. The units were identified by their conduction velocity as belonging either to group III (2.5-20 m/s, 48 U) or group IV (less than 2.5 m/s, 29 U). After the identification, the resting activity was measured, and the evoked activity was determined using local mechanical stimulation with glass rods and von Frey hairs, and passive movements of the knee joint. The results were compared with those obtained in a similar study of fine articular units from normal joints. Resting activity was observed in 75% of the group III and 83% of the group IV units. The discharges were irregular and often of high frequency. Both the percentages of units with resting activity and the frequencies of their discharges were more than twice as high as in the control sample. Nearly all units from inflamed joints had low threshold to movements (group III 89%, group IV 72%), and most units responded well to flexion and extension. In contrast, in units from normal joints only 33% of the group III and 10% of the group IV units responded well to passive movements in the normal working range of the joint. In inflamed as well as in normal joints the responses were mostly tonic in character and adapted slowly or not at all when the joint was held in a new position. In normal joints 24% of the group III and 36.5% of the group IV afferent units with local mechanosensitive receptive fields could not be excited by any physiological or noxious joint movements. Such units were only very occasionally seen in the present sample. The average number of receptive fields per unit found in inflamed joints exceeded considerably that in normal units, but no systematic drop in von Frey thresholds was seen when comparing the control sample with the inflamed one. From the above data we conclude that an acute inflammation sensitizes many fine articular units, making them active at rest and increasing the responsiveness more readily to normally innocuous joint movements. Both nociceptors and units with low threshold to movement seem to become sensitized by the inflammation.(ABSTRACT TRUNCATED AT 400 WORDS)
10.1152/jn.1985.54.5.1109
A single capsaicin injection partially depletes neuropeptides but does not ameliorate inflammation severity in established feline antigen induced arthritis.
Marshall K W,Theriault E,Homonko D A
The Journal of rheumatology
OBJECTIVE:To investigate the effect of the neuropeptide depleting agent capsaicin on neuropeptides in both synovial and nonsynovial articular tissues and on the relative degree of joint inflammation in established antigen induced arthritis (AIA). METHODS:AIA was created in both knees in 3 cats. Once AIA was established, the left knee of each animal received a single 0.5 ml injection of capsaicin (0.3 mg/ml). Three days later, the knees were harvested and dissected into 11 regions. Eleven articular cartilage tissues from both the experimental (capsaicin) and control (non-capsaicin) knees were examined for the immunocytochemical presence of substance P (SP) and calcitonin gene related peptide (CGRP). Additionally, the synovium was examined to determine the severity of joint inflammation. RESULTS:Nerve fibers immunoreactive for SP or CGRP were found in all 11 tissues in each of the non-capsaicin treated AIA knees. Both perivascular and "free" SP and CGRP immunoreactive fibers were present in all 11 articular structures. In the knees treated with capsaicin, however, 48% of the joint tissues examined completely lacked SP immunoreactivity, while 12% had no CGRP immunoreactivity. Inflammatory disease severity was not ameliorated by the single intraarticular injection of capsaicin used in this study. CONCLUSION:These data indicate that SP and CGRP immunoreactivity is maintained in synovial and nonsynovial articular tissues of non-capsaicin treated knees during subacute joint inflammation. In the capsaicin treated AIA knees, however, there was partial neuropeptide depletion. Nerve fibers containing SP were more sensitive to the peptide depleting effects of capsaicin than were CGRP positive fibers. Depletion of SP and CGRP from some joint tissues did not correlate with a decrease in joint inflammation. Studies incorporating a broad range of dosages will be required to determine whether intraarticular treatment with capsaicin can effectively deplete neuropeptides and thereby ameliorate established inflammatory arthritis.
Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.
Afilalo Marc,Etropolski Mila S,Kuperwasser Brigitte,Kelly Kathy,Okamoto Akiko,Van Hove Ilse,Steup Achim,Lange Bernd,Rauschkolb Christine,Haeussler Juergen
Clinical drug investigation
BACKGROUND:Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity. OBJECTIVE:to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. METHODS:this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. RESULTS:efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). CONCLUSION:treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.
10.2165/11533440-000000000-00000
The contribution of neurogenic inflammation in experimental arthritis.
Levine J D,Moskowitz M A,Basbaum A I
Journal of immunology (Baltimore, Md. : 1950)
The release of the peptide neurotransmitter substance P from the peripheral terminals of nociceptive afferent neurons and the release of catecholamines from postganglionic sympathetic efferent neurons produce physiologic changes associated with acute inflammation. The contribution of these neurogenic mechanisms to inflammatory diseases has not been determined. Activation of central neural circuits elicits similar physiologic changes, and lesions of the peripheral and central nervous system are associated with alteration in activity of inflammatory diseases. We have evaluated the contribution of neurogenic inflammation to the severity of joint injury in experimentally induced arthritis in the rat. The finding of a greater density of substance P-containing nociceptive afferents in a joint that develops more severe arthritis (ankle) suggests a role of substance P in joint injury. Direct evidence that the proinflammatory factor released from these nociceptors is substance P is provided by the finding that the injection of substance P into a joint which normally develops less severe arthritis (knee) increases the severity of arthritis in that joint. A contribution of catecholamines to the severity of joint injury was suggested by the finding that both guanethidine-induced sympathectomy and reserpine-induced depletion of catecholamines attenuated the severity of joint injury. Finally, a contribution of central neural circuits to inflammatory processes was studied in a model in which activation of nociceptive afferents elicited swelling and tenderness at a remote site. This reflex neurogenic inflammation was inhibited by intracerebroventricular injections of morphine, which also attenuated the severity of arthritis. These studies provide evidence that elements of the peripheral afferent and sympathetic efferent neurons and of descending supraspinal, opioid-mediated, circuits in the central nervous system modulate the severity of joint injury in experimental arthritis in the rat.
Control of arthritis pain with anti-nerve-growth factor: risk and benefit.
Seidel Matthias F,Lane Nancy E
Current rheumatology reports
Arthritis is characterized by pain and inflammation. Recently, attention has been focused on nerve-growth factor (NGF), a neurotrophin that is a key regulator of peripheral nociception because it mediates overexpression of proinflammatory neuron-derived molecules such as substance P, serotonin, and calcitonin gene-related peptide. Antibodies have been generated for NGF and its receptor that are effective in reducing pain in preclinical pain models, and clinical trials in patients with advanced knee and hip osteoarthritis and low-back pain. Results show pain reduction is rapid and sustained. Adverse events with anti-NGF included transient paraesthesia and edema, rapidly progressive OA, and, in a small number of patients treated with both anti-NGF and nonsteroidal anti-inflammatory drugs, osteonecrosis. Inhibition of the NGF-stimulated nociceptive pathway seems to be effective; however, the adverse effects require further investigation.
10.1007/s11926-012-0289-8
Reducing joint destruction due to septic arthrosis using an adenosine2A receptor agonist.
Cohen Steven B,Gill Sanjitpal S,Baer Geoffrey S,Leo Brian M,Scheld W Michael,Diduch David R
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
We assessed the efficacy of a new adenosine A2A agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at 1, 4, and 7 days. Knees in all ATL146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATL146e compared to infected (p<0.00004) and antibiotics controls (p<0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL146e groups when compared to infected (p<0.03) and antibiotics controls (p<0.05). Addition of an adenosine A2A agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the A2A receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis.
10.1016/j.orthres.2003.08.011
Muscle function in juvenile chronic arthritis.
Lindehammar H,Bäckman E
The Journal of rheumatology
OBJECTIVE:Muscle strength and thickness were studied in children with juvenile chronic arthritis (JCA) to evaluate their muscle function. METHODS:We studied voluntary isometric, isokinetic, and nonvoluntary isometric muscle strength, as well as muscle thickness, in 20 children with JCA. Thickness of the quadriceps muscle was measured by ultrasound. Results were compared with reference values for healthy children and a matched control group. RESULTS:Isometric muscle strength in knee extensors, elbow flexors, and wrist dorsiflexors was reduced in children with JCA. In muscles near an inflamed joint, the strength was 45-65% of expected value. In muscles without adjacent arthritis, the strength was slightly decreased (80-90% of expected value). Isometric and isokinetic strength in ankle dorsiflexors was reduced only in children with ankle arthritis. Nonvoluntary muscle strength in thumb adductors during electrical stimulation of the ulnar nerve was reduced in children with arthritis in the hand. Thickness of the quadriceps muscle was reduced both in children with and without knee arthritis (75 and 90% of expected). CONCLUSION:Children with JCA have reduced muscle strength and thickness, which is most pronounced in muscles near an inflamed joint.
Efficacy of multimodal perioperative analgesia protocol with periarticular medication injection in total knee arthroplasty: a randomized, double-blinded study.
Kelley Todd C,Adams Mary Jo,Mulliken Brian D,Dalury David F
The Journal of arthroplasty
Pain control is necessary for successful rehabilitation and outcome after total knee arthroplasty. Our goal was to compare the clinical efficacy of periarticular injections consisting of a long-acting local anesthetic (ropivacaine) and epinephrine with and without combinations of an α2-adrenergic agonist (clonidine) and/or a nonsteroidal anti-inflammatory agent (ketorolac). In a double-blinded controlled study, we randomized 160 patients undergoing total knee arthroplasty to receive 1 of 4 intraoperative periarticular injections: Group A, ropivacaine, epinephrine, ketorolac, and clonidine; Group B, ropivacaine, epinephrine, and ketorolac; Group C, ropivacaine, epinephrine, and clonidine; Group D (control), ropivacaine and epinephrine. Compared with Group D, Group A and B patients had significantly lower postoperative visual analog pain scores and nurse pain assessment and Group C patients had a significantly greater reduction in physical therapist pain assessment. We found no differences in other parameters analyzed.
10.1016/j.arth.2013.03.008
The effect of intra-articular injection of Diprospan at the knee joint on the hypothalamic-pituitary-adrenal axis.
Habib George,Zahran Rana,Najjar Ronza,Badarny Samih,Jabbour Adel,Artul Suheil,Hakim Geries,Jabaly-Habib Haneen
Swiss medical weekly
QUESTIONS UNDER STUDY:In this work we wanted to evaluate the effect of intra-articular injection (IAI) at the knee joint of 1 ml of Diprospan on the hypothalamic-pituitary-adrenal (HPA) axis. METHODS:Consecutive patients attending the rheumatology or orthopaedic clinic with osteoarthritic knee pain not responding satisfactorily to medical and physical therapy were asked to participate in our study. After consent, patients had ultrasound-guided IAI of 1 ml of Diprospan, containing 2 mg of betamethasone sodium phosphate and 5 mg of betamethasone dipropionate. Demographic, clinical, laboratory and radiographic variables were documented. Just prior to the knee injection and 1, 2, 4 and 6 weeks later, patients had a 1-µg adrenocorticotropic hormone (ACTH) stimulation test. Secondary adrenal insufficiency (SAI) was defined as a poststimulation (30 minutes after ACTH injection) serum cortisol level of less than 18 µg/dl (~500 nmol/l) and lack of a rise of >6 µg/dl (~166 nmol/l) over the basal level in poststimulation serum cortisol. RESULTS:Twenty patients completed the study. There were 3 male and 17 female patients, with a mean age of 58.6±9.5 years. Six (30%) patients had evidence of SAI and in five of them it was seen at one time-point, mostly at week 2 after the IAI. In one patient, SAI was prolonged and observed from week 1 to week 4. CONCLUSIONS:IAI at the knee joint of 1 ml of Diprospan was associated with a transient high rate of SAI.
10.4414/smw.2015.14134
Quantification of cat's articular afferents containing calcitonin gene-related peptide or substance P innervating normal and acutely inflamed knee joints.
Hanesch U,Heppelmann B,Schmidt R F
Neuroscience letters
In cats with an acute (32 h) unilateral knee joint inflammation the proportion of calcitonin gene-related peptide-(CGRP) and substance P-(SP) immunoreactive articular afferents, retrogradely labelled by Fast Blue (FB), were determined using immunohistochemistry. The proportion of neurons containing CGRP was significantly higher on the inflamed side (52%) than on the contralateral side (39%) and in controls (42%). However, the proportion of SP-immunoreactive articular perikarya on the inflamed side (26%) did not differ from the contralateral side (24%) and the control cats (22%). These data indicate that acute inflammation induces the synthesis of CGRP but not of SP in joint afferents.
10.1016/s0304-3940(97)00645-9
[Anesthetic management using esmolol for arthroscopic synovectomy in a patient with thyroid storm].
Torigoe Kei,Suzuki Hiroto,Nakajima Waka,Takahashi Minori,Aoyagi Mitsuo
Masui. The Japanese journal of anesthesiology
We report a case of a 47-year-old woman with past medical history of Graves disease who presented with thyroid storm, a state of physiologic decompensation due to severe thyrotoxicosis, and arthritis purulenta. Antithyroid therapy ameliorated thyrotoxicosis in 4 days, and arthroscopic synovectomy of the right knee was performed. Anesthesia was induced with intravenous propofol. Esmolol, an ultra-short-acting beta blocker listed in national drug tariff of Japan for intraoperative continuous iv infusion in March 2008, was also administered to control heart rate. Then, laryngeal mask airway was inserted and echo-guided femoral nerve block was done with ropivacaine. Anesthesia was maintained with i.v. infusion of propofol and fentanyl. Short episode of supraventricular tachycardia occurred twice, but each tachycardia disappered in about a half minute. The postoperative course was uneventful. Esmolol probably acted to prevent intraoperative tachycardia due to increased beta-adrenergic tone.
Effect of hyaluronic acid (MW 500-730 kDa) on proteoglycan and nitric oxide production in human osteoarthritic chondrocyte cultures exposed to hydrostatic pressure.
Fioravanti A,Cantarini L,Chellini F,Manca D,Paccagnini E,Marcolongo R,Collodel G
Osteoarthritis and cartilage
OBJECTIVE:This study investigated the in vitro effects of hyaluronic acid (HA) of molecular weight (MW) 500-730 kDa on human articular chondrocytes cultivated for 48 h in the presence of interleukin-1beta (IL-1beta) with and without hydrostatic cyclical pressure. DESIGN:The effects of 10 and 100 microg/ml HA with and without IL-1beta were assessed in the culture medium of cells exposed to pressurization cycles in the form of sinusoidal waves (minimum pressure 1MPa, maximum pressure 5MPa) at a frequency of 0.25Hz for 3h, by the immunoenzymatic method on microplates for the quantitative measurement of human proteoglycans (PG) and by the Griess method for nitrites (NO). Morphological analyses were performed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). RESULTS:The presence of IL-1beta determines a significant decrease in PG and a significant increase in NO concentrations measured in the culture medium. When the cells are cultured in the presence of IL-1beta and HA at the two concentrations, a statistically significant restoration of PG and a decrease in NO levels are observed. Under pressurization conditions, we observed that the PG concentration in the medium of cells presented a very significant increase in all the conditions used in the study, except for IL-1beta alone. NO production decreased very significantly in the presence of IL-1beta+HA 10 and IL-1beta+HA 100. The results of metabolic evaluation are confirmed by morphological findings obtained by TEM and SEM. CONCLUSIONS:These in vitro studies confirm both the protective role of HA (MW 500-730 kDa), which counteracts the IL-1beta-induced effects, and the importance of pressure on chondrocyte metabolism and morphology.
10.1016/j.joca.2005.03.006
Regulation of the nitric oxide production resulting from the glucocorticoid-insensitive expression of iNOS in human osteoarthritic cartilage.
Vuolteenaho K,Moilanen T,Al-Saffar N,Knowles R G,Moilanen E
Osteoarthritis and cartilage
OBJECTIVE:Nitric oxide (NO) produced by cartilage and synovial membranes is implicated in the pathogenesis of osteoarthritis (OA) and inhibitors of NO synthesis may have indications in the treatment or prevention of joint destruction in OA. Because the signaling mechanisms as well as the NOS isoform involved in induction of NO production in human cartilage remain in many parts unclear, the present study was designed to investigate the regulation of inducible NO synthesis in human intact OA cartilage. METHODS:Cartilage specimens were collected from OA patients undergoing knee replacement surgery and studied for iNOS expression and NO production in organ culture to allow intact chondrocyte-matrix interactions. J774 macrophages were used for comparison as a well-documented source of iNOS. RESULTS:OA cartilage expressed iNOS and produced NO in the absence of exogenous cytokines. Addition of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) or lipopolysaccharide (LPS) into the culture medium enhanced NO production in a dose-and time-dependent manner. Various NOS inhibitors suppressed NO production in the following order of potency: 1400W (novel selective iNOS inhibitor)=L-NIO>L-NMMA>L-NAME. Cycloheximide (an inhibitor of protein synthesis), pyrrolidine dithiocarbamate (PDTC; an NF-kappa B inhibitor) and genistein (an inhibitor of tyrosine protein kinases) inhibited cytokine-induced NO production, while dexamethasone, diaminohydroxypyrimidine (DAHP; an inhibitor of tetrahydrobiopterin synthesis) and PD 98059 (p42/44 MAP kinase inhibitor) had no effect. CONCLUSIONS:The results suggest that NO synthesis in human osteoarthritic cartilage derives from the glucocorticoid-insensitive expression of iNOS. Very similar mechanisms appear to regulate inducible NO synthesis in human osteoarthritic cartilage and J774 macrophages with the exception that dexamethasone inhibited NO production in J774 cells but not in osteoarthritic cartilage.
10.1053/joca.2001.0431
Effects of TNFalpha-antagonists on nitric oxide production in human cartilage.
Vuolteenaho K,Moilanen T,Hämäläinen M,Moilanen E
Osteoarthritis and cartilage
OBJECTIVE:Nitric oxide (NO) produced by cartilage and synovial membrane is implicated in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In inflamed joints NO is synthesized in response to proinflammatory cytokines and it is involved in the joint destruction. The aim of the present study was to investigate the effects of TNFalpha-antagonists infliximab and etanercept on NO production in human cartilage. DESIGN:Cartilage specimen obtained from OA patients undergoing knee replacement surgery were studied for iNOS expression and NO production in organ culture to allow intact chondrocyte-matrix interactions. TNFalpha and soluble TNFalpha receptor release was measured by ELISA. RESULTS:Osteoarthritic cartilage produced NO spontaneously and its production was enhanced by proinflammatory cytokines TNFalpha (tumor necrosis factor alpha), IL-1beta (interleukin-1beta), IL-17 (interleukin-17) and by bacterial lipopolysaccharide (LPS). TNFalpha-antagonists infliximab and etanercept inhibited TNFalpha-induced NO production in a dose dependent manner but they had no effect on IL-1beta-, IL-17- and LPS-stimulated NO synthesis. TNFalpha and soluble TNFalpha receptors (sTNFRI and sTNFRII) were produced by human osteoarthritic cartilage. A neutralizing antibody against soluble TNFRI enhanced spontaneous NO production whereas an antibody against soluble TNFRII had no effect. CONCLUSIONS:TNFalpha-antagonists infliximab and etanercept suppressed TNFalpha-induced NO production. This effect was not seen on IL-1-, IL-17- or LPS-induced NO production suggesting that TNFalpha is not an autacoid mediator in these processes. The studies with neutralizing antibodies against soluble TNFRI suggest that endogenous cartilage-derived TNFalpha-antagonists modulate NO production in osteoarthritic cartilage.
10.1053/joca.2002.0521
Imputing at-work productivity loss using results of a randomized controlled trial comparing tapentadol extended release and oxycodone controlled release for osteoarthritis pain.
Lerner Debra,Chang Hong,Rogers William H,Benson Carmela,Chow Wing,Kim Myoung S,Biondi David
Journal of occupational and environmental medicine
OBJECTIVE:: To determine the impact of tapentadol extended release (ER) versus placebo or oxycodone controlled release (CR) on the work productivity of adults with chronic moderate to severe knee osteoarthritis pain. METHODS:: Using clinical trial data on pain outcomes, a validated methodology imputed treatment group differences in at-work productivity and associated differences in productivity costs (assuming a $100,000 annual salary per participant). RESULTS:: Imputed improvements in at-work productivity were significantly greater for tapentadol ER compared with either placebo (mean, 1.96% vs 1.51%; P = 0.001) or oxycodone CR (mean, 1.96% vs 1.40%; P < 0.001). Mean net savings per participant were $450 (P < 0.01) for tapentadol ER versus placebo and $560 (P = 0.001) for tapentadol ER versus oxycodone CR. CONCLUSION:: Effective osteoarthritis pain treatment also may help employees to function better at work and reduce their employers' productivity costs.
10.1097/JOM.0b013e31825f31a1
Anti‑inflammatory and anti‑catabolic effect of non‑animal stabilized hyaluronic acid and mesenchymal stem cell‑conditioned medium in an osteoarthritis coculture model.
Simental-Mendía Mario,Lozano-Sepúlveda Sonia Amelia,Pérez-Silos Vanessa,Fuentes-Mera Lizeth,Martínez-Rodríguez Herminia Guadalupe,Acosta-Olivo Carlos Alberto,Peña-Martínez Víctor Manuel,Vilchez-Cavazos Félix
Molecular medicine reports
Previous clinical studies have reported the clinical effectiveness of non‑animal stabilized hyaluronic acid (NASHA) and adipose‑derived mesenchymal stromal/stem cells (MSC) in the treatment of knee osteoarthritis (OA). Unlike MSC secreted mediators, in vitro anti‑inflammatory effects of NASHA have not been evaluated. We aimed to evaluate and compare the anti‑inflammatory effect of NASHA and MSC conditioned medium (stem cell‑conditioned medium; SC‑CM), in an explant‑based coculture model of OA. Cartilage and synovial membrane from seven patients undergoing total knee arthroplasty were used to create a coculture system. Recombinant IL‑1β was added to the cocultures to induce inflammation. Four experimental groups were generated: i) Basal; ii) IL‑1β; iii) NASHA (NASHA + IL‑1β); and iv) SC‑CM (SC‑CM + IL‑1β). Glycosaminoglycans (GAG) released in the culture medium and of nitric oxide (NO) production were quantified. Gene expression in cartilage and synovium of IL‑1β, matrix metallopeptidase 13 (MMP13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) and tissue inhibitor of metalloproteinases 1 (TIMP1) was measured by reverse transcription‑quantitative PCR. Media GAG concentration was decreased in cocultures with NASHA and SC‑CM (48 h, P<0.05; 72 h, P<0.01) compared with IL‑1β. Production of NO was significantly lower only in SC‑CM after 72 h (P<0.01). In cartilage, SC‑CM inhibited the expression of IL‑1β, MMP13 and ADAMTS5, while NASHA had this effect only in MMP13 and ADAMTS5. In synovium, SC‑CM decreased the expression level of MMP13 and ADAMTS5, while NASHA only decreased ADAMTS5 expression. Both NASHA and SC‑CM increased TIMP1 expression in cartilage and synovium. Treatments with NASHA and SC‑CM were shown to be a therapeutic option that may help counteract the catabolism produced by the inflammatory state in knee OA. The anti‑inflammatory mediators produced by MSC promote a lower expression of inflammatory targets in our study model.
10.3892/mmr.2020.11004
Treatment of experimental poly-D-lysine arthritis in rabbits by non-steroidal anti-inflammatory compounds.
Phillips N C
Agents and actions
The effect of five non-steroidal anti-inflammatory compounds on experimental poly-D-lysine arthritis in the rabbit knee joint have been determined. Two non-invasive methods of assessing the inflammation, measurement of swelling and temperature have been used to follow the effect of treatment. The rank order of potency for the reduction of temperature was indomethacin greater than flurbiprofen greater than diclofenac sodium greater than sulindac greater than fenclofenac. Reduction in joint temperature was shown not be be due to vasoconstrictor effect. Reduction of swelling was variable and not dose-related. The method described allows the activity of such compounds on experimental articular arthritis to be determined rapidly.
Inducible nitric oxide synthase is expressed in synovial fluid granulocytes.
Cedergren J,Forslund T,Sundqvist T,Skogh T
Clinical and experimental immunology
The objective of the study was to evaluate the NO-producing potential of synovial fluid (SF) cells. SF from 15 patients with arthritis was compared with blood from the same individuals and with blood from 10 healthy controls. Cellular expression of inducible nitric oxide synthase (iNOS) was analysed by flow cytometry. High-performance liquid chromatography was used to measure l-arginine and l-citrulline. Nitrite and nitrate were measured colourimetrically utilizing the Griess' reaction. Compared to whole blood granulocytes in patients with chronic arthritis, a prominent iNOS expression was observed in SF granulocytes (P < 0.001). A slight, but statistically significant, increase in iNOS expression was also recorded in lymphocytes and monocytes from SF. l-arginine was elevated in SF compared to serum (257 +/- 78 versus 176 +/- 65 micro mol/l, P = 0.008), whereas a slight increase in l-citrulline (33 +/- 11 versus 26 +/- 9 micro mol/l), did not reach statistical significance. Great variations but no significant differences were observed comparing serum and SF levels of nitrite and nitrate, respectively, although the sum of nitrite and nitrate tended to be elevated in SF (19.2 +/- 20.7 versus 8.6 +/- 6.5 micro mol/l, P = 0.054). Synovial fluid leucocytes, in particular granulocytes, express iNOS and may thus contribute to intra-articular NO production in arthritis.
10.1046/j.1365-2249.2002.01959.x
Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling.
Zhou Yan,Liu Shi-Qing,Yu Ling,He Bin,Wu Shi-Hao,Zhao Qi,Xia Shao-Qiang,Mei Hong-Jun
Apoptosis : an international journal on programmed cell death
Chondrocyte apoptosis is an important mechanism involved in osteoarthritis (OA). Berberine (BBR), a plant alkaloid derived from Chinese medicine, is characterized by multiple pharmacological effects, such as anti-inflammatory and anti-apoptotic activities. This study aimed to evaluate the chondroprotective effect and underlying mechanisms of BBR on sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis and surgically-induced rat OA model. The in vitro results revealed that BBR suppressed SNP-stimulated chondrocyte apoptosis as well as cytoskeletal remodeling, down-regulated expressions of inducible nitric oxide synthase (iNOS) and caspase-3, and up-regulated Bcl-2/Bax ratio and Type II collagen (Col II) at protein levels, which were accompanied by increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased phosphorylation of p38 mitogen-activated protein kinase (MAPK). Furthermore, the anti-apoptotic effect of BBR was blocked by AMPK inhibitor Compound C (CC) and adenosine-9-β-D-arabino-furanoside (Ara A), and enhanced by p38 MAPK inhibitor SB203580. In vivo experiment suggested that BBR ameliorated cartilage degeneration and exhibited an anti-apoptotic effect on articular cartilage in a rat OA model, as demonstrated by histological analyses, TUNEL assay and immunohistochemical analyses of caspase-3, Bcl-2 and Bax expressions. These findings suggest that BBR suppresses SNP-stimulated chondrocyte apoptosis and ameliorates cartilage degeneration via activating AMPK signaling and suppressing p38 MAPK activity.
10.1007/s10495-015-1152-y
Aurothiomalate and hydroxychloroquine inhibit nitric oxide production in chondrocytes and in human osteoarthritic cartilage.
Vuolteenaho K,Kujala P,Moilanen T,Moilanen E
Scandinavian journal of rheumatology
OBJECTIVES:Nitric oxide (NO) is a destructive mediator produced by activated chondrocytes. The aim of the present study was to investigate the effect of disease-modifying anti-rheumatic drugs (DMARDs) on interleukin-1beta (IL-1beta)-induced NO production in chondrocyte cultures, and in human osteoarthritic cartilage. RESULTS:Aurothiomalate, hydroxychloroquine, methotrexate and leflunomide inhibited IL-1beta-induced inducible NO synthase (iNOS) expression and NO production in immortalized H4 chondrocytes, while penicillamine and sulfasalazine had no effect. This can be explained by the fact that the four effective DMARDs also suppressed IL-1beta-induced activation of nuclear factor kappa B (NF-kappaB), which is a crucial transcription factor for iNOS. Aurothiomalate and hydroxychloroquine also inhibited IL-1beta-induced NO production in OA cartilage whereas methotrexate and leflunomide had no effect. CONCLUSION:Aurothiomalate and hydroxychloroquine suppressed IL-1beta-induced NO production in chondrocyte cultures and in OA cartilage. The results suggest an additional anti-inflammatory mechanism for aurothiomalate and hydroxychloroquine and indicates their possible therapeutic value in the treatment of osteoarthritis (OA).
10.1080/03009740510026797
Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin.
Liu Feng-Cheng,Lu Jeng-Wei,Chien Chiao-Yun,Huang Hsu-Shan,Lee Chia-Chung,Lien Shiu-Bii,Lin Leou-Chyr,Chen Liv Weichien,Ho Yi-Jung,Shen Min-Chung,Ho Ling-Jun,Lai Jenn-Haung
International journal of molecular sciences
In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2-benzo[][1,3]oxazine-2,4(3)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)⁻nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.
10.3390/ijms19051453
Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis.
Ohtori Seiji,Inoue Gen,Orita Sumihisa,Takaso Masashi,Eguchi Yawara,Ochiai Nobuyasu,Kishida Shunji,Kuniyoshi Kazuki,Aoki Yasuchika,Ishikawa Tetsuhiro,Miyagi Masayuki,Kamoda Hiroto,Suzkuki Miyako,Nakamura Junichi,Kubota Gou,Sakuma Yoshihiro,Oikawa Yasuhiro,Toyone Tomoaki,Inage Kazuhide,Sainoh Takeshi,Yamauchi Kazuyo,Takahashi Kazuhisa
Yonsei medical journal
PURPOSE:Osteoarthritic pain is largely considered to be inflammatory pain. Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis (OA) in which the subchondral bone junction is destroyed, and this induces neuropathic pain (NP). Pregabalin was developed as a pain killer for NP; however, there are no reports on pregabalin use in OA patients. The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients. MATERIALS AND METHODS:Eighty-nine knee OA patients were evaluated in this randomized prospective study. Patients were divided into meloxicam, pregabalin, and meloxicam+pregabalin groups. Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain scales among groups were compared using a Kruskal-Wallis test. RESULTS:Before drug application, there was no significant difference in VAS and WOMAC scores among the three groups (p>0.05). Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1, 2, and 4 weeks, and WOMAC score at 4 weeks, compared with the other groups (p<0.05). No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group (p>0.05). CONCLUSION:Meloxicam+pregabalin was effective for pain in OA patients. This finding suggests that OA pain is a combination of inflammatory and NP.
10.3349/ymj.2013.54.5.1253
mGluR1 and mGluR5 antagonists in the amygdala inhibit different components of audible and ultrasonic vocalizations in a model of arthritic pain.
Han Jeong Seok,Neugebauer Volker
Pain
Pain has a strong emotional component. The amygdala plays a key role in emotionality and is also involved in pain processing and pain modulation. Our previous studies showed an important role of group I metabotropic glutamate receptors (mGluRs) in pain-related synaptic plasticity and sensitization of neurons in the central nucleus of the amygdala (CeA). Here we address the roles of mGluR1 and mGluR5 subtypes in the CeA in the modulation of supraspinally organized behavioral responses in a model of arthritic pain. Audible and ultrasonic (25+/-4 kHz) vocalizations were measured in awake rats during and after innocuous and noxious stimulation (15 s) of the knee joint. Vocalizations were recorded in the same animals before arthritis, 6 h after arthritis induction and during administration of antagonists selective for mGluR1 (CPCCOEt) and mGluR5 (MPEP) into the CeA through stereotaxically implanted microdialysis probes. The duration of audible and ultrasonic vocalizations increased in the arthritic pain state. The duration of vocalizations during stimulation (VDS), which are organized at the brainstem level, was significantly reduced by CPCCOEt but not by MPEP. Vocalizations that continued after stimulation (VAS), which are organized in the limbic forebrain, particularly the amygdala, were inhibited by CPCCOEt and MPEP. These findings suggest differential roles of mGluR1 and mGluR5 in the CeA in pain-related vocalizations. Both mGluR1 and mGluR5 contribute to vocalizations generated in the amygdala whereas mGluR1, but not mGluR5, is involved in the amygdala-mediated modulation of vocalizations originating from activity in the brainstem.
10.1016/j.pain.2004.10.022
Enhanced group II mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala.
Han Jeong S,Fu Yu,Bird Gary C,Neugebauer Volker
Molecular pain
BACKGROUND:The latero-capsular part of the central nucleus of the amygdala (CeLC) is the target of the spino-parabrachio-amygdaloid pain pathway. Our previous studies showed that CeLC neurons develop synaptic plasticity and increased neuronal excitability in the kaolin/carrageenan model of arthritic pain. These pain-related changes involve presynaptic group I metabotropic glutamate receptors (mGluRs) and postsynaptic NMDA and calcitonin gene-related peptide (CGRP1) receptors. Here we address the role of group II mGluRs. RESULTS:Whole-cell current- and voltage-clamp recordings were made from CeLC neurons in brain slices from control rats and arthritic rats (>6 h postinjection of kaolin/carrageenan into the knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of afferents from the pontine parabrachial (PB) area. A selective group II mGluR agonist (LY354740) decreased the amplitude of EPSCs more potently in CeLC neurons from arthritic rats (IC50 = 0.59 nM) than in control animals (IC50 = 15.0 nM). The inhibitory effect of LY354740 was reversed by a group II mGluR antagonist (EGLU) but not a GABAA receptor antagonist (bicuculline). LY354740 decreased frequency, but not amplitude, of miniature EPSCs in the presence of TTX. No significant changes of neuronal excitability measures (membrane slope conductance and action potential firing rate) were detected. CONCLUSION:Our data suggest that group II mGluRs act presynaptically to modulate synaptic plasticity in the amygdala in a model of arthritic pain.
10.1186/1744-8069-2-18
Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies.
Gaynor P,McCarberg B,Zheng W,Shoemaker S,Duenas H
International journal of clinical practice
AIMS:Report weight change baseline up to 12-15 months in duloxetine-treated patients during clinical trials of chronic painful conditions of diabetic peripheral neuropathic pain (DPNP), fibromyalgia, chronic low back pain (CLBP) and chronic knee pain as a result of osteoarthritis. METHODS:Weight change data from 16 duloxetine studies in chronic painful conditions were pooled by pain condition and duration, creating 10 datasets. Datasets included placebo-controlled, open-label and routine-care-controlled designs. Assessments included mean weight change from baseline, baseline body mass index category, potentially clinically significant (PCS) weight change and weight-related treatment-emergent adverse events. RESULTS:Total number of patients was 5111 with mean baseline weight ranging from 70 to 97 kg. All duloxetine groups had significant mean weight loss compared with placebo at acute phase completion (p ≤ 0.001). In studies > 3 months, patients from fibromyalgia and CLBP studies had overall mean weight increase (up to 1.1 kg), whereas patients in DPNP studies had overall mean weight loss (-0.33 to -1.7 kg) at end-point. Overall, the percentage of patients with PCS weight gain was 0.4-16% and PCS weight loss was 2.5-9.9%. DISCUSSION:Weight change data in clinical trials of patients with fibromyalgia or CLBP treated with duloxetine for up to 15 months were consistent with data reported in 10 clinical trials of patients with major depressive disorder (MDD) using duloxetine up to 52 weeks. Patients with DPNP had weight loss at end-point. CONCLUSION:Mean weight changes and percentages of patients with PCS weight loss and weight gain observed in DPNP, fibromyalgia and CLBP with long-term duloxetine treatment were consistent with those reported previously for MDD studies.
10.1111/j.1742-1241.2011.02635.x
Effect of hypoxia/reoxygenation on the cytokine-induced production of nitric oxide and superoxide anion in cultured osteoarthritic synoviocytes.
Chenevier-Gobeaux C,Simonneau C,Lemarechal H,Bonnefont-Rousselot D,Poiraudeau S,Rannou F,Ekindjian O G,Anract P,Borderie D
Osteoarthritis and cartilage
OBJECTIVE:Hypoxia/reoxygenation (H/R) is an important feature in the osteoarthritis (OA) physiopathology. Nitric oxide (NO) is a significant proinflammatory mediator in the inflamed synovium. The purpose of this study was to investigate the effects of H/R on inducible NO synthase (iNOS) activity and expression in OA synoviocytes. In addition we studied the relationship between nitrosative stress and NADPH oxidase (NOX) in such conditions. METHODS:Human cultured synoviocytes from OA patients were treated for 24 h with interleukin 1-β (IL-1β), tumour necrosis factor α (TNF-α) or neither; for the last 6 h, they were submitted to either normoxia or three periods of 1-h of hypoxia followed by 1-h of reoxygenation. ·NO metabolism (iNOS expression, nitrite and peroxynitrite measurements) was investigated. Furthermore, superoxide anion O2(·-) production, NOX subunit expression and nitrosylation were also assessed. RESULTS:iNOS expression and nitrite (but not peroxynitrite) production were ~0.20 to ~0.12 nmol min(-1) mg proteins(-1) (P < 0.05), while NOXs' subunit expression and p47-phox phosphorylation were increased. NOXs and p47-phox were dramatically nitrosylated under H/R conditions (P < 0.05 vs normoxia). Using NOS inhibitors under H/R conditions, p47-phox nitrosylation was prevented and O2(·-) production was restored at normoxic levels (0.21 nmol min(-1) mg of proteins(-1)). CONCLUSIONS:Our results provide evidence for an up-regulation of iNOS activity in OA synoviocytes under H/R conditions, associated to a down-regulation of NOX activity through nitrosylation. These findings highlight the importance of radical production to OA pathogenesis, and appraise the metabolic modifications of synovial cells under hypoxia.
10.1016/j.joca.2013.03.010
Activation of stress-activated protein kinase in osteoarthritic cartilage: evidence for nitric oxide dependence.
Clancy R,Rediske J,Koehne C,Stoyanovsky D,Amin A,Attur M,Iyama K,Abramson S B
Osteoarthritis and cartilage
OBJECTIVE:We have demonstrated in bovine chondrocytes that nitric oxide (NO) mediates IL1 dependent apoptosis under conditions of oxidant stress. This process is accompanied by activation of c-Jun NH2-terminal kinase (JNK; also called stress-activated protein kinase). In these studies we examined activation of JNK in explant cultures of human osteoarthritic cartilage obtained at joint replacement surgery and we characterized the role of peroxynitrite to act as an upstream trigger. DESIGN:A novel technique to isolate chondrocyte proteins (<10% of total cartilage protein) from cartilage specimens was developed. It was used to analyse JNK activation by a western blot technique. To examine the hypothesis that chondrocyte JNK activation is a result of increased peroxynitrite, in vitro experiments were performed in which cultured chondrocytes were incubated with this oxidant. RESULTS:Activated JNK was detected in the cytoplasm of osteoarthritis (OA) affected chondrocytes but not in that of controls. In vitro, chondrocytes produce NO and superoxide anion. IL-1 (48 h), which induces nitric oxide synthase, resulted in an activation of JNK; this effect was reversed by N-monomethylarginine (NMA). TNFalpha treated chondrocytes at 48 h produce superoxide anion (EPR method). Exposure of cells to peroxynitrite led to an accumulation of intracellular oxidants, in association with JNK activation and cell death by apoptosis. CONCLUSION:We suggest that JNK activation is among the IL-1 elicited responses that injure articular chondrocytes and this activation of JNK is dependent on intracellular oxidant formation (including NO peroxynitrite). In addition, the extraction technique here described is a novel method that permits the quantitation and study of proteins such as JNK involved in the signaling pathways of chondrocytes within osteoarthritic cartilage.
10.1053/joca.2000.0388
Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.
Buynak Robert,Rappaport Stephen A,Rod Kevin,Arsenault Pierre,Heisig Fabian,Rauschkolb Christine,Etropolski Mila
Clinical therapeutics
PURPOSE:Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. METHODS:Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. FINDINGS:Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. IMPLICATIONS:Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.).
10.1016/j.clinthera.2015.08.014
Efficacy and safety of tapentadol prolonged release for moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo- and oxycodone controlled release-controlled studies.
Current medical research and opinion
OBJECTIVE:To compare efficacy and safety of tapentadol prolonged-release (PR) and oxycodone-controlled release (CR) in moderate-to-severe chronic osteoarthritis knee pain. METHODS:Data from two double-blind, randomized, placebo- and oxycodone CR-controlled phase 3 studies with a 3-week titration period and 12-week controlled dose adjustment maintenance period were pooled. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). RESULTS:A total of 2,010 patients were assessed. For both primary end-points, tapentadol PR was significantly more effective than oxycodone CR (LS mean difference of -0.41 [95% CI = -0.65, -0.16; p = 0.001] at week 12 and -0.35 [95% CI = -0.58, -0.12; p = 0.003] over 12 weeks of maintenance [last observation carried forward]). Significantly better outcomes than for oxycodone CR were also observed for patient global impression of change, both Short Form-36 component scores, and EuroQoL-5Dimensions health status index (all p < 0.001). Relative risk for vomiting, constipation, nausea, somnolence, and pruritus was lower for tapentadol PR than for oxycodone CR. A higher proportion of oxycodone CR patients discontinued treatment (64% vs 42.2% for tapentadol PR); time to treatment discontinuation due to an adverse event was significantly shorter for oxycodone CR (p < 0.001). CONCLUSIONS:The analyses suggest that tapentadol PR provided superior pain relief and a more improved overall health status than oxycodone CR in a large patient population with moderate-to-severe chronic osteoarthritis pain. Compared to oxycodone CR, tapentadol PR showed a more favorable tolerability profile with better gastrointestinal tolerability.
10.1080/03007995.2017.1335188
Functional network architecture predicts psychologically mediated analgesia related to treatment in chronic knee pain patients.
Hashmi Javeria Ali,Kong Jian,Spaeth Rosa,Khan Sheraz,Kaptchuk Ted J,Gollub Randy L
The Journal of neuroscience : the official journal of the Society for Neuroscience
Placebo analgesia is an indicator of how efficiently the brain translates psychological signals conveyed by a treatment procedure into pain relief. It has been demonstrated that functional connectivity between distributed brain regions predicts placebo analgesia in chronic back pain patients. Greater network efficiency in baseline brain networks may allow better information transfer and facilitate adaptive physiological responses to psychological aspects of treatment. Here, we theorized that topological network alignments in resting state scans predict psychologically conditioned analgesic responses to acupuncture treatment in chronic knee osteoarthritis pain patients (n = 45). Analgesia was induced by building positive expectations toward acupuncture treatment with verbal suggestion and heat pain conditioning on a test site of the arm. This procedure induced significantly more analgesia after sham or real acupuncture on the test site than in a control site. The psychologically conditioned analgesia was invariant to sham versus real treatment. Efficiency of information transfer within local networks calculated with graph-theoretic measures (local efficiency and clustering coefficients) significantly predicted conditioned analgesia. Clustering coefficients in regions associated with memory, motivation, and pain modulation were closely involved in predicting analgesia. Moreover, women showed higher clustering coefficients and marginally greater pain reduction than men. Overall, analgesic response to placebo cues can be predicted from a priori resting state data by observing local network topology. Such low-cost synchronizations may represent preparatory resources that facilitate subsequent performance of brain circuits in responding to adaptive environmental cues. This suggests a potential utility of network measures in predicting placebo response for clinical use.
10.1523/JNEUROSCI.3155-13.2014
Effects of nimesulide on pain and on synovial fluid concentrations of substance P, interleukin-6 and interleukin-8 in patients with knee osteoarthritis: comparison with celecoxib.
Bianchi M,Broggini M,Balzarini P,Franchi S,Sacerdote P
International journal of clinical practice
OBJECTIVE:This study was designed to investigate the analgesic effects of nimesulide and celecoxib in patients with knee osteoarthritis (OA). In patients with joint effusion, the effects of these non-steroidal anti-inflammatory drugs (NSAIDs) on synovial fluid concentrations of substance P (SP), interleukin (IL)-6 and IL-8 also were evaluated. METHODS:Patients were randomly assigned either nimesulide (100 mg twice a day) or celecoxib (200 mg once a day) for 2 weeks. The intensity of joint pain was assessed with a 100-mm visual analogue scale (VAS). Furthermore, patients completed questions about analgesic efficacy and overall tolerability of the treatments on a five-point categorical scale. Synovial fluid samples were drawn at baseline, 30 min after the first drug intake (day 1), and 30 min after the last drug intake (day 14). RESULTS:We enrolled 44 patients, 20 of whom had a joint effusion. In this group, the effects of nimesulide were more marked than for celecoxib, with evidence of a faster onset of the analgesic action. Both after a single or repeated administration, nimesulide significantly reduced the synovial fluid concentrations of SP and IL-6. Celecoxib, on the other hand, did not change the concentrations of SP and significantly reduced the levels of IL-6 only on day 14. None of the drugs affected IL-8. Both drugs were generally well tolerated. CONCLUSIONS:These results provide evidence that nimesulide is an effective agent for the symptomatic treatment of OA. The effect on inflammatory pain mediators is consistent with the fast analgesic action of this NSAID.
10.1111/j.1742-1241.2007.01453.x
Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis.
Schaible H G,Schmidt R F
Journal of neurophysiology
1. In 37 cats anesthetized with alpha-chloralose recordings were made from single-afferent units of the medial articular nerve (MAN) of the right knee joint. First the mechanosensitivity of such units was characterized while the joint was in normal condition. Thereafter, keeping the afferents under continuous observation, an experimental arthritis was induced by injecting kaolin and carrageenan into the joint cavity. The effects of the developing arthritis including the time course of the changes were studied on low- and high-threshold units and on afferents that had no mechanosensitivity in the normal joint. 2. The arthritis increased the mechanosensitivity in the majority of the low-threshold units, i.e., in units that responded already in the normal joint to movements in the working range. Enhanced responses to movements were found for 12 of 16 thick myelinated group II, 10 of 10 fine myelinated group III, and 1 of 3 unmyelinated group IV afferents. The augmentation of reactions developed in most cases within the first hour after the injection of the inflammatory compounds, sometimes starting immediately after the injection. A further rise of the mechanosensitivity was observed within the following 2-4 h. In most group III units enhanced responses for movements were accompanied by an induction or increase of resting discharges. In 1 group II and 1 group IV unit spontaneous activity developed in the absence of any change of movement-sensitivity. 3. The inflammation led to enhanced mechanosensitivity in high-threshold afferents, i.e., in units that responded in the normal joint only to noxious movements exceeding the working range of the knee. One group II, 10 of 12 group III, and 5 of 10 group IV units of this type became responsive to movements in the working range during development of arthritis, in most cases within the second to third hour after induction of inflammation with a further increase later on. In a high proportion of these units resting activity was induced too. Few high-threshold units developed spontaneous discharges but no responses to movements in the working range. The time course for development of resting activity was similar to that for lowering of the mechanical threshold. 4. The experimental arthritis induced afferent activity in 1 of 2 group III and 10 of 14 group IV units that in the normal joint were unresponsive to local mechanical stimulation and to innocuous/noxious movements (but responsive to a bolus of a KCl-solution applied intraarterially close to the joint).(ABSTRACT TRUNCATED AT 400 WORDS)
10.1152/jn.1988.60.6.2180
The synovial fluid neuropeptide PACAP may act as a protective factor during disease progression of primary knee osteoarthritis and is increased following hyaluronic acid injection.
Innate immunity
The correlation of serum and synovial fluid (SF) pituitary adenylate cyclase-activating polypeptide (PACAP) levels with disease progression of primary knee osteoarthritis (OA) was explored. Radiographic severity of OA was determined by Kellgren-Lawrence (K-L) grades. PACAP levels were measured by ELISA before treatment, and 4 and 8 wk following hyaluronic acid (HA) injection. Levels of IL-1β and MMP-3 were also detected. The numeric pain scale (NPS), revised Oxford Knee Score (OKS), and American Knee Society Score (AKSS) were employed to evaluate to symptomatic severity. Receiver-operating-characteristic (ROC) curve analysis was carried out to compare the diagnostic value of PACAP, IL-1β, and MMP-3 for the K-L grade. PACAP concentrations in SF but not serum were significantly lower in OA patients compared with controls. SF PACAP levels were negatively associated with K-L grades and higher NPS as well as worse AKSS and OKS. Further analysis demonstrated that PACAP concentration in SF was negatively correlated with expressions of IL-1β as well as MMP-3 and may act as a marker for radiographic progression along with MMP-3. Last, we found SF PACAP levels exhibited an incremental trend after HA injection. These findings confirmed the crucial role of PACAP deficiency in the development of primary knee OA.
10.1177/1753425919839125
Effects of glucosamine hydrochloride on the production of prostaglandin E2, nitric oxide and metalloproteases by chondrocytes and synoviocytes in osteoarthritis.
Nakamura H,Shibakawa A,Tanaka M,Kato T,Nishioka K
Clinical and experimental rheumatology
OBJECTIVES:To determine the response of glucosamine hydrochloride on chondrocytes and synoviocytes in terms of prostaglandin E2 (PGE2), nitric oxide (NO) and matrix metalloproteases (MMPs). METHODS:Chondrocytes and synoviocytes were prepared from joint specimens of patients who underwent total knee arthroplasty for osteoarthritis (OA). Chondrocytes from patients with femoral neck fracture were served as a normal control. Culture cells were stimulated by 5 ng/ml of IL-1beta and treated with various concentration of glucosamine hydrochloride (from 1 microg/ml to 500 microg/ml). PGE2, NO, MMP-1, MMP-3, and MMP-13 levels were evaluated in the culture supernatant. Further, the expression of COX-2 mRNA was studied by semiquantitative PCR. RESULTS:With IL-1beta stimulation, the levels of these mediators increased dramatically, except for NO from synoviocytes. After stimulation, levels of these mediators in OA chondrocytes were higher than synoviocytes and normal chondrocytes, and the level of MMP-3 was higher than those of MMP-1 and MMP-13. Glucosamine hydrochloride at a concentration of 100 microg/ml suppressed PGE2 production, and partly suppressed NO production. It also suppressed the production of MMPs from normal chondrocytes and synoviocytes but not from OA chondrocytes. CONCLUSION:Glucosamine modulates the metabolism of chondrocytes and synoviocytes and its mode of action differs between cells and conditions.
Efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo-, and active-controlled trials.
Current medical research and opinion
OBJECTIVE:To compare efficacy and safety of tapentadol prolonged release (PR) vs oxycodone controlled release (CR) in younger patients (<65 years of age) and in elderly patients (≥65 and ≥75 years of age) in the treatment of moderate-to-severe chronic osteoarthritis (OA) knee pain. METHODS:Data from two double-blind, randomized, placebo-, and oxycodone CR-controlled phase 3 trials were pooled and stratified by age. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). RESULTS:A total of 1357 patients <65 years, 653 patients ≥65 years, and 176 patients ≥75 years of age were assessed. The comparison between tapentadol PR and oxycodone CR showed numerically better pain relief under tapentadol PR for both primary end-points in all three age groups. More favorable improvements were also observed for patient global impression of change, the Short Form-36 physical component score, and EuroQoL-5Dimensions health status index. In the elderly, incidences of dizziness and somnolence were comparable between active treatments, but incidences of nausea, vomiting, and constipation were considerably lower under tapentadol PR. Treatment completion rates were lowest under oxycodone CR; > 50% of elderly oxycodone CR patients named side-effects as the main reason for discontinuation. CONCLUSIONS:Tapentadol PR was effective in the treatment of moderate-to-severe chronic OA pain in elderly and younger patients. Compared to oxycodone CR, the overall and the gastrointestinal tolerability profile in particular were better in all tapentadol PR groups, regardless of age.
10.1080/03007995.2018.1520085
Spontaneous hemarthrosis of the knee associated with clopidogrel and aspirin treatment.
Gille J,Bernotat J,Böhm S,Behrens P,Löhr J F
Zeitschrift fur Rheumatologie
We report a case of a 76-year-old-man who developed spontaneous hemarthrosis of his right knee following clopidogrel-aspirin treatment. Clopidogrel is an ADP receptor antagonist and in combination with aspirin widely used in patients with atherosclerotic vascular disease to reduce the incidence of ischemic events. To date, no case of spontaneous hemarthrosis following clopidogrel-aspirin therapy has been reported. Prompt aspiration after discontinuing the ADP receptor antagonist-aspirin combination therapy can assist early diagnosis and may prevent further damage to the joint. In conclusion, spontaneous hemarthrosis is a possible complication following clopidogrel-aspirin therapy and is recommended to be evaluated when appropriate clinical symptoms (e.g., intraarticular effusion) present.
10.1007/s00393-003-0420-3
Efficacy of duloxetine and gabapentin in pain reduction in patients with knee osteoarthritis.
Enteshari-Moghaddam Afsaneh,Azami Ahad,Isazadehfar Khatereh,Mohebbi Hamed,Habibzadeh Afshin,Jahanpanah Parinaz
Clinical rheumatology
INTRODUCTION:Knee osteoarthritis (OA) is a common form of arthritis in elders which can lead to reduced daily activity and quality of life. It is important to administer a proper treatment with high efficacy and low side effects. In this study, we evaluated the efficacy of duloxetine and gabapentin in patients with moderate to severe knee OA. METHOD:In this randomized clinical trial, 150 patients with moderate to severe knee OA were randomly allocated to receive duloxetine 30 mg (n = 50), gabapentin 300 mg (n = 50), or acetaminophen 1000 mg (n = 50) all twice a day for 12 weeks. Pain severity using visual analogue scale (VAS) and functional status using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were measured before, 2 weeks, 1 month, and 3 months after intervention. RESULTS:WOMAC total and its subscale score were significantly lower in duloxetine compared to gabapentin in 2 weeks and 1 months after intervention, with no significant difference at the end of the third month. Both gabapentin and duloxetine groups had significantly more reduction in pain VAS and WOMAC and its subscales compared to acetaminophen group, with no significant difference between groups. CONCLUSIONS:Both gabapentin and duloxetine have similar and acceptable effects in pain reduction and improvement of functional status in patients with knee OA at the end of the third month's treatment. Duloxetine effects begin from the first weeks, while gabapentin effects begin gradually with the best at the end of the third month. KEY POINTS:• Medical treatment is used for releiving pain in knee osteoarthritis. • Gabapentin and duloxetine are both effective in reducing pain in knee osteoarthritis.
10.1007/s10067-019-04573-7
Histamine stimulates prostaglandin E production by rheumatoid synovial cells and human articular chondrocytes in culture.
Taylor D J,Yoffe J R,Brown D M,Woolley D E
Arthritis and rheumatism
Histamine stimulates prostaglandin E (PGE) production by cultures of adherent rheumatoid synovial cells and human articular chondrocytes. When subcultured synovial fibroblasts or human articular chondrocytes were "primed" by preincubation with conditioned media from primary adherent rheumatoid synovial cell cultures (synovial factor), each produced even higher PGE levels upon histamine exposure. This histamine stimulation was prevented by histamine H1, but not H2, antagonists and was more marked if serum was absent from the culture media. Thus, histamine-induced PGE production by these cells is mediated via H1 receptor activation and subsequent arachidonic acid liberation.
10.1002/art.1780290202
Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation.
Decaris E,Guingamp C,Chat M,Philippe L,Grillasca J P,Abid A,Minn A,Gillet P,Netter P,Terlain B
Arthritis and rheumatism
OBJECTIVE:To investigate involvement of the nervous system in ipsilateral and contralateral joint inflammation. METHODS:Freund's complete adjuvant (CFA; 1 mg or 1 microg) was injected unilaterally and the messages (a) from the hind paw to the ipsilateral and contralateral knees and (b) from one knee to the contralateral knee were analyzed. The degenerative impact of the local injury on distant cartilage was assessed using patellar proteoglycan synthesis as an indicator. Neurogenic mechanisms were blocked either by spinal cord compression or by injection of neurokinin 1 (NK-1) antagonist, or they were mimicked by intraarticular injection of substance P. The data were compared with those gathered in a model of systemic inflammation, characterized by fever and serum interleukin-6 production. RESULTS:After unilateral subcutaneous injection of CFA, proteoglycan anabolism decreased bilaterally. Spinal cord compression and administration of the NK-1 antagonist inhibited the response in the contralateral limb. Following 1 mg CFA subcutaneous injection, the ipsilateral response implicated both neurogenic and systemic mechanisms, whereas the nervous system alone was implicated after 1 microg subcutaneous CFA injection. The 1 microg CFA intraarticular injection induced a degenerative contralateral signal, which was abolished by spinal cord compression and by pretreatment with the NK-1 antagonist. Intraarticular injection of 1 microg CFA also induced an ipsilateral increase of anabolism, which was enhanced by spinal cord compression. Similar results were obtained after intraarticular injections of substance P. These effects were not reproduced with turpentine treatment, a systemic model, in which spinal cord compression had no effect. CONCLUSION:A unilateral inflammation can induce, by neurogenic mechanisms, distal bilateral degeneration of articular cartilage, implicating involvement of neuropeptides.
10.1002/1529-0131(199909)42:9<1951::AID-ANR22>3.0.CO;2-D
The effect of a single dose of preemptive pregabalin administered with COX-2 inhibitor: a trial in total knee arthroplasty.
Lee Jin Kyu,Chung Kyu-Sung,Choi Choong Hyeok
The Journal of arthroplasty
We sought to compare a group (Group L) (n=21) of patients that underwent total knee arthroplasty and received a single preoperative dose of pregabalin combined with a COX-2 inhibitor with a control group (Group C) (n=20) that only received a COX-2 inhibitor in terms of (1) acute postoperative pain intensity, (2) analgesic consumption, and (3) functional recovery. Mean cumulative fentanyl consumption during the first 48 hours was lower in Group L than in Group C (P<0.05). The pain scores at rest were lower in Group L at 6 and 12 hours after surgery (P<0.05). No significant intergroup difference was noted in functional recovery. The addition of pregabalin led to an additive reduction in early postoperative pain and analgesic consumption.
10.1016/j.arth.2014.04.004
Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses.
Lorenz J,Schäfer N,Bauer R,Jenei-Lanzl Z,Springorum R H,Grässel S
Osteoarthritis and cartilage
OBJECTIVE:Norepinephrine (NE) was measured in synovial fluid of trauma patients and sympathetic nerve fibers were detected in healthy and osteoarthritic (OA) joint tissues indicating that cartilage pathophysiology might be influenced by sympathetic neurotransmitters. The aim of this study was to elucidate the mostly unknown role of NE in OA chondrocyte metabolism and inflammatory responses. METHODS:Articular cartilage was received after total knee replacement surgery from OA patients. Expression of adrenergic receptors (AR) and tyrosine hydroxylase (TH) was tested with end point polymerase chain reaction (PCR) and immunohistochemistry. 3-dimensional (3D) cell cultures were employed to analyze effects of NE on chondrocyte cell metabolism and the expression of interleukins (ILs), matrix metalloproteases (MMPs), tissue inhibitor of metalloproteases (TIMPs), glycosaminoglycan (GAG) and collagen II under non- and inflammatory conditions. Chondrocyte monolayer cultures were used to specify AR subtypes, to analyze cell cycle distribution and to determine catecholamines in cell culture supernatants. RESULTS:AR subtypes and TH were detected in chondrocytes, whereas NE was not released in measurable amounts. 10(-6) M NE reversed IL-1β induced changes in IL-8, MMP-13, GAG and collagen II expression/production indicating for β-AR signaling. Additionally, NE caused cell cycle slow down and decreased proliferation via β-AR signaling. 10(-8) M NE increased the number of proliferating cells and induced apoptosis via α1-AR signaling. CONCLUSIONS:NE affects chondrocytes from OA cartilage regarding inflammatory response and its cell metabolism in a dose dependent manner. The sympathetic nervous system (SNS) may have a dual function in OA pathology with preserving a stable chondrocyte phenotype via β-AR signaling and OA pathogenesis accelerating effects via α-AR signaling.
10.1016/j.joca.2015.08.007
Evidence and recommendations for use of intra-articular injections for knee osteoarthritis.
Nguyen Christelle,Lefèvre-Colau Marie-Martine,Poiraudeau Serge,Rannou François
Annals of physical and rehabilitation medicine
Pharmacological treatments are widely recommended in international guidelines for management of osteoarthritis (OA). However, the use of intra-articular (IA) therapies of diverse active drugs remains controversial. We critically reviewed studies of the efficacy and safety of IA injections of corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and botulinum toxin A (BTA) and evidence-based international recommendations for their use in treating knee OA. The process of article selection was unsystematic. Articles were selected on the basis of authors' expertise, self-knowledge, and reflective practice. Only studies assessing knee OA were included. IA CS and HA injections were conditionally to fully recommended for treating knee OA. No recommendations have been formulated for IA PRP or BTA. The evidence remains inconsistent and controversial for the use of IA therapies for knee OA. The characteristics of and selection criteria for the OA population that would likely benefit from these therapies need to be identified. Accurately phenotyping and selecting patients is mandatory in future randomized controlled trials. Therefore, efficacy and safety meta-analyses should be performed, as should qualitative and sensitivity analyses of published trial results.
10.1016/j.rehab.2016.02.008
Do dorsal root reflexes augment peripheral inflammation?
Rees H,Sluka K A,Westlund K N,Willis W D
Neuroreport
Efferent activity was recorded in knee joint afferents in response to mechanical stimulation of the hindlimb following induction of acute arthritis. The activity was abolished by application of lidocaine or crushing the nerve proximally and by dorsal rhizotomy but not by sympathectomy. It was concluded that this activity represents dorsal root reflexes in response to natural stimulation of the hindlimb. We propose that increased activity of articular afferents and of dorsal horn neurons during arthritis results in the pathological activation of the central terminals of primary afferents by enhancing primary afferent depolarization. Dorsal root reflexes could then release substances in the knee joint and thus contribute to the acute inflammatory response.
10.1097/00001756-199403000-00021
[Efficacy and safety of amtolmetin guacyl in the treatment of acute osteoarthritis].
Biasi G,Marcolongo R
Minerva medica
BACKGROUND:This open phase IV multicentre trial was carried out to evaluate the efficacy and tolerability of amtolmethin guacyl in patients with acute osteoarthritis in at least one of the following locations: knee, hip, vertebral column. Amtolmethin guacyl is a drug belonging to the NSAID class whose action is comparable to that of other active ingredients belonging to the same class, but it is particularly interesting that a low incidence of collateral effects involving the gastric mucosa, equal to around 5%, has been reported in all clinical trials. It has been demonstrated that amtolmethin guacyl provokes an increased production of nitric oxide (NO), an important mediator of the gastric mucosa defence system through the induction of the nitric oxide synthetase (NOS) enzyme. METHODS:A total of 41 centres took part in the trial and an overall population of 388 patients were recruited. The protocol specified that the drug should be taken for one month at a dose of 1200 mg/die (2 tablets b.i.d.) for 3 days and 600 mg/die (1 tablet) for the remaining 27 days. At screening, after 7 days (T1) and at the end of treatment (T2), the parameters of efficacy were evaluated using a semiquantitative scale for the following symptoms: spontaneous pain and pain on movement, joint function and swelling. All patients were asked to keep a daily diary to evaluate gastric tolerability, whereas overall tolerability was evaluated by recording adverse effects and determining the common laboratory parameters. The statistical analysis was calculated both according to intention to treat (379 patients) and by protocol (372 patients), using Friedman's test to analyse the 4 scales of signs and symptoms (basal visit vs T1 vs T2). RESULTS:A statistically significant difference (p<0.01) was found in both analyses for all 4 parameters examined between the basal evaluation and the two evaluations during and post-treatment. CONCLUSIONS:The analysis of vital parameters, laboratory parameters and adverse effects confirmed the good tolerability of the product.
Tapentadol prolonged-release for moderate-to-severe chronic osteoarthritis knee pain: a double-blind, randomized, placebo- and oxycodone controlled release-controlled study.
Serrie Alain,Lange Bernd,Steup Achim
Current medical research and opinion
OBJECTIVE:To assess efficacy and safety of tapentadol prolonged release (PR) for moderate-to-severe chronic osteoarthritis knee pain. METHODS:Patients (n = 990) were randomized (1:1:1) to tapentadol PR, oxycodone controlled release (CR; reference compound for assay sensitivity), or placebo for a double-blind 3-week titration and 12-week maintenance period. Primary efficacy end-points were change from baseline in average pain intensity at week 12 of maintenance (US end-point) and over the entire maintenance period (non-US end-point) with "last observation carried forward" as imputation method for missing scores. RESULTS:Both primary end-points were not significantly different for tapentadol PR nor for oxycodone CR vs placebo at week 12 (least squares [LS] mean difference = -0.3 [95% CI = -0.61-0.09]; p = 0.152 and 0.2 [95% CI = -0.16-0.54]; p = 0.279, respectively) and over the maintenance period (LS mean difference = -0.2 [95% CI = -0.55-0.07]; p = 0.135 and 0.1 [95% CI = -0.18-0.44]; p = 0.421, respectively). Considerably more patients receiving tapentadol PR than oxycodone CR completed the trial (58.3% vs 36.6%). This is consistent with better results with tapentadol PR on the overall health status (PGIC) compared to oxycodone CR. Indeed, respectively, 56% and 42.5% rated at least "much improved" at the end of treatment. Incidences of gastrointestinal adverse events were higher for both active treatments compared to placebo. Tapentadol PR was associated with a better gastrointestinal tolerability profile with incidences of constipation (17.9% vs 35%) and of the composite of nausea and/or vomiting (23.8% vs 46.8%) significantly lower vs oxycodone CR (p < 0.001). CONCLUSIONS:The study did not demonstrate assay sensitivity. The finding that both primary end-points for tapentadol PR were not met can, thus, not be interpreted. Tapentadol PR was better tolerated than oxycodone CR, largely due to fewer gastrointestinal side-effects.
10.1080/03007995.2017.1335189
Differential changes of group II and group III mGluR function in central amygdala neurons in a model of arthritic pain.
Li Weidong,Neugebauer Volker
Journal of neurophysiology
Metabotropic glutamate receptors (mGluRs) play important roles in neuroplasticity and disorders such as persistent pain. Group I mGluRs contribute to pain-related sensitization and synaptic plasticity of neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC), although the roles of groups II and III mGluRs are not known. Extracellular single-unit recordings were made from 60 CeLC neurons in anesthetized adult rats. Background activity and evoked responses were measured before and during the development of the kaolin/carrageenan-induced knee-joint arthritis. Drugs were administered into the CeLC by microdialysis before and/or after arthritis induction. A selective group III mGluR agonist (LAP4) inhibited CeLC neurons' responses to stimulation of the knee and ankle in arthritis (n = 7) more potently than under normal conditions (n = 14). A selective group II agonist (LY354740) inhibited responses under normal conditions (n = 12) and became more potent in inhibiting responses to noxious stimulation of the knee in arthritis (n = 10). The effect of LY354740 on innocuous stimulation of the knee and stimulation of the ankle did not change in arthritis. Antagonists for groups II (EGLU, n = 9) and III (UBP1112, n = 8) had no effects under normal conditions. In arthritis, UPB1112 (n = 5) facilitated the responses to stimulation of knee and ankle, whereas EGLU (n = 5) selectively increased the responses to stimulation of the knee. These data suggest that mGluRs of groups II and III can inhibit nociceptive processing in CeLC neurons. The increased function and endogenous activation of group II mGluRs in the arthritis pain model appear more input-selective than the general changes of group III mGluRs.
10.1152/jn.00495.2006
Changes in plasma opioid concentrations after physiotherapeutic exercises for arthritic patients.
Jones C A,Rees J M,Dodds W N,Jayson M I
Neuropeptides
Plasma concentrations of [met]enkephalin (ME) and beta-endorphin (beta E) were measured in samples obtained immediately before and after physiotherapeutic exercises for patients with ankylosing spondylitis (AS), osteoarthritis (OA), or knee injuries. Correlations were sought between opioid peptide concentrations or changes therein, and nature, severity and duration of disease, age, severity of pain reported and pain threshold. No correlation was found with any of the pain parameters. However, there was a possible relationship between age or duration of disease and changes in ME concentrations.
Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis.
Weber Alexander E,Jalali Omid,Limfat Sean,Shkhyan Ruzanna,Van Der Horst Robert,Lee Siyoung,Lin Yucheng,Li Liangliang,Mayer Erik N,Wang Liming,Liu Nancy Q,Petrigliano Frank A,Lieberman Jay R,Evseenko Denis
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA. METHODS:Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage. RESULTS:Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls). CONCLUSION:The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.
10.1002/art.41250
Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis.
Niccoli L,Bellino S,Cantini F
Clinical and experimental rheumatology
OBJECTIVE:The primary endpoint of this study was to compare the renal tolerability of amtolmetin guacyl (AMG), diclofenac and rofecoxib in elderly patients with symptomatic osteoarthritis (OA). The assessment of efficacy was the secondary endpoint. METHODS:90 patients who satisfied the American College of Rheumatology classification criteria for hand, hip or knee OA were randomly assigned to 3 treatment groups receiving either: AMG 1,200 mg over thefirst 3 days and and 600 mg/day thereafter; diclofenac 150 mg/day; or rofecoxib 25 mg/day for 2 weeks. At baseline and after therapy patients were clinically assessed by the same examiner who was unaware of the treatment arm assignement. Serum and urinary parameters of renal function and the outcome measures of efficacy were evaluated before (t(0)) and after therapy (t(1)). RESULTS:Diclofenac produced a significant reduction in creatinine clearance (t(0) = 88.93 +/- 11.59; t(1) = 75.90 +/- 16.32; p: < 0.001) and in the daily urine volume (t(0) = 1,337.93 +/- 202.07; t(1) = 1,027.59 +/- 249.14; p: < 0.001). In the same treatment group a significant increase in serum creatinine, blood urea nitrogen, uric acid and potassium were observed. Rofecoxib treated patients showed a significant increase in body weight (t(0) = 75.31 +/- 4.26; t(1) = 76.54 +/- 4.84; p: < 0.001), systolic blood pressure (t(0) = 144 +/- 10.86; t(1) = 154 +/- 11.8; p < 0.001), diastolic blood pressure (t(0) = 80 +/- 6.05; t(1) = 89 +/- 7.66; p < 0.001) and serum sodium (t(0) = 138.73 +/- 1.28; t(1) = 140.12 +/- 1.80; p < 0.005) associated with a significant decrease in the daily urine volume (t(0) = 1294.64 +/- 205.21; t, = 1,115.48 +/- 238.47; p < 0.001) and creatinine clearance (t(0)= 86.73 +/- 8.14; t(1) = 83.15 +/- 7.96; p < 0.01). No significant changes in the clinical and humoral parameters were recorded in AMG treated patients. Diclofenac was more efficacious than the other 2 drugs (p < 0.001). No differences were observed between AMG and rofecoxib. Side effects related to altered kidney function were significantly higher in the rofecoxib group (p < 0.005). CONCLUSION:Diclofenac mainly impaired blood renal flow and the glomerularfiltration rate, while rofecoxib negatively influenced the renal sodium-water exchange. AMG demonstrated a renal sparing effect, although the eract mechanism is unclear
Aceclofenac increases the synthesis of interleukin 1 receptor antagonist and decreases the production of nitric oxide in human articular chondrocytes.
Maneiro E,López-Armada M J,Fernández-Sueiro J L,Lema B,Galdo F,Blanco F J
The Journal of rheumatology
OBJECTIVE:Interleukin 1 receptor antagonist (IL-1Ra) may play an important role in cartilage degradation by inhibiting IL-1 activity and therefore blocking IL-1 stimulation of prostaglandin E2 (PGE2) synthesis. Nitric oxide (NO) formation is increased during inflammation. High concentrations of NO exert negative effects on chondrocyte functions. We investigated the possible effects of 3 different nonsteroidal antiinflammatory drugs (NSAID; aceclofenac, piroxicam, aspirin) on IL-1Ra and NO production in human articular chondrocytes. METHODS:Normal and osteoarthritic (OA) cartilage samples were obtained from autopsy and prosthetic joint surgery, respectively. Chondrocytes were isolated and stimulated with 4 different stimuli: IL-1, tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), and insulin-like growth factor (IGF). The 3 NSAID were added simultaneously to each different concentration of stimulus. IL-1Ra was measured in supernatant by ELISA; nitrites were quantified by the Griess reaction; PGE2 level was measured by enzyme immunoassay. RESULTS:OA samples spontaneously produced higher levels of IL-1Ra than normal samples (130+/-2.3 vs 30+/-3.1 pg/mI). IL-1, TNF-alpha, and LPS produced dose dependent increases in synthesis of IL-1Ra. In their presence, IL-1Ra was detected in supernatant at 48 h, but its highest level was measured at 144 h. The most potent stimulus was IL-1, followed by TNF-alpha. Fetal bovine serum and IGF in turn did not modify the basal levels of IL-1Ra. In contrast to piroxicam and aspirin, aceclofenac 10 microg/ml and TNF-alpha 10 ng/ml increased almost 46 times the basal amount of IL-1Ra produced by OA chondrocytes. Additionally, aceclofenac and aspirin inhibited NO synthesis. Finally, the 3 NSAID reduced the levels of PGE2 detected after stimulation with IL-1. CONCLUSION:Proinflammatory stimuli induce IL-IRa synthesis in human articular chondrocytes. Aceclofenac may modulate PGE2 production by increasing IL-IRa production and decreasing NO synthesis. Some NSAID exert diverse prostaglandin independent effects.
Reduction in joint swelling and hyperalgesia following post-treatment with a non-NMDA glutamate receptor antagonist.
Sluka K A,Jordan H H,Westlund K N
Pain
The experimental arthritis of the knee joint used in the present study leads to joint swelling, increased joint temperature, limping, guarding, and a decrease in paw withdrawal latency (PWL) to radiant heat (hyperalgesia) within hours in rats. Unexpectedly, administration of the non-NMDA receptor antagonist, CNQX, in the spinal cord 4 h after initiation of the arthritis significantly reduced the degree of joint inflammation and returned PWL times to baseline. Therefore, the present results indicate that established joint swelling and hyperalgesia can be reduced significantly by CNQX.
10.1016/0304-3959(94)90052-3
Comparison between intra-articular Botulinum toxin type A, corticosteroid, and saline in knee osteoarthritis: a randomized controlled trial.
Clinical rehabilitation
OBJECTIVE:To compare the effectiveness of intra-articular injection (IAI) with Botulinum toxin type A (BTA), triamcinolone hexacetonide (TH), and saline in primary knee osteoarthritis. DESIGN:A randomized controlled trial, with blinded patients and assessor. SETTING:Outpatient rheumatology service. SUBJECTS:Patients with knee osteoarthritis grades II and III. INTERVENTIONS:Patients received IAI with 100 IU BTA, 40 mg TH, or isotonic saline solution (SS) 0.9%. MAIN MEASURES:Patients were assessed at baseline and at 4, 8, and 12 weeks with the following instruments: visual analog scale for pain during movement (VASm; primary outcome) and visual analog scale for pain at rest (VASr), Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, 6-minute walk test, Timed Up and Go test, Short Form (SF)-36 questionnaire, range of motion of knee, and ultrasound (US) measurement of synovial hypertrophy. RESULTS:In total, 105 patients were randomized, with 35 in each group; 96 were female (91.4%) and 9 were male (8.6%), with a mean age of 64.2 years (±6.9). At 12 weeks, the TH group showed better results only for VASm. At four weeks, the TH group showed better results than the BTA and SS groups for VASm (-68.9% (37.8) vs. -35.3% (40.3) vs. -35.9% (51.4)), WOMAC pain (-56.0% (30.7) vs. -30.8% (34.3) vs. -30.0% (39.9)), WOMAC stiffness (-53.4% (38.4) vs. -17.2% (59.3) vs. -17.3% (78.1)), WOMAC function (-48.2% (34.6) vs. 30.8% (33.6) vs. -13.6% (64.9)), WOMAC total score (-51.2% (31.0) vs. -30.9% (30.0) vs. -18.8% (54.8)), and US measurement of synovial hypertrophy (-11.6% (44.9) vs. -1.5% (47.9) vs. +28.6% (81.3)). CONCLUSION:IAI with TH had a higher effectiveness than that with TBA or SS in the short-term assessment (four weeks) for pain in movement, WOMAC, and US measurement of synovial hypertrophy.
10.1177/0269215519827996
Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis.
Alvarez-Soria M A,Herrero-Beaumont G,Moreno-Rubio J,Calvo E,Santillana J,Egido J,Largo R
Osteoarthritis and cartilage
OBJECTIVE:To simultaneously study the effect of a selective cyclooxygenase-2 (COX-2) inhibitor and that of a classic non-steroidal anti-inflammatory drug (NSAID) on the expression of pro-inflammatory genes in the cartilage of patients with severe knee osteoarthritis (OA) and in cultured human OA chondrocytes. METHODS:A 3-month clinical trial was carried out on 30 patients with severe knee OA scheduled for knee replacement surgery. Patients were randomized into two groups: patients treated with celecoxib (CBX) and patients treated with aceclofenac (ACF). OA patients who did not want to be treated served as the control group. After surgery, cartilage was processed for molecular biology studies. We also employed cultured chondrocytes from different OA patients to examine NSAID effects on pro-inflammatory gene expression in cells stimulated with interleukin (IL)-1beta. RESULTS:Both CBX and ACF inhibited COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and inducible nitric oxide synthase (iNOS) synthesis in the articular cartilage of OA patients. In cultured chondrocytes, both NSAID decreased COX-2 and mPGES-1 synthesis and prostaglandin E2 (PGE2) release induced by IL-1beta, while no effect was observed on nitric oxide or iNOS synthesis. In OA patients, only CBX decreased tumor necrosis factor alpha and IL-1beta expression in the cartilage, while both NSAID diminished IL-1beta induced cytokine synthesis in cultured OA chondrocytes. CONCLUSIONS:Both NSAID diminished PGE2 release and induced a decrease in COX-2 and mPGES-1 synthesis in the cartilage from OA patients and in OA chondrocytes. These data suggest that prolonged therapy with PGE2 blocking agents decreases PGE2 production not only by direct inhibition of COX-2 activity, but also by down-regulating COX-2 and mPGES-1 synthesis in the cartilage. However, CBX and ACF seem to have a different anti-inflammatory profile in controlling pro-inflammatory gene expression in the cartilage.
10.1016/j.joca.2008.04.022
Glatiramer acetate inhibits degradation of collagen II by suppressing the activity of interferon regulatory factor-1.
Lu Huading,Zeng Chun,Zhao Huiqing,Lian Liyi,Dai Yuhu
Biochemical and biophysical research communications
Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of osteoarthritis (OA).Interferon regulatory factor 1 (IRF-1) is an important transcriptional factor accounting for inflammation response induced by TNF-α. The physiological function of IRF-1 in OA is still unknown. In this study, we reported that the expression levels of IRF-1 in OA chondrocytes were significantly higher compared to those in normal chondrocytes, which was reversed by treatment with Glatiramer acetate (GA), a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). We also found that GA is able to attenuate the upregulation of IRF-1 induced by TNF-α. Matrix metalloproteinase13 (MMP-13) is one of the downstream target genes of IRF-1, which can induce the degradation of collagen II. Importantly, our results indicated that GA suppressed the expression of MMP-13 as well as the degradation of collagen II. In addition, GA also suppressed TNF-α-induced production of NO and expression of iNOS. Finally, we found that the inhibition of STAT1 activation played a critical role in the inhibitory effects of GA on the induction of IRF-1 and MMP-13. These data suggest that GA might have a potential effect in therapeutic OA.
10.1016/j.bbrc.2014.03.041
Effectiveness of Ultrasound-Guided Canal Adductor Blockade for Chronic Pain and Functioning in Knee Osteoarthritis: A Prospective Longitudinal Observational Study.
BioMed research international
METHODS:Seventy-seven patients with chronic knee osteoarthritis pain received ultrasound-guided ACB with 14 ml 0.25% levobupivacaine and 100 mcg clonidine. At baseline and 1 month after the blockade, we assessed maximal and minimal pain intensity in the knee using a numeric rating scale (NRS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). The range of motion in extension and flexion (ROMext and ROMflex) and quadriceps muscle strength of both knees (QS), Timed Up and Go Test (TUG), and 30-Second Chair Stand Test (30CST) results were determined at baseline, 1 hour, 1 week, and 1 month after the blockade. RESULTS:ACB with levobupivacaine and clonidine appeared to decrease pain severity (NRS 8.13 to 4.2, < 0.001 and NRS 3.32 to 1.40, < 0.001). Similarly, knee ROMext decreased from 3.90 preintervention to 2.89 postintervention at 1 month, < 0.001; ROMflex decreased from 5.70 to 3.29, < 0.001; TUG time decreased from 3.22 to 2.93, <0.001; QS increased from 18.43 to 22.77, < 0.001; CST increased from 8.23 to 10.74, < 0.001. The KOOS for pain (36.40 to 58.34), symptoms (52.55 to 64.32), activities of daily living functions (ADLs, 36.36 to 60.77), and quality of life (QoL, 17.87 to 30.97) also increased, all < 0.001. CONCLUSION:ACB appeared to decrease pain and increase ambulation. If our preliminary results are reproducible in a planned randomized controlled trial, ACB could be a useful adjunctive pain therapy in patients with disabling pain due to knee OA.
10.1155/2022/5270662
[Hydrogen sulfide in cartilage and its inhibitory effect on matrix metalloproteinase 13 expression in chondrocytes induced by interlukin-1β].
Pan L P,Cao Y P,Wen L C,Chai W B,DU J B,Jin H F,Liu J,Yang X,Meng Z C,Liu H,Cui Y P,Wang R,Wu H,Zhou X T,Li X,Li Z Y,Talatibaike M
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences
OBJECTIVE:To investigate whether endogenous hydrogen sulfide (H2S) was involved in the pathogenesis of osteoarthritis (OA) and its underlying mechanism, to detect H2S and its synthases expression in knee cartilage in patients diagnosed with different severity of OA, and to explore the transcription and expression of gene MMP-13 in chondrocytes treated with IL-1β or H2S. METHODS:Synovial fluids of the in-patients with different severity of OA hospitalized in Peking University First Hospital were collected for measurement of H2S content using methylene blue assay. Articular cartilages of the patients who underwent knee arthroplasty were collected for the cell culture of relatively normal chondrocytes. The chondrocytes were cultured to the P3 generation and H2S molecular probes were used for detection of endogenous H2S generation in the chondrocytes. Immunocytochemistry was used to detect the localization of H2S synthases including cystathionine β-synthase (CBS), cystathionine-γ-lyase (CSE), and mercaptopyruvate sulfurtransferase (MPST) in OA chondrocytes. Western blot was used to quantify the protein expressions of CSE, MPST, and CBS in cartilage tissues of the patients who were diagnosed with OA and underwent knee arthroplasty. The relatively normal human chondrocytes were cultured to passage 3 and then divided into 4 groups for different treatments: (1)the normal control group, no reagent was added; (2)the IL-1β group, 5 μg/L of IL-1β was added; (3)the IL-1β+H2S group, 200 μmol/L of NaHS was added 30 min before adding 5 μg/L of IL-1β;(4)the H2S group, 200 μmol/L of NaHS was added. The transcription and expression of gene MMP-13 in chondrocytes of each group were determined with Real-time PCR and Western blot, respectively. And the total NF-κB p65 and phosphorylated NF-κB p65 in chondrocytes were detected with Western blot. RESULTS:The content of H2S in the synovial fluid of degenerative knee was (14.3±3.3) μmol/L. Expressions of endogenous H2S and its synthases including CBS, CSE and MPST were present in the cytoplasm of chondrocytes.CSE protein expression in Grade 3 (defined by outerbridge grading) cartilage tissues was significantly increased as compared with that of Grade 1 cartilage tissues (1.67±0.09 vs. 1.26±0.11, P< 0.05). However, no significant difference of CBS or MPST expression among the different groups was observed. The expression of MMP-13 protein in the IL-1βgroup was significantly higher than that in the normal chondrocytes (1.87±0.67 vs. 0.22±0.10, P<0.05), and that in the IL-1β+H2S group was significantly decreased than that in the IL-1β group (0.55±0.11 vs. 1.87±0.67, P< 0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The transcription of MMP-13 protein in the IL-1β group was significantly higher than that in the normal chondrocytes (31.40±0.31 vs. 1.00±0.00, P<0.05), and that in the IL-1β+H2S group was significantly decreased than that in the IL-1β group (24.41±1.28 vs. 31.40±0.31, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The total NF-κB p65 in the IL-1β group was significantly higher than that in the normal chondrocytes (2.13±0.08 vs. 0.73±0.08, P< 0.05), and that in the IL-1β+H2S group was significantly decreased than that in the IL-1β group (1.24±0.13 vs. 2.13±0.08, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The phosphorylated NF-κB p65 in IL-1β group was significantly higher than that in the normal chondrocytes (1.30±0.13 vs. 0.19±0.04, P<0.05), and that in IL-1β+H2S group was significantly decreased than that in the IL-1β group (0.92±0.26 vs. 1.30±0.13, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. CONCLUSION:H2S affected the cartilage degeneration by partly inhibiting the degradation of extracellular matrix.
L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in plasma and synovial fluid of patients with knee osteoarthritis.
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND:The aim of this study was to investigate the involvement of the nitric oxide (NO) pathway in osteoarthritis (OA). MATERIAL AND METHODS:The study groups consisted of 32 patients with knee OA and 31 healthy controls. In peripheral venous blood samples (from the OA patients and the controls) and in synovial fluid samples (from the OA patients), the concentrations of L-arginine (ARN), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were evaluated. In plasma samples, thiobarbituric acid reactive substances (TBARS) were also measured. RESULTS:Plasma ARN concentrations were lower in the OA patients than in controls (53.55 ± 16.37 vs. 70.20 ± 25.68 µmol/l) (P<0.05), while plasma ADMA concentrations were similar. Accordingly, the ARN/ADMA ratio was lower in the OA patients than in the control group (80.85 ± 29.58 vs. 110.51 ± 30.48, P<0.05). Plasma SDMA and TBARS concentrations were higher in the OA patients than in controls (0.69 ± 0.15 vs. 0.60 ± 0.10 µmol/l, P<0.05 and 1.21 ± 0.29 vs. 0.55 ± 0.12, respectively) (P<0.001). In the OA patients, ADMA concentrations were significantly higher in the synovial fluid than in plasma (0.75 ± 0.09 vs. 0.69 ± 0.14 µmol/l, P<0.05), as were ARN concentrations (76.96 ± 16.73 vs. 53.55 ± 16.73 µmol/l) (P<0.00001). Conclusions These results indicate a poor availability of NO in the synovial fluid of the OA patients, which may contribute to the progression of OA. The decreased ARN/ADMA ratio and the increased SDMA and TBARS in the plasma of the OA patients suggest an impairment of endothelial function in these subjects.
10.12659/MSM.889275
Nitric oxide induced cell death in human osteoarthritic synoviocytes is mediated by tyrosine kinase activation and hydrogen peroxide and/or superoxide formation.
Jovanovic Dragan V,Mineau François,Notoya Kohei,Reboul Pascal,Martel-Pelletier Johanne,Pelletier Jean-Pierre
The Journal of rheumatology
OBJECTIVE:To investigate the regulation of osteoarthritis (OA) synovial fibroblast nitric oxide (NO) induced cell death. METHODS:Cultured synovial fibroblasts from human OA synovium were incubated with NO donor sodium nitroprusside (SNP) in the absence or presence of specific inhibitors of different protein kinases, cyclooxygenase-2 (COX-2), caspase-3 and caspase-9, inducible NO synthase, and in the absence or presence of prostaglandin E2 (PGE2). Experiments were also performed using scavengers of NO (carboxy-PXTO), peroxynitrite (uric acid), and superoxide (taxifolin). The level of cell death was measured by MTT and DNA fragmentation. RESULTS:Human OA synovial fibroblasts incubated with SNP decreased cell viability and increased DNA fragmentation in a dose dependent manner. This was associated with increased levels of both COX-2 and PGE2 production. Selective inhibition of COX-2 by NS-398 significantly inhibited SNP induced cell death, even in the presence of exogenously added PGE2. Experiments revealed that SNP treated cells expressed increased levels of active caspase-3 and caspase-9, while Bcl-2 was downregulated. Incubation of these treated cells with inhibitors of caspase-3 (Z-DEVD-FMK) or caspase-9 (Z-LEHD-FMK) protected viability of SNP treated OA synovial fibroblasts, indicating that NO mediated cell death was mainly related to apoptosis. This was also confirmed by measuring the DNA fragmentation (TUNEL method) and the level of active caspase-3 (immunocytochemistry) in these cells. Data also showed that SNP induces the activation of kinases MEK 1/2, p38, and tyrosine kinases. Specific inhibition of tyrosine kinases completely abrogated the SNP induced cell death. In turn, this cell death protection was associated with a marked inhibition of caspase-3 and caspase-9 activities, as well as COX-2/PGE2 production. Moreover, data showed that the NO donor SNP induced cell death was not solely related to the production of NO or peroxynitrite, but to the generation of reactive oxygen species (ROS) such as hydrogen peroxide and/or superoxide. CONCLUSION:Our results provided strong evidence of the role of tyrosine kinase and mitogen activated protein kinase activation, by upregulation of COX-2 expression, in NO induced OA synovial fibroblast death. The generation of ROS such as hydrogen peroxide and superoxide appeared to be a major factor in the death of these cells.
[A study of opioid peptides in synovial fluid and synovial tissue in patients with rheumatoid arthritis].
Suzuki N,Yoshino S,Nakamura H
Arerugi = [Allergy]
Authors have often experienced that psychological stress influences rheumatoid arthritis (RA). In addition, recent reports show a modulatory role for neuropeptide such as substance P in arthritis. These findings prompted us to study endogenous opioid peptides in RA, which are found mainly in the brain and have an effect on the central nervous system. We examined methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk) and beta-endorphin (beta-end) in opioid peptides. We measured these peptides in plasma and synovial fluid samples obtained from 28 knees of 24 RA patients and the quantity in the synovial tissue of 13 knees. We also measured plasma and synovial fluid samples from patients with osteoarthritis of the knee and plasma samples from healthy candidates. Leu-enk and beta-end levels in synovial fluid were significantly higher than plasma levels only in RA. Larger quantity of Leu-end and beta-end were contained apparently in the synovial tissue than Met-enk. The synovial tissue with proliferative change tends to contain larger quantity of opioid peptides. These results indicate that the synovial tissue produces or secretes Leu-enk and beta-end and that opioid peptides are related to the degree of inflammation in RA.
An I2 imidazoline ligand, RS 45041, potentiates hyperalgesia in acute arthritis.
Houghton A K,Westlund K N
Neuroreport
Descending inhibition is increased after the induction of inflammation of the knee. The present study investigated whether this effect is mediated through alpha 2-adrenoceptors and/or I2 imidazoline receptors in the rat. An alpha 2-adrenoceptor antagonist, RX 821002, a selective I2 imidazoline ligand, RS 45041, and idazoxan, which has affinity for both these receptor types, were administered. After the induction of acute arthritis by intra-articular injection of kaolin and carrageenan, the agents binding to I2 imidazoline receptors further reduced the paw withdrawal latency to radiant heat beyond that induced by acute arthritis, i.e. these drugs were pronociceptive, potentiating hyperalgesia. These results suggest that I2 imidazoline receptors have an important role to play in modulation of hyperalgesia during acute inflammation. Development of I2 imidazoline drugs may prove useful in the treatment of hyperalgesia.
10.1097/00001756-199606170-00011
Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene.
Warner S C,Walsh D A,Laslett L L,Maciewicz R A,Soni A,Hart D J,Zhang W,Muir K R,Dennison E M,Leaverton P,Rampersaud E,Cooper C,Spector T D,Cicuttini F M,Arden N K,Jones G,Doherty M,Valdes A M
European journal of pain (London, England)
BACKGROUND:Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK ). SP and NK receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA. METHODS:Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed. RESULTS:Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10 , OR = 0.79 95% 0.68-0.90 after meta-analysis). CONCLUSIONS:This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA. SIGNIFICANCE:This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested.
10.1002/ejp.1027
Interleukin-1β and tumor necrosis factor-α increase stiffness and impair contractile function of articular chondrocytes.
Chen Cheng,Xie Jing,Rajappa Ravikumar,Deng Linhong,Fredberg Jeffrey,Yang Liu
Acta biochimica et biophysica Sinica
Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are major proinflammatory cytokines involved in osteoarthritis (OA). These cytokines disturb chondrocyte metabolism by suppressing the synthesis of extracellular matrix proteins and stimulating the release of catabolic proteases, but little is known about their role in chondrocyte mechanics. Thus, the aim of this study was to measure the effects of IL-1β and TNF-α on the mechanical properties of the chondrocytes. Chondrocytes from goat knee joints were cultured in 96-well plates. The cellular stiffness and contractile function were probed using optical magnetic twisting cytometry, the cytoskeleton and the expression of extracellular matrix proteins were visualized using immunofluorescent staining, and chondrocyte phenotypical expression was measured by western blot analysis. Results showed that chondrocyte stiffness was dramatically decreased by disruption of F-actin but was unaffected by disruption of the intermediate filament vimentin. Treatment with 10 ng/ml IL-1β or 40 ng/ml TNF-α for 24 h substantially increased the expression level of F-actin and cellular stiffness, and impaired cell stiffening in response to the contractile agonist histamine, but these effects were blocked by the Rho-associated protein kinase inhibitor Y27632. In conclusion, IL-1β and TNF-α substantially change the mechanical properties of the chondrocytes in vitro. While changes of chondrocyte mechanics in vivo during OA progression remain unclear, this finding reveals a prominent role of these cytokines in cellular mechanics and provides insight for anti-cytokine therapies of OA.
10.1093/abbs/gmu116
Intra-articular botulinum toxin type A for treatment of knee osteoarthritis: Clinical trial.
Najafi Sharif,Sanati Ehsan,Khademi Mahsa,Abdorrazaghi Fateme,Mofrad Reza Kazempoor,Rezasoltani Zahra
Toxicon : official journal of the International Society on Toxinology
In recent years, there is a growing interest in new medical applications of botulinum toxin, including pain control, osteoarthritis treatment, and wound healing. While clinical applications of botulinum toxin seem promising, existing evidence regarding the therapeutic effects is still inadequate. The aim was to assess the efficacy of a single injection of abobotulinumtoxin A into the knee joint cavity to reduce pain in elderly people. We carried out a single group clinical trial in a University Hospital. Thirty participants (24 women) more than 50 years of age with knee osteoarthritis were included. Diagnosis of osteoarthritis was based on clinical and radiologic findings. We gave a single injection containing 250 units of Dysport (= 100 units of botulinum neurotoxin type A) diluted with 5 ml of normal saline. The primary outcome measure was knee pain. The secondary outcome was the patients' opinion about their knee and associated problems measured with the Knee injury and Osteoarthritis Outcome Score. The outcomes were measured at the baseline and at 4 weeks after the intervention. Within-group comparisons based on the Knee injury and Osteoarthritis Outcome Scores showed favorable results for joint pain and stiffness, sports, severity of symptoms, quality of life, and daily activities (all p-values < 0.001). Also, pain intensity, joint effusion, knee clicking and locking, and flexion-extension scores showed significant beneficial results (all p-values ≤ 0.005). We concluded that botulinum neurotoxin type A is an effective and safe initial treatment of knee osteoarthritis with clear clinical advantages. Patients' satisfaction, minimum adverse effects in addition to single-dose prescription make the toxin as a choice for the first-line therapy of osteoarthritis at least at the short-term in elderly people. The symptom relief increases the patient's compliance and willing to participate in other therapeutic programs. REGISTRATION: Iranian Registry of Clinical Trials (IRCT) website http://www.irct.ir/, a WHO Primary Register setup, with registration code: Irct ID: IRCT20180416039323N1.
10.1016/j.toxicon.2019.04.003
Decreased production of inflammatory mediators in human osteoarthritic chondrocytes by conjugated linoleic acids.
Shen Chwan-Li,Dunn Dale M,Henry Jack H,Li Yong,Watkins Bruce A
Lipids
Osteoarthritic chondrocytes (OC) produce excessive prostaglandin E2 (PGE2) and nitric oxide (NO), which function as inflammation mediators in the pathogenesis of osteoarthritis (OA). This study examined the effect of CLA alone and in combination with other PUFA on the FA composition and the production of PGE2 and NO in OC cultures isolated from OA patients. Human OC were grown in monolayer and treated with one of the following PUFA treatments: CLA, CLA + arachidonic acid (CLA/AA), CLA + EPA (CLA/EPA), linoleic acid (LA), LA + AA (LA/AA), LA + EPA (LA/EPA), and ethanol (as a vehicle control) at 10 and 20 microM for 6 d. Supplementation of PUFA at 10 microM for 6 d did not introduce any cytotoxic effects or morphological changes in OC, whereas 20 microM resulted in apoptosis. Cultures of OC treated with CLA, CLA/AA, and CLA/EPA had higher concentrations of CLA isomers, and these isomers were not detected in other treatments. Supplementation of CLA or LA alone to the OC led to a lower PGE2 production compared to the control. Combination of CLA/EPA resulted in the lowest PGE2 production in cultured OC. OC cultures treated with CLA were lower in NO production than the control, whereas the LA/AA treatment demonstrated the lowest NO production. The fact that CLA alone or in combination with other PUFA modulated PGE2 and NO production in human OC cultures suggests that these 18:2 isomers may have the potential to influence OA pathogenesis.
Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol.
Bianchi M,Broggini M,Balzarini P,Baratelli E,Ferrario P,Panerai A E,Sacerdote P
International immunopharmacology
Both the analgesic drugs tramadol and paracetamol are widely used for the symptomatic therapy of osteoarthritis (OA). The aim of this double-blind, randomised study in patients with knee OA was to compare their effects on synovial fluid concentrations of interleukin (IL)-6 and substance P (SP). Moreover, we evaluated plasma and synovial fluid concentrations of tramadol and its active metabolite (O-desmethyl-tramadol, M1) after oral treatment with this drug. Twenty patients were enrolled. A group of 10 patients received tramadol (50 mg three times a day), and another group of 10 patients were treated with paracetamol (500 mg three times a day) for 7 days. Both drugs significantly reduced the intensity of joint pain. The synovial fluid concentrations of SP were significantly reduced only by the treatment with tramadol. In this group of patients, IL-6 synovial fluid concentrations were slightly, but not significantly, decreased. Paracetamol did not significantly change the synovial fluid concentrations of SP and IL-6. After oral administration, a considerable amount of tramadol was measurable in synovial fluid. Both in plasma and synovial fluid the concentrations of M1 were markedly lower than those of tramadol, with a T/M1 ratio of 14.7+/-4.6 and 9.3+/-3.9, respectively. These data demonstrate that the activity of tramadol may involve the modulation of inflammatory mediators. Moreover, they indicate that after oral treatment with tramadol, both the parent drug and its active metabolite can penetrate into synovial fluid.
10.1016/j.intimp.2003.08.011
Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis.
Liu Y Z,Jackson A P,Cosgrove S D
Osteoarthritis and cartilage
OBJECTIVES:The role of calcium phosphate and pyrophosphate crystals in osteoarthritis (OA) is unclear: are they a symptom of the damage that occurs to the joint or a key intermediate in the progression of inflammation and joint damage that occurs in OA? The proinflammatory and catabolic response of synthetic calcium phosphate and pyrophosphate crystals and crystals extracted from human osteoarthritic knee cartilage has been investigated. The crystal forms eliciting a response have been characterised allowing a comparison of the biological effects of synthetic and native calcium crystals on human osteoarthritic chondrocytes and synoviocytes to be carried out. METHODS:Calcium phosphate and pyrophosphate crystals were synthesised in vitro and their crystal forms characterised by X-ray powder diffraction (XRPD). The inorganic crystalline material present in human osteoarthritic cartilage was extracted and its structural composition elucidated by XRPD. These crystals were applied to human primary osteoarthritic chondrocytes and synoviocytes and the production of proinflammatory and catabolic mediators measured. RESULTS:The crystals extracted from human osteoarthritic knee cartilage were identified as consisting of a mixture of monoclinic and triclinic calcium pyrophosphate dihydrate (m-CPPD and t-CPPD). These crystals elicited an inflammatory and catabolic response in human primary osteoarthritic chondrocytes and synoviocytes as measured by an increase in nitric oxide (NO), matrix metalloproteinase 13 (MMP-13) and prostaglandin E2 (PGE(2)) production. NO, MMP-13 and PGE(2) production was also increased when the synthetic calcium hydrogen phosphate dihydrate (DCPD) and calcium pyrophosphate hydrates were applied to the cells. CONCLUSIONS:Crystals extracted from human osteoarthritic knee cartilage induce the production of proinflammatory and catabolic mediators (NO, MMP-13 and PGE(2)) in human primary chondrocytes and synoviocytes. Synthetic calcium phosphate and pyrophosphate crystals elicit a similar response in those cells. Our findings suggest that these crystals could contribute to cartilage degradation and synovitis in OA.
10.1016/j.joca.2009.04.022
Phase 2 enzyme inducer sulphoraphane blocks prostaglandin and nitric oxide synthesis in human articular chondrocytes and inhibits cartilage matrix degradation.
Kim Hyun-Ah,Yeo Yunshin,Jung Hyun A,Jung Young O,Park Su J,Kim Song J
Rheumatology (Oxford, England)
OBJECTIVE:We explored the inhibitory effect of sulphoraphane (SFN), a potent inducer of Phase 2 enzymes, on cytokine-induced prostaglandin E(2) (PGE2) and nitric oxide (NO) production and cartilage degradation in articular chondrocytes. The regulatory mechanism of SFN on nuclear factor (NF)-κB was investigated. METHODS:Chondrocytes were obtained from patients with knee OA. Chondrocytes were stimulated with IL-1β or TNF-α with or without pre-incubation with SFN. Production of PGE2 and NO was evaluated by the Griess reaction and an ELISA. The expression of microsomal PGE synthase (mPGES), cyclo-oxygenase (COX)-2 and inducible NO synthase (iNOS) was evaluated by real-time RT-PCR and western blot analysis. The regulation of NF-κB activity was explored using luciferase and chromatin immunoprecipitation assays as well as a western blot for phosphorylated IκB kinase (IKK), IκB and the degradation of IκB. Proteoglycan and type II collagen degradation products released from explant cultures were analysed using the dimethylmethylene blue assay and an ELISA for C-terminal telopeptides of type II collagen. RESULTS:SFN inhibited the production of PGE2 and NO induced by IL-1β and TNF-α. At a concentration as low as 5 μM, SFN completely inhibited mPGES, COX-2 and iNOS at the mRNA and protein levels, and proteoglycan and type II collagen degradation product release in explant culture. Various signalling pathways required for the NF-κB activation were affected by SFN. CONCLUSION:SFN inhibited a broad range of catabolic mechanisms in articular chondrocytes. SFN may be a safe and effective candidate drug for the inhibition of cartilage degradation in arthritic diseases.
10.1093/rheumatology/ker525
SIRT1 regulation of apoptosis of human chondrocytes.
Takayama Koji,Ishida Kazunari,Matsushita Takehiko,Fujita Norifumi,Hayashi Shinya,Sasaki Ken,Tei Katsumasa,Kubo Seiji,Matsumoto Tomoyuki,Fujioka Hiroyuki,Kurosaka Masahiro,Kuroda Ryosuke
Arthritis and rheumatism
OBJECTIVE:SIRT1 is known to inhibit apoptosis and to promote survival of various types of cells. However, the roles of SIRT1 in apoptosis of human chondrocytes have never been reported. We undertook this study to investigate the relationship of SIRT1 to apoptosis of human chondrocytes, which is a characteristic feature of osteoarthritis (OA). METHODS:The expression of SIRT1 in human chondrocytes was examined by reverse transcription-polymerase chain reaction, immunoblotting, and immunohistology of human cartilage samples. The expression of SIRT1 under catabolic, mechanical, and nutritional stresses was investigated by immunoblotting. To examine the effect of SIRT1 on apoptosis, SIRT1 was inhibited by small interfering RNA (siRNA) and activated by resveratrol during nitric oxide (NO)-induced apoptosis. TUNEL staining and immunoblotting of cleaved poly(ADP-ribose) polymerase (PARP) were performed to detect apoptosis. To examine the mechanisms of apoptosis, we used immunoblotting to determine the levels of cleaved caspases and mitochondria-related apoptotic signaling proteins, Bax and Bcl-2, in the mitochondrial fraction. RESULTS:SIRT1 expression was confirmed in human chondrocytes and human cartilage samples. All catabolic, mechanical, and nutritional stresses inhibited SIRT1 expression. SIRT1 inhibition by siRNA for SIRT1 increased the percentage of TUNEL-positive cells and increased the amounts of cleaved PARP and cleaved caspases 3 and 9 induced by NO. In contrast, treatment with resveratrol decreased the percentage of TUNEL-positive cells and decreased the amounts of cleaved PARP and cleaved caspases 3 and 9 induced by NO. Furthermore, in the mitochondrial fraction, SIRT1 inhibition by siRNA for SIRT1 increased the amount of Bax but reduced the amount of Bcl-2, while resveratrol reduced the amount of Bax but increased the amount of Bcl-2. CONCLUSION:These results indicate that SIRT1 regulates apoptosis in human chondrocytes through the modulation of mitochondria-related apoptotic signals. Further research on SIRT1 might contribute to resolving the pathogenesis of OA.
10.1002/art.24864
Tapentadol vs oxycodone for postoperative pain treatment the first 7 days after total knee arthroplasty: a randomized clinical trial.
Pain
ABSTRACT:Pain after total knee arthroplasty is a prevalent condition. This study compared the effectiveness of tapentadol extended-release (ER) 50 mg × 2, oxycodone controlled-release (CR) 10 mg × 2, and placebo, as added to a multimodal analgesic regime both in-hospital and at home the first week after total knee arthroplasty. The study was randomized and blinded for investigators, staff, outcome assessors, and patients. Follow-up included pain intensity on mobilization, pain at rest, worst pain in the previous 24 hours, and adverse effects measured on 0 to 10 numerical rating scales. A total of 134 patients in 3 study groups received their allocated intervention and were included in the analysis. The primary outcome pain on mobilization the 7 first postoperative days reported as area under the curve was 528.1 (SD 267.5, interquartile range (IQR) 356.6-665.4) for placebo, 427.2 (SD 203.9, IQR 303.6-544.3) for tapentadol ER, and 507.9 (SD 243.7, IQR 292.4-686.8) for oxycodone CR (P = 0.12). With the exception of constipation being less prevalent in the tapentadol ER group (P = 0.02), we found no significant differences between treatment groups for the secondary outcomes. Tapentadol ER as an add-on to multimodal analgesia did not significantly improve pain relief when compared to oxycodone CR or placebo. Constipation was lowest in the tapentadol ER group.
10.1097/j.pain.0000000000002026
Subacute pain after total knee arthroplasty.
Sauter Axel,Breivik Harald
Journal of pain & palliative care pharmacotherapy
Acute pain during and immediately after total knee arthroplasty (TKA) can be well controlled by spinal anesthesia, local infiltration analgesia, and peripheral nerve blocks; this enables early or fast-track rehabilitation. However, about half of patients have clinically significant pain in the following weeks. Active movements and rehabilitation of joint function, muscle strength, and ability to maintain balance and prevent falls all become more difficult when the joint is painful on movement. Intensive analgesic and antihyperalgesic treatment during the first few weeks after TKA surgery may reduce the risk of chronic pain after this operation, which is itself intended to remove the patient's chronic osteoarthritis pain. Spinal cord stimulation may be an effective option for patients with mainly neuropathic pain after TKA surgery.
10.3109/15360288.2014.911797
Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis.
Richardson Denise,Pearson Richard G,Kurian Nisha,Latif M Liaque,Garle Michael J,Barrett David A,Kendall David A,Scammell Brigitte E,Reeve Alison J,Chapman Victoria
Arthritis research & therapy
INTRODUCTION:Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA. METHODS:Thirty-two OA and 13 RA patients undergoing total knee arthroplasty were included in this study. Clinical staging was conducted from x-rays scored according to Kellgren-Lawrence and Larsen scales, and synovitis of synovial biopsies was graded. Endocannabinoid levels were quantified in synovial fluid by liquid chromatography-mass spectrometry. The expression of CB1 and CB2 protein and RNA in synovial biopsies was investigated. Functional activity of these receptors was determined with mitogen-activated protein kinase assays. To assess the impact of OA and RA on this receptor system, levels of endocannabinoids in the synovial fluid of patients and non-inflamed healthy volunteers were compared. The activity of fatty acid amide hydrolase (FAAH), the predominant catabolic endocannabinoid enzyme, was measured in synovium. RESULTS:CB1 and CB2 protein and RNA were present in the synovia of OA and RA patients. Cannabinoid receptor stimulation of fibroblast-like cells from OA and RA patients produced a time-dependent phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2 which was significantly blocked by the CB1 antagonist SR141716A. The endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) were identified in the synovial fluid of OA and RA patients. However, neither AEA nor 2-AG was detected in synovial fluid from normal volunteers. FAAH was active in the synovia of OA and RA patients and was sensitive to inhibition by URB597 (3'-(aminocarbonyl) [1,1'-biphenyl]-3-yl)-cyclohexylcarbamate). CONCLUSION:Our data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.
10.1186/ar2401
Descending Control of Nociceptive Processing in Knee Osteoarthritis Is Associated With Intracortical Disinhibition: An Exploratory Study.
Tarragó Maria da Graca L,Deitos Alícia,Brietzke Aline Patrícia,Vercelino Rafael,Torres Iraci L S,Fregni Felipe,Caumo Wolnei
Medicine
Based on the hypothesis that an imbalance in excitatory and inhibitory input is a central mechanism of knee osteoarthritis chronic pain (KOACP), this exploratory study had the following aims: to compare whether the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system indexed by the motor-evoked potential (MEP) and the cortical salient period (CSP) in patients with severe osteoarthritis (OA) and healthy controls; and to determine if there is correlation between the measures of intracortical inhibition (CSP, MEP) with changes on the numerical pain scale (NPS [0-10]) in KOACP during a conditioned pain modulation (CPM)-task considering the effect of self-reported function assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and analgesic use.In a cross-sectional study, we included females (n = 21), with disability by pain or stiffness due to KOACP and healthy controls (n = 10), aged 19 to 75 years. The motor cortex excitability parameters (MEP and CSP) were assessed using the transcranial magnetic stimulation. We assessed the pain and disability by the WOMAC, and change on NPS (0-10) during CPM-task.A Multivariate analysis of covariance revealed that the adjusted mean (SD) on the MEP amplitude was 13.53% higher in the OA than in healthy subjects (1.33 [0.49] vs 1.15 [0.13]), respectively (P = 0.16). The adjusted mean (SD) on the CSP observed in OA patients was 23.43% lower than in healthy subjects (54.54 [16.10] vs 70.94 [22.87]), respectively (P = 0.01). The function of the descending pain modulatory system assessed by change on NPS (0-10) during a CPM-task was negatively correlated with the cortical excitability parameter indexed by the CSP (P = 0.001). Also, the CSP was negatively correlated with the pain and disability assessed by the WOMAC index.These findings support the hypothesis that the change in cortical plasticity in KOACP is associated with less intracortical inhibition, as measured by the CSP. These results show that the neural change in the motor cortex in KOACP is associated with pain and disability levels, and also with decreased activation of the endogenous pain-modulating system by a CPM-task.
10.1097/MD.0000000000003353
Degeneration of normal articular cartilage induced by late phase osteoarthritic synovial fluid in beagle dogs.
Xu Qing Rong,Dong Ying Hai,Chen Shun Le,Bao Chun De,Du Hui
Tissue & cell
OBJECTIVE:To investigate the pathogenesis of late phase osteoarthritic (OA) synovial fluid (SF) on normal articular cartilage in vivo and provide an understanding of degenerative cartilage extending in OA joint. METHODS:A random knee, each of 8 beagle dogs, received anterior cruciate ligament transection (ACLT) and was confirmed to have late phase OA degenerative changes at 24 weeks after operation. Thereafter, one random elbow of each canine was injected with autologous late phase OA knee SF. The contralateral elbow was injected with normal saline (NS) of the same volume as SF aspirated from ACLT knee. These two groups of elbows were labeled "SF" and "NS". 8 other beagle dogs were left intact and placed in Group Control. After aseptic arthrocentesis was performed weekly on both elbows for 24 weeks, morphological changes were observed in the cartilage of the elbows, and expressions of 7 biological etiological factors of chondrocytes of the elbows were determined in Group SF, Group NS and Group Control, respectively. RESULTS:Morphological changes were observed in articular cartilage of the elbows in Group SF. Levels of unit area of collagen type I in the noncalcified, calcified and full zones of articular cartilage of the elbows in Group SF increased significantly. Level of unit area of collagen type III in the calcified zone of articular cartilage of the elbows in Group SF remained unchanged. Meanwhile, expressions of MMP-1 and MMP-3 of chondrocytes of the elbows in Group SF increased significantly. There was almost no difference between articular cartilage in Group NS and Group Control. CONCLUSION:Based on these results, we conclude that OA degeneration of normal articular cartilage can be independently induced by late phase OA SF. Endogenous OA biological etiological factor may be one of the reasons causing degenerative cartilage extending in OA joint.
10.1016/j.tice.2008.06.004
Long-Term Effectiveness and Tolerability of Pain Treatment with Tapentadol Prolonged Release.
Mateos Rafael Galvez,Bernal Daniel Samper,Morera Luis Miguel Torres,Ferri Cesar Margarit,Escobar Ana Esquivias
Pain physician
BACKGROUND:The central analgesic tapentadol prolonged release (PR) has proven effective and generally well tolerated in a broad range of chronic pain conditions. Long-term data of its use are still scarce. OBJECTIVES:To evaluate long-term effectiveness, tolerability, and safety of tapentadol PR in patients with severe chronic osteoarthritis (OA) knee pain or low back pain (LBP) who responded to tapentadol in 1 of 4 preceding 12-week phase 3b clinical trials. STUDY DESIGN:Open-label, uncontrolled, observational extension study of up to 72 weeks. SETTING:Fourteen centers in Spain. Protocol approval by the reference ethics committee for all the participating centers. METHODS:Eligible patients started the extension trial on the tapentadol PR dosage optimized for them in the preceding trial; dose adjustments were permitted throughout the extension. Treatment effectiveness outcomes included changes in pain intensity, sleep, state of health, quality of life, patient and clinician global impression of change, and patients' satisfaction with treatment. Patients with OA knee pain also answered the Western Ontario and McMaster Universities OA index, and patients with LBP with a possible neuropathic pain component completed neuropathic pain-related questionnaires. RESULTS:Eighty-three patients were enrolled: 40 with OA knee pain, 43 with LBP. The full analysis set consisted of 81 patients. Mean pain intensity remained relatively stable over the 72-week extension period with mean increases from baseline of 0.44 (95% confidence interval [CI], -0.1,1.0; Numeric Rating Scale) for all patients, 0.2 (95% CI, -0.5, 0.9) for patients with OA, and 0.68 (95% CI, -0.2, 1.6) for patients with LBP. State of health and quality of life baseline ratings were maintained; overall impression of change was "improved." Most patients (88.9%) reported at least good treatment satisfaction at the end of treatment. Mean daily tapentadol PR doses slightly increased from 313.3 ± 139.5 mg at baseline to 315.7 ± 140.1 mg at end of study. Uptitration was required for 8.4% of the patients, 4.8% had a dose reduction during the trial. Adverse events considered probably/likely or certainly related to tapentadol PR treatment by the investigator were documented for 18.1% of all patients, most commonly constipation (7.2%). Seven patients (8.4%) experienced adverse events leading to premature discontinuation. LIMITATIONS:An open-label design, stable concomitant analgesics (World Health Organization step I), and dose adjustments were allowed during the study. All patients had benefitted from tapentadol PR in preceding trials. CONCLUSIONS:Sustained pain relief and quality of life for up to 72 treatment weeks under relatively stable dosing, as well as the good safety profile, indicate the usefulness of tapentadol PR for patients who suffer from severe chronic OA knee pain and LBP with limited risk for tolerance development.
Dynamic in-vivo force transfer in the lapine knee loaded by quadriceps muscle contraction.
Leumann Andre,Fortuna Rafael,Leonard Tim,Valderrabano Victor,Herzog Walter
Clinical biomechanics (Bristol, Avon)
BACKGROUND:The rabbit knee is a frequently used model for experimental osteoarthritis (OA). Despite the acknowledged importance of joint loading in the onset and progression of OA, the load transfer in the three compartments of the intact rabbit knee remains unknown. Therefore, this study was aimed at determining load transfer in the three compartments for isometric, concentric, and eccentric knee extensor contractions. METHODS:Maximal and sub-maximal isometric, concentric, and eccentric knee extensor contractions were produced by electrical stimulation of the femoral nerve in 13 rabbits. Knee extensor forces were measured using a custom-built servomotor. Contact areas and pressure distributions were measured in the patello-femoral, and the medial and lateral tibio-femoral joints using Fuji Presensor film. FINDINGS:Contact areas and peak pressures increased with increasing quadriceps forces for all compartments. Maximal knee extensor forces, joint moments, and contact pressures reached values of 504 N, 5.5 Nm and 60 MPa, respectively. Force transfer in the patello-femoral joint was about twice that observed in the individual tibio-femoral joints. During isometric contractions, force transfer was higher in the medial compared to the lateral tibio-femoral joint, while this trend was reversed for dynamic contractions. INTERPRETATION:The results of this study suggest that the increasing muscular forces are transferred through an increased contact area, thereby limiting the increase in average contact pressure. These results may be used as reference data for contact pressures in the intact rabbit knee and may form the foundation for studies using the lapine knee as an experimental model of osteoarthritis.
10.1016/j.clinbiomech.2012.12.004
Effectiveness and tolerability of tapentadol prolonged release compared with prior opioid therapy for the management of severe, chronic osteoarthritis pain.
Clinical drug investigation
BACKGROUND:Tapentadol prolonged release (PR; 100-250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment. OBJECTIVE:The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR (50-250 mg twice daily) after direct rotation from World Health Organization (WHO) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability. METHODS:This open-label, phase 3b study (NCT00982280) was conducted from October 2009 through June 2010 (prematurely terminated due to slow recruitment and study drug shortages) in clinical care settings in Europe and Australia. The study population included patients with severe, chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening, responded to therapy (average pain intensity [11-point numerical rating scale-3 (NRS-3)] ≤5 at screening), and reported opioid-related adverse effects as their reason for changing analgesics. Patients switched directly from WHO step III therapy to tapentadol. Patients received oral tapentadol PR (50-250 mg twice daily) during 5-week titration and 7-week maintenance periods. Oral tapentadol immediate release (IR) was permitted (≤twice/day, ≥4 h apart) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids (combined dose of tapentadol [PR and IR] ≤500 mg/day). This study was planned to evaluate conversion to tapentadol PR, based on responder rate 1 (percentage of patients with same/less pain [NRS-3] versus Week -1) at Week 6 (primary endpoint), adverse events (AEs), and discontinuation rates. Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids (PR and PR plus IR formulations). RESULTS:Of 82 patients enrolled, 63 received study medication. In the per-protocol population, responder rate 1 at Week 6 (last observation carried forward) was 94.3 % (50/53; P < 0.0001 vs. the null hypothesis rate [<60 %]). Mean (standard deviation) pain intensity scores were 4.7 (0.66) at baseline, 2.5 (1.46) at Week 6, and 1.8 (1.41) at Week 12 in the main analysis population (change from baseline at Weeks 6 and 12, P < 0.0001). Tapentadol to transdermal buprenorphine equianalgesic ratios (PR [n = 48], 262.9:1; PR plus IR [n = 48], 281.1:1) and tapentadol to oral oxycodone equianalgesic ratios (PR [n = 4], 4.3:1; PR plus IR [n = 6], 4.6:1) were calculated for the main analysis population. In the safety population, prevalence of AEs reported as associated with prior opioids at Week -1 (reasons for rotation) and related to tapentadol treatment at Week 12 decreased over time; the most common were nausea (46.0 vs. 24.1 %) and constipation (31.7 vs. 7.4 %). Overall, 14.3 % of patients discontinued the study early; reasons included AEs (9.5 %), lack of efficacy (3.2 %), and withdrawal of consent (1.6 %). CONCLUSIONS:Significant improvements in effectiveness were observed for tapentadol PR (50-250 mg twice daily) versus WHO step III opioids in patients with severe, chronic osteoarthritis knee pain who previously responded to WHO step III therapy. Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies.
10.1007/s40261-013-0102-0
Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in central amygdala neurons.
Li Weidong,Neugebauer Volker
Journal of neurophysiology
The laterocapsular division of the central nucleus of the amygdala (CeA) is now defined as the "nociceptive amygdala" because of its high content of neurons that respond to painful stimuli. The majority of these neurons become sensitized in a model of arthritis pain. Here we address the role of G protein-coupled group I metabotropic glutamate receptor subtypes mGluR1 and mGluR5 in nociceptive processing under normal conditions and in pain-related sensitization. Extracellular single-unit recordings were made from 65 CeA neurons in anesthetized rats. Each neuron's responses to brief mechanical stimuli, background activity, receptive field size, and threshold were measured before and after induction of the kaolin/carrageenan mono-arthritis in one knee and before and during applications of agonists and antagonists into the CeA by microdialysis. All neurons received excitatory input from the knee(s) and responded most strongly to noxious stimuli. Before arthritis, a group I mGluR1 and mGluR5 agonist (DHPG, n = 10) potentiated the responses to innocuous and noxious stimuli. This effect was mimicked by an mGluR5 agonist (CHPG, n = 15). In the arthritis pain state (>6 h after induction), the facilitatory effects of DHPG (n = 9), but not CHPG (n = 7), increased. An mGluR1 antagonist (CPCCOEt) had no effect before arthritis (n = 12) but inhibited the responses of sensitized neurons in the arthritis pain state (n = 8). An mGluR5 antagonist (MPEP) inhibited brief nociceptive responses under normal conditions (n = 19) and prolonged nociception in arthritis (n = 8). These data suggest a change of mGluR1 function and activation in the amygdala in pain-related sensitization, whereas mGluR5 is involved in brief as well as prolonged nociception.
10.1152/jn.00485.2003
The glutamatergic N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the joint contribute to the induction, but not maintenance, of arthritic pain in rats.
Zhang Guo Hua,Yoon Young Wook,Lee Kyu Sang,Min Sun Seek,Hong Seung Kil,Park Ji Yong,Han Hee Chul
Neuroscience letters
To determine whether both the N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the knee joint contribute to the induction and/or maintenance of arthritic pain, we examined the effects of intra-articular injection of NMDA receptor antagonist dizocilpine (MK-801) and non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) on the decrease in weight load induced by carrageenan injection into the knee joint cavity in rats. Injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.25, 0.625 and 2.5 mM) immediately prior to carrageenan injection (2%, 40 microl) significantly prevented the pain-related behavior. However, injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.625 and 2.5 mM) 5 h after carrageenan injection had no effect on pain-related behavior. These results suggest that both the NMDA and non-NMDA receptors in the knee joint are involved in the induction, but not maintenance, of arthritic pain.
10.1016/j.neulet.2003.08.009
Onset of response with duloxetine treatment in patients with osteoarthritis knee pain and chronic low back pain: a post hoc analysis of placebo-controlled trials.
Williamson Owen D,Schroer Melissa,Ruff Dustin D,Ahl Jonna,Margherita Anthony,Sagman Doron,Wohlreich Madelaine M
Clinical therapeutics
BACKGROUND:Knowing when to change pain-medication strategy is not well researched and remains a gap in treating chronic pain. OBJECTIVE:Our aim was to determine how long to treat osteoarthritis (OA) knee pain and chronic low back pain (CLBP) with duloxetine before considering a change in medication strategy. METHODS:We employed a post hoc analysis of changes in pain-severity data from placebo-controlled studies of duloxetine treatment in nondepressed patients with OA knee pain and CLBP. The studies were selected for inclusion in the analyses based on similarity of study design. Pain severity was recorded daily in patient diaries using an ordinal 11-point numerical rating scale (0 = no pain to 10 = most severe pain). The weekly means of the daily 24-hour average pain severity ratings from these diaries were pooled within disease states. Moderate response was defined as at least a 30% reduction from baseline in pain severity, and minimal improvement was defined as <10% reduction from baseline. The probability of achieving at least moderate pain reduction during 3 months treatment with duloxetine was estimated by Kaplan-Meier methods in patients with no or minimal improvement after 2, 4, and 6 weeks of treatment, as well as in all patients who had not yet achieved a moderate response (<30% reduction in pain severity). RESULTS:There were 239 OA patients and 541 CLBP patients who were randomly assigned to treatment with duloxetine 60/120 mg/d. OA and CLBP patients with minimal improvement at 2 weeks of treatment had <40% probability of achieving a moderate response, and at 4 weeks of treatment their chances were reduced to <30% in OA patients and <25% in CLBP patients. In patients showing <30% improvement at week 2 of treatment, OA patients had a 62% probability of achieving a moderate response, and CLBP patients had a 52% probability for a moderate response, and at 4 weeks of treatment, their chances were reduced to <50% in OA patients and <40% in CLBP patients. CONCLUSIONS:Patients taking duloxetine for OA or CLBP who have <10% reduction in pain after 4 weeks of treatment have limited possibility for eventually achieving even moderate pain reduction by the end of 12 weeks. ClinicalTrials.gov identifier: NCT00433290, NCT00408421, NCT00424593, NCT00408876, NCT00767806.
10.1016/j.clinthera.2014.02.009
Regulation of nitric oxide production in osteoarthritic and rheumatoid cartilage. Role of endogenous IL-1 inhibitors.
Vuolteenaho Katriina,Moilanen Taemu,Hämäläinen Mari,Moilanen Eeve
Scandinavian journal of rheumatology
OBJECTIVE:To investigate the endogenous regulation of interleukin-1 (IL-1) cytokine network in osteoarthritic (OA) and rheumatoid (RA) cartilage in relation to nitric oxide (NO) production. METHODS:Cartilage specimen obtained from OA and RA patients undergoing knee replacement surgery were studied for iNOS expression, NO and IL-1 antagonist production in tissue culture. RESULTS:OA cartilage responded to IL-1beta-stimulation with higher NO production than RA cartilage, whereas there was no difference in NO synthesis between OA and RA samples when stimulated by TNFalpha or LPS. Interleukin-1 receptor antagonist (IL-1Ra) production was higher in RA cartilage than in OA cartilage, and its production was increased by NO synthase inhibitor 1400W. CONCLUSION:IL-1beta is a potent stimulator of NO production by the iNOS pathway in RA and more pronouncedly in OA cartilage. This process is regulated by cartilage derived IL-1 antagonists, and is implicated in cartilage destruction and synovial inflammation in OA and RA joints.
Inhibitory effect on nitric oxide production and free radical scavenging activity of Thai medicinal plants in osteoarthritic knee treatment.
Anuthakoengkun Areeya,Itharat Arunporn
Journal of the Medical Association of Thailand = Chotmaihet thangphaet
BACKGROUND:Thai medicine plants used for Osteoarthritis of knee (OA) treatment consist of twelve plants such as Crinumn asiaticum, Cleome viscosa, Drypetes roxburghii, Piper longum, Piper nigrum, Plumbago indica, Alpinia galanga, Curcuma aromatica, Globba malaccensis, Zingiber montanum, Zingiber officinale andZingiberzerumbet. They showedhighfrequency in OA formula. OBJECTIVE:To investigate inhibitory effect on LPS-induced nitric oxide (NO) release from RAW264. 7 cell and free radical scavenging activity usingDPPH assay of these ethanolic plant extracts. MATERIAL AND METHOD:Plant materials were extracted by maceration in 95% ethanol. Anti-inflammatory activity were tested on LPS-induced NO production. Free radical scavenging activity was performed by DPPH assay. RESULTS:All of ethanolic extracts exhibited potent inhibitory effect on NO release. The ethanolic extract of Z. zerumbet exhibited the highest inhibitory effect followed by Z. montanum and G. malaccensis, respectively. Except A. galanga and C. viscosa, all extracts possessed more influential than indomethacin (IC50 = 20.32±3.23 μLg/ml), a positive control. The investigation on antioxidant activity suggested that the ethanolic extracts of D. roxburghii, Z. officinale, Z. montanum, C. aromatic, A. galanga, P indica, G malaccensis, P nigrum exhibited antioxidant activity. By means ofD. roxburghii had the highest electron donating activity,followed by Z. officinale. Moreover both extracts were more effective than BHT apositive control (EC50 = 14.04±1.95 μg/ml). CONCLUSION:Thai medicinal plants had anti-inflammatory activity and could inhibit destruction of articular cartilage that corresponded to the traditional medicine and supported using these medicinal plants for OA treatment.
Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint.
Russell F A,Schuelert N,Veldhoen V E,Hollenberg M D,McDougall J J
British journal of pharmacology
BACKGROUND AND PURPOSE:The PAR(2) receptors are involved in chronic arthritis by mechanisms that are as yet unclear. Here, we examined PAR(2) activation in the rat knee joint. EXPERIMENTAL APPROACH:PAR(2) in rat knee joint dorsal root ganglia (DRG) cells at L3-L5, retrogradely labelled with Fluoro-gold (FG) were demonstrated immunohistochemically. Electrophysiological recordings from knee joint nerve fibres in urethane anaesthetized Wistar rats assessed the effects of stimulating joint PAR(2) with its activating peptide, 2-furoyl-LIGRLO-NH(2) (1-100 nmol·100 μL(-1) , via close intra-arterial injection). Fibre firing rate was recorded during joint rotations before and 15 min after administration of PAR(2) activating peptide or control peptide. Leukocyte kinetics in the synovial vasculature upon PAR(2) activation were followed by intravital microscopy for 60 min after perfusion of 2-furoyl-LIGRLO-NH(2) or control peptide. Roles for transient receptor potential vanilloid-1 (TRPV1) or neurokinin-1 (NK(1) ) receptors in the PAR(2) responses were assessed using the selective antagonists, SB366791 and RP67580 respectively. KEY RESULTS:PAR(2) were expressed in 59 ± 5% of FG-positive DRG cells; 100 nmol 2-furoyl-LIGRLO-NH(2) increased joint fibre firing rate during normal and noxious rotation, maximal at 3 min (normal; 110 ± 43%, noxious; 90 ± 31%). 2-Furoyl-LIGRLO-NH(2) also significantly increased leukocyte rolling and adhesion over 60 min. All these effects were blocked by pre-treatment with SB366791 and RP67580 (P < 0.05 compared with 2-furoyl-LIGRLO-NH(2) alone). CONCLUSIONS AND IMPLICATIONS:PAR(2) receptors play an acute inflammatory role in the knee joint via TRPV1- and NK(1) -dependent mechanisms involving both PAR(2) -mediated neuronal sensitization and leukocyte trafficking.
10.1111/j.1476-5381.2012.02120.x
Epigallocatechin-3-gallate inhibits interleukin-1beta-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: suppression of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor kappaB.
Singh Rashmi,Ahmed Salahuddin,Islam Najmul,Goldberg Victor M,Haqqi Tariq M
Arthritis and rheumatism
OBJECTIVE:The proinflammatory cytokine interleukin-1beta (IL-1beta) induces the production of high levels of nitric oxide (NO) in human chondrocytes. Green tea (Camellia sinensis) polyphenols are potent antiinflammatory agents and have been shown to inhibit NO production in tumor cell lines. In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on IL-1beta-induced production of NO in primary human osteoarthritis (OA) chondrocytes. METHODS:Human chondrocytes were derived from OA cartilage and were treated with EGCG (100 microM) and IL-1beta (2 ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) messenger RNA and protein expression was determined by real-time quantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. Production of NO was determined as nitrite in culture supernatant. Activation and translocation of nuclear factor kappaB (NF-kappaB), levels of inhibitor of nuclear factor kappaB (IkappaB), and NF-kappaB DNA binding activity were determined by Western blotting and a highly sensitive and specific enzyme-linked immunosorbent assay. Activity of IkappaB kinase was determined using in vitro kinase assay. RESULTS:Human chondrocytes cotreated with EGCG produced significantly less NO compared with chondrocytes stimulated with IL-1beta alone (P < 0.005). The inhibition of NO production correlated with the suppression of induction and expression of NF-kappaB-dependent gene iNOS. EGCG inhibited the activation and translocation of NF-kappaB to the nucleus by suppressing the degradation of its inhibitory protein IkappaBalpha in the cytoplasm. CONCLUSION:Our results indicate that EGCG inhibits the IL-1beta-induced production of NO in human chondrocytes by interfering with the activation of NF-kappaB through a novel mechanism. Our data further suggest that EGCG may be a therapeutically effective inhibitor of IL-1beta-induced inflammatory effects that are dependent on NF-kappaB activation in human OA chondrocytes.
10.1002/art.10443
Decreased response of rat knee joint blood vessels to phenylephrine in chronic inflammation: involvement of nitric oxide.
Badavi M,Khoshbaten A,Hajizadeh S
Experimental physiology
The effect of chronic inflammation induced by Freund's Complete Adjuvant (FCA) on rat articular blood vessels and knee joint diameter was investigated. Blood flow changes in response to phenylephrine (an 1-adrenoceptor agonist) in FCA-treated and contralateral knee joints were studied over a 40 day period, using the laser Doppler flowmetery (LDF) technique. Unilateral injection of FCA (0.2 ml) increased the injected knee diameter on all days examined post-injection (P < 0.001) and its maximum increase (53 +/- 2 %) was reached on day 3. After this, the diameter decreased gradually but did not return to its initial value. In control animals, topical application of 10-13-10- 7 mol phenylephrine onto the exposed joint capsule decreased blood flow dose dependently (11. 1 +/- 4.4 to 58.2 +/- 4.5 %, respectively, P < 0.001). Unilateral injection with FCA attenuated the phenylephrine response in both ipsilateral and contralateral knees compared with the response of control animals (5.2 +/- 1.6 to 48.3 +/- 6.1 % and 1.9 +/- 2.2 to 45. 3 +/- 5.6 %, respectively, P < 0.05). The reduction persisted for 3 weeks after FCA injection (ipsilateral for 21 days; contralateral for 30 days, P < 0.001). Subsequently the response returned towards normal. To avoid the influence of 2-adrenoceptors, yohimbine (an 2-adrenoceptor antagonist) was injected (0.5 mg kg-1, I.P.) 30 min before phenylephrine application. Yohimbine blocked the vasoconstrictor effect of 10-10-10-7 mol clonidine (an 2-adrenoceptor agonist, topical application) by 44-67.7 % inhibition, respectively (P < 0.001). Prazosin (an 1-adrenoceptor antagonist, 0.1 mg kg-1, I.P.) blocked the vasoconstrictor effect of phenylephrine (10-10-10-7 mol, topical application) effectively (42 to 69.8 % inhibition, respectively, P < 0.001). To assess the role of nitric oxide (NO) on the observed responses, N G-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) was applied topically (0.2 micromol) 5 min before phenylephrine application. L-NAME application at 7 and 14 days after FCA injection potentiated the vasoconstrictor response in the FCA-treated knee (P < 0.001) but had no significant effect on the contralateral knee. Blood pressure monitoring during phenylephrine, clonidine and L-NAME administration indicated that topical application of the drugs had no significant effect on the systemic blood pressure. These findings indicate that the vasoconstrictor response to phenylephrine was decreased in chronic inflammation and increased NO production could be involved.
Acute inflammation in the rat knee joint attenuates sympathetic vasoconstriction but enhances neuropeptide-mediated vasodilatation assessed by laser Doppler perfusion imaging.
Lam F Y,Ferrell W R
Neuroscience
The effect of sympathetic nerve stimulation and topical application of substance P and calcitonin gene-related peptide on the blood flow of the exposed rat knee joint capsule was investigated. The responses of normal animals were compared to those of animals with acutely inflamed joints induced by intra-articular injection of 2% carrageenan. Laser Doppler perfusion imaging was used to examine the spatial distribution of blood flow in the knee joint capsule. Animals with acute joint inflammation showed markedly reduced vasoconstrictor responses to sympathetic nerve stimulation, but enhanced vasodilator responses to both substance P and calcitonin gene-related peptide when compared to normal. Prior application of either substance P or calcitonin gene-related peptide to the normal joint attenuated sympathetic vasoconstrictor responses. In the acutely inflamed knee, sympathetic vasoconstriction was replaced by a vasodilator response in the presence of neuropeptides. The reduced effectiveness of sympathetically mediated vasoconstriction and enhanced responsiveness to substance P and calcitonin gene-related peptide could contribute to the hyperaemia characteristic of inflamed joints.
10.1016/0306-4522(93)90170-k
Thermal and mechanical antinociceptive action of spinal vs peripherally administered clonidine in the rat inflamed knee joint model.
Buerkle H,Schäpsmeier M,Bantel C,Marcus M A,Wüsten R,Van Aken H
British journal of anaesthesia
It has been demonstrated recently that in addition to its spinal analgesic actions, the alpha 2 adrenoreceptor agonist clonidine also has peripheral analgesic activity. Few data are available regarding the antinociceptive effects of spinal vs peripherally delivered clonidine in inflammatory pain. Thus we have studied spinal (intrathecal = i.t.) and peripheral (intra-articular = i.a.) administration of clonidine in the rat inflamed knee joint model. Thermal and mechanical antinociception was assessed in rats over 28 h using a modified Hargreaves box and von Frey hairs after induction of tonic persistent inflammatory pain by injection of a kaolin-carrageenan mixture into the right knee joint. Thirty minutes after injection of kaolin-carrageenan, clonidine was administered via an i.t. catheter or by i.a. injection into the right inflamed knee joint or by subcutaneous injection (s.c.) (highest effective intra-articular dose). The specific site of action was assessed using the alpha 2 antagonist yohimbine i.t., i.a. or s.c. Clonidine i.t. resulted in thermal and mechanical antinociception during ongoing inflammation, which was not enhanced by inflammation. In contrast, i.a. delivery of clonidine, which also produced a dose-dependent thermal and mechanical antinociceptive effect, revealed a leftward shift in the antinociceptive activity produced by ongoing inflammation. Yohimbine inhibited the antinociceptive action of clonidine at the site of delivery. We suggest that clonidine produces potent thermal and mechanical antinociception regardless of the route of administration. However, chronic inflammatory processing appears to enhance the antinociceptive efficacy of the peripheral alpha 2 agonist.
10.1093/bja/83.3.436
Intraneuronal substance P contributes to the severity of experimental arthritis.
Levine J D,Clark R,Devor M,Helms C,Moskowitz M A,Basbaum A I
Science (New York, N.Y.)
There is evidence that substance P is a peptide neurotransmitter of some unmyelinated primary afferent nociceptors and that its release from the peripheral terminals of primary afferent fibers mediates neurogenic inflammation. The investigators examined whether substance P also contributes to the severity of adjuvant-induced arthritis, an inflammatory disease in rats. They found that, in the rat, joints that developed more severe arthritis (ankles) were more densely innervated by substance P-containing primary afferent neurons than were joints that developed less severe arthritis (knees). Infusion of substance P into the knee increased the severity of arthritis; injection of a substance P receptor antagonist did not. These results suggest a significant physiological difference between joints that develop mild and severe arthritis and indicate that release of intraneuronal substance P in joints contributes to the severity of the arthritis.
10.1126/science.6208609
Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci.
LeGrand A,Fermor B,Fink C,Pisetsky D S,Weinberg J B,Vail T P,Guilak F
Arthritis and rheumatism
OBJECTIVE:In osteoarthritis (OA), a combination of biochemical and biomechanical factors may damage both menisci and articular cartilage. Nitric oxide (NO) and prostaglandin E2 (PGE2) have been implicated as mediators of inflammation in OA. The goals of this study were to determine if menisci from patients with OA produce NO and PGE2, and if the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor a (TNFalpha), and IL-17 augment NO and PGE2 production by these tissues. METHODS:Menisci were obtained from 17 patients (age 47-75 years) undergoing total knee replacement for OA. Tissue explants were cultured alone or with IL-1beta, IL-17, or TNFalpha, and the release of NO and PGE2 from the tissue as well as the presence of type 2 nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX-2) antigens were measured. RESULTS:All menisci constitutively produced NO, and significant increases in NO production were observed in the presence of IL-1beta, TNFalpha, or IL-17 (P < 0.05). The combination of IL-17 and TNFalpha significantly increased NO production compared with either cytokine alone. Basal and cytokine-stimulated NO synthesis was inhibited by the NOS inhibitors NG-monomethyl-L-arginine or N-3-aminoethylbenzylacetamidine (1400W). IL-1beta significantly increased PGE2 production. The combination of IL-1beta and TNFalpha had an additive effect on PGE2 production, while addition of IL-17 to TNFalpha or IL-1beta synergistically enhanced PGE2 production. Inhibition of NO production by 1400W significantly increased IL-1beta-stimulated PGE2 production, and inhibition of PGE2 production by the COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide significantly increased IL-17-stimulated NO production. CONCLUSION:Menisci from humans with OA spontaneously produced NO and PGE2 in a manner that was synergistically or additively augmented by cytokines. NO and PGE2 exhibited reciprocal regulatory effects on one another, suggesting that pharmaceutical agents designed to inhibit NOS2 or COX-2 production may in fact be influencing both pathways.
10.1002/1529-0131(200109)44:9<2078::AID-ART358>3.0.CO;2-J
An adenosine A2A receptor agonist reduces interleukin-8 expression and glycosaminoglycan loss following septic arthrosis.
Cohen Steven B,Leo Brian M,Baer Geoffrey S,Turner Maria A,Beck Gina,Diduch David R
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
The purpose of this study was to determine whether an adenosine A(2A) receptor agonist (ATL146e) might augment the current treatment regimen of antibiotics plus irrigation and debridement to prevent the arthritic effects associated with joint sepsis. Staphylococcus aureus bacteria were injected into knees of rabbits, which were divided into 4 treatment groups (12 rabbits per group): no treatment, ATL146e only, antibiotics only, or antibiotics plus ATL146e. Analysis at days 1, 3, and 7 consisted of gross joint appearance, synovial fluid, serum, histologic, immunohistochemical, and biochemical analysis. Synovial fluid cultures at day 7 were negative in all antibiotic and antibiotic plus ATL146e treated knees indicating clearance of bacteria. Average WBC counts from synovial fluid aspirates significantly decreased with treatment of antibiotics alone and antibiotics plus ATL146e. Treatment with antibiotics plus ATL146e significantly decreased the Interleukin-8 content when compared to other treatment groups (p<0.001) indicating inflammatory response suppression. Histologic grading resulted in notably improved scores in the antibiotics plus ATL146e group compared to other treatment groups (p < or =0.001). Glycosaminoglycan assay values were significantly greater in the ATL146e plus antibiotics group compared to the untreated control group (p<0.04) indicating chondroprotection. The results of this study indicate that administration of an adenosine A(2A) agonist in combination with antibiotic therapy diminishes joint WBC chemotaxis and reduces joint inflammation, while not compromising the clearance of intraarticular bacteria in a rabbit model. Early bacterial clearance with modulation of the inflammatory response appears to prevent the early degradative effects of joint sepsis.
10.1016/j.orthres.2005.01.015
Interplay of vitamin D and nitric oxide in post-menopausal knee osteoarthritis.
Abu El Maaty Mohamed A,Hanafi Rasha S,El-Badawy Samir,Gad Mohamed Z
Aging clinical and experimental research
AIM:Mounting evidence has presented nitric oxide (NO) and vitamin D (vitD) as having independently complex roles in osteoarthritis (OA). However, a mechanistic or an observational connection between them has never been investigated in the disease. This study investigates the correlation between circulating 25-hydroxyvitamin D [25(OH)D] and total NO as nitrate/nitrite (NO x ) in patients with knee OA. METHODS:The recruited subjects comprised 36 post-menopausal women with knee OA, ages 50-60 years, as well as 10 healthy males, 20-30 years of age. 25(OH)D and NO x levels were determined using high-performance liquid chromatography and spectrophotometrically using Griess reaction, respectively. RESULTS:The mean (SEM) 25(OH)D and NO x concentrations of OA patients were 25.0 (1.6) ng/mL and 32.45 (2.18) μM, respectively, and 35.4 (2.1) ng/mL and 25.49 (2.23) μM, respectively, for controls. Comparison of mean 25(OH)D and NO x concentrations of OA patients and controls yielded significant results (P = 0.001 and 0.034, respectively). NO notably decreased with decreasing 25(OH)D concentration in patients. However, significant results in terms of mean NO x concentration were observed in the comparison of normal and deficient vitD OA groups (P = 0.048). CONCLUSION:Results suggest that vitD increases NO production and inducible NO synthase expression in osteoarthritic chondrocytes possibly leading to a protective effect.
10.1007/s40520-013-0192-9
Functional role of hedgehog pathway in osteoarthritis.
Xiao Wen-Feng,Li Yu-Sheng,Deng Ang,Yang Yun-Tao,He Miao
Cell biochemistry and function
The hedgehog signalling pathway is one of the key regulators of metazoan development, and it plays an important role in the regulation of a variety of developmental and physiological processes. But it is aberrantly activated in many human diseases, including osteoarthritis (OA). In this study, we have reviewed the association of hedgehog signalling pathway in the development and progression of OA and evaluated the efforts to target this pathway for the prevention of OA. Usually in OA, activation of hedgehog induces up-regulation of the expression of hypertrophic markers, including type X collagen, increases production of nitric oxide and prostaglandin E2, several matrix-degrading enzymes including matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs in human knee joint cartilage leading to cartilage degeneration, and thus contributes in OA. Targeting hedgehog signalling might be a viable strategy to prevent or treat OA. Chemical inhibitors of hedgehog signalling is promising, but they cause severe side effects. Knockdown of HH gene is not an option for OA treatment in humans because it is not possible to delete HH in larger animals. Efficient knockdown of HH achieved by local delivery of small interfering RNA in future studies utilizing large animal OA models might be a more efficient approach for the prevention of OA. However, it remains a major problem to develop one single scaffold due to the different physiological functions of cartilage and subchondral bones possess. More studies are necessary to identify selective inhibitors for efficiently targeting the hedgehog pathway in clinical conditions.
10.1002/cbf.3448
Bone sialoprotein as a potential key factor implicated in the pathophysiology of osteoarthritis.
Pesesse L,Sanchez C,Walsh D A,Delcour J-P,Baudouin C,Msika P,Henrotin Y
Osteoarthritis and cartilage
OBJECTIVE:We previously identified an association between bone sialoprotein (BSP) and osteoarthritic (OA) chondrocyte hypertrophy but the precise role of BSP in ostearthritis (OA) has not been extensively studied. This study aimed to confirm the association between BSP and OA chondrocyte hypertrophy, to define its effect on molecules produced by chondrocytes and to analyse its association with cartilage degradation and vascular density at the osteochondral junction. METHOD:Human OA chondrocytes were cultivated in order to increase hypertrophic differentiation. The effect of parathyroid hormone-related peptide (PTHrP), interleukin (IL)-1β or tumour necrosis factor (TNF)-α on BSP was analysed by real-time reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of BSP on OA chondrocytes production of inflammatory response mediators (IL-6, nitric oxide), major matrix molecule (aggrecan), matrix metalloprotease-3 and angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, IL-8, and thrombospondin-1) were investigated. BSP was detected by immunohistochemistry and was associated with cartilage lesions severity and vascular density. RESULTS:PTHrP significantly decreased BSP, confirming its association with chondrocyte hypertrophy. In presence of IL-1β, BSP stimulated IL-8 synthesis, a pro-angiogenic cytokine but decreased the production of TSP-1, an angiogenesis inhibitor. The presence of BSP-immunoreactive chondrocytes in cartilage was associated with the severity of histological cartilage lesions and with vascular density at the osteochondral junction. CONCLUSION:This study supports the implication of BSP in the pathology of OA and suggests that it could be a key mediator of the hypertrophic chondrocytes-induced angiogenesis. To control chondrocyte hypertrophic differentiation is promising in the treatment of OA.
10.1016/j.joca.2014.01.010
Articular cartilage degradation is prevented by tanshinone IIA through inhibiting apoptosis and the expression of inflammatory cytokines.
Jia Pei-Tong,Zhang Xing-Lin,Zuo Hai-Ning,Lu Xing,Li Lin
Molecular medicine reports
The present study aimed to investigate the effect of tanshinone IIA on the degradation of articular cartilage in a rat model of osteoarthritis (OA). The OA rat model was established by anterior cruciate ligament transection (ACLT) and medial meniscus resection (MMx). The animals were treated for 28 days with 0.25‑0.5 mg/kg doses of tanshinone IIA following ACLT + MMx. The knee joints of the rats in the ACLT + MMx group exhibited marked alterations in articular cartilage histopathology and higher Mankin scores, compared with those in the normal group. Tanshinone IIA treatment at a dose of 0.5 mg/kg significantly inhibited cartilage degradation and improved Mankin scores in the OA rat model (P<0.002). Tanshinone IIA treatment completely inhibited the ACLT + MMx‑induced accumulation of inflammatory cells and disintegration of synovial lining in the rats. An increase in the dose of tanshinone IIA between 0.25 and 0.5 mg/kg reduced the proportion of apoptotic chrondrocytes from 41 to 2% on day 29. Treatment of the rats in the ACLT + MMx group with 0.5 mg/kg doses of tanshinone IIA markedly inhibited the expression level of matrix metalloproteinase and increased the expression of tissue inhibitor of metalloproteinase in the rat articular cartilage tissues. Tanshinone IIA treatment significantly reduced the levels of inflammatory cytokines, including interleukin‑1β, tumor necrosis factor‑α and nitric oxide in rat serum samples. The protein expression levels of bone morphogenetic protein and transforming growth factor‑β were significantly increased by tanshinone IIA in the ACLT + MMx rats. Therefore, tanshinone IIA inhibited articular cartilage degradation through inhibition of apoptosis and expression levels of inflammatory cytokines, offering potential for use in the treatment of OA.
10.3892/mmr.2017.7340
A quantitative approach to measure joint pain in experimental osteoarthritis--evidence of a role for nitric oxide.
Castro R R,Cunha F Q,Silva F S,Rocha F A C
Osteoarthritis and cartilage
OBJECTIVES:To describe a method to study joint pain in experimental osteoarthritis (OA) and to study nitric oxide (NO) participation in experimental OA. DESIGN:Rats were subjected to anterior cruciate ligament transection (ACLT) (OA group) of the right knee and evaluated during 28 days. A sham group was false operated and a naive group received no manipulation. Joint pain was measured by recording the time the right hind paw fails to touch the surface while walking. Cell influx (CI) and nitrite levels were measured in joint exudates. Expression of inducible NO synthase (iNOS) in synovia was detected by immunostaining. For the specific purpose of pharmacological manipulation, groups received either indomethacin (2 mg/kg/day s.c. (subcutaneous)), meloxicam (6 mg/kg/day s.c.), morphine (200 microg intra-articularly), the non-selective NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME; 30 mg/kg/bid i.p. (intra-peritoneal)) or the selective iNOS inhibitor 1400W (0.5 mg/kg/day s.c.), given 30 min prior (prophylactic) or 4 days after (therapeutic) ACLT, until sacrifice, at 7 days. The respective non-treated groups received the vehicles. RESULTS:The OA group developed joint pain, as compared to sham and control groups (P<0.05). Significantly increased nitrite levels and iNOS immunostaining were seen in the OA group. Both indomethacin and meloxicam inhibited joint pain (P<0.05). Morphine inhibited joint pain, whereas this effect was blocked by co-administration of the mu-opioid receptor naloxone. CI was similar among all groups. Prophylactic but not therapeutic L-NAME or 1400W reduced joint pain. CONCLUSION:We describe a method to quantitate joint pain associated to weight bearing in the ACLT model. The joint pain is sensitive to classical antinociceptive compounds. NO release is associated to joint pain though NOS inhibition does not inhibit ongoing pain.
10.1016/j.joca.2006.01.013
Chondrocyte apoptosis and regional differential expression of nitric oxide in the medial meniscus following partial meniscectomy.
Kobayashi K,Mishima H,Hashimoto S,Goomer R S,Harwood F L,Lotz M,Moriya H,Amiel D
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Partial medial meniscectomy leads to tibial articular cartilage degeneration. Nitric oxide (NO) production increases with the development of osteoarthritis (OA) and has been shown to have a catabolic effect on chondrocytes. Since distribution of chondrocytic and fibroblastic cell types within the total cell population comprising meniscus is region-specific, we compared NO production in the peripheral and central regions of the medial meniscus 12 weeks after partial medial meniscectomy and assessed chondrocyte apoptosis and NO production in the tibial articular cartilage. Additionally, transcriptional gene expression of inducible nitric oxide synthetase (iNOS) and immunohistochemical staining of nitrotyrosine were examined. The results showed that following partial medial meniscectomy, NO production in the central region of the medial meniscus and in the tibial articular cartilage were significantly higher than respective NO levels in normal and sham-operated controls. Reverse transcription polymerase chain reaction (RT-PCR) revealed a high transcriptional expression of the iNOS gene in the central region of the meniscus and in tibial articular cartilage following partial medial meniscectomy. Nitrotyrosine immunoreactivity was prominent in the central region of the medial meniscus and in the deep layer of the tibial articular cartilage and apoptotic cells were also detected in situ in the superficial zone of the tibial articular cartilage and central regions of the medial meniscus following partial medial meniscectomy. These observations suggest that the central region of the meniscus is responsible for NO synthesis associated with apoptosis in both meniscal and articular cartilage cells following partial meniscectomy.
10.1016/S0736-0266(01)00023-7
Nicotine Attenuates Osteoarthritis Pain and Matrix Metalloproteinase-9 Expression via the α7 Nicotinic Acetylcholine Receptor.
Teng Peng,Liu Yuan,Dai Yan,Zhang Haijun,Liu Wen-Tao,Hu Jun
Journal of immunology (Baltimore, Md. : 1950)
Osteoarthritis (OA) is a degenerative joint disease that causes chronic disability among the elderly. Despite recent advances in symptomatic management of OA by pharmacological and surgical approaches, there remains a lack of optimal approaches to manage inflammation in the joints, which causes cartilage degradation and pain. In this study, we investigated the efficacy and underlying mechanisms of nicotine exposure in attenuating joint inflammation, cartilage degradation, and pain in a mouse model of OA. A mouse model of OA was induced by injection of monosodium iodoacetate into the knee joint. Cell culture models were also used to study the efficacy and underlying mechanisms of nicotine treatment in attenuating symptoms of OA. Nicotine treatment reduced mechanical allodynia, cartilage degradation, and the upregulation of matrix metalloproteinase-9 (MMP-9), a hallmark of joint inflammation in OA, in mice treated with monosodium iodoacetate. The effects of nicotine were abolished by the selective α7 nicotinic acetylcholine receptor (nAChR) blocker, methyllycaconitine . In RAW264.7 cells and murine primary bone marrow-derived macrophages, nicotine significantly inhibited MMP-9 production induced by LPS. In addition, nicotine significantly enhanced PI3K/Akt and inhibited NF-κB translocation from the cytosol to the nucleus in an α7-nAChR-dependent manner, suggesting that nicotine acts on α7-nAChRs to inhibit MMP-9 production by macrophages through modulation of the PI3K/Akt-NF-κB pathway. Our results provide novel evidence that nicotine can attenuate joint inflammation and pain in experimental OA via α7-nAChRs. α7-nAChR could thus serve as a highly promising target to manage joint inflammation and pain in OA.
10.4049/jimmunol.1801513
Mast cells are important regulator of acupoint sensitization via the secretion of tryptase, 5-hydroxytryptamine, and histamine.
Ding Ning,Jiang Jing,Qin Pingping,Wang Qiaoxia,Hu Jiatong,Li Zhigang
PloS one
Mast cells (MCs) play a crucial role in mediating the establishment of networks among the circulatory, nervous and immune system at acupoints. However, the changes which occur in MCs during acupoint sensitization, i.e. the dynamic transformation of an acupoint from a "silenced" to an "activated" status, remain uncharacterized. To investigate the morphological and functional changes of MCs as an aid to understanding the cellular mechanism underlying acupoint sensitization, a rat model of knee osteoarthritis (OA) was induced by an injection of mono-iodoacetate (MIA) on day 0. On day 14, toluidine blue and immunofluorescence staining were used to observe the recruitment and degranulation of MCs and the release of mast cell co-expressed mediators: tryptase, 5-hydroxytryptamine (5-HT) and histamine (HA) at the acupoints Yanglingquan (GB34), Heding (EX-LE2) and Weizhong (BL40). Results showed that the number of MCs as well as the percentages of degranulated and extensively degranulated MCs at the acupoints GB34 and EX-LE2 in the light (A), mild (B), heavy (C) osteoarthritis groups were larger than those in the normal control (N) and normal saline (NS) groups (p < 0.01). Comparisons among the A, B and C groups suggested that the number and the degranulation extent of the MCs at the acupoints GB34 and EX-LE2 were positively correlated with the severity of the disease. Some MCs in the A, B and C group showed the release of 5-HT, HA, and tryptase in degranulation at the acupoints GB34 and EX-LE2. Such changes in MCs were not observed at the acupoint BL40. In conclusion, this study confirmed that acupoint sensitization is associated with the increase in recruitment and degranulation levels of MCs on a acupoint-specific and disease severity-dependent manner. The release of tryptase, 5-HT, and HA during MC degranulation is likely to be one of the cellular mechanisms occurring during acupoint sensitization.
10.1371/journal.pone.0194022
A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis.
Steels Elizabeth,Venkatesh Ruchitha,Steels Eleanor,Vitetta Gemma,Vitetta Luis
Inflammopharmacology
BACKGROUND:The aim of the study was to assess the safety, tolerability and efficacy of palmitoylethanolamide (PEA) when dosed at 300 mg and 600 mg per day on symptoms of knee osteoarthritis. METHODS:This was a single site, comparative, double-blind placebo controlled study in adults with mild to moderate knee osteoarthritis with 111 participants randomized to receive 300 mg PEA, 600 mg PEA or placebo each day, in divided doses b.i.d, for 8 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The secondary outcomes were the Numerical Rating Scales (NRS) for pain, the Depression Anxiety Stress Scale (DASS), the Perceived Stress Scale (PSS), the Pittsburg Sleep Quality Index (PSQI), the Short Form Health Survey (SF-36), the use of rescue pain medication and clinical safety assessment. RESULTS:There was a significant reduction in the total WOMAC score in the 300 mg PEA (p = 0.0372) and the 600 mg PEA (p = 0.0012) groups, the WOMAC pain score (300 mg PEA, p = 0.0074; 600 mg PEA, p = < 0.001), the WOMAC stiffness score (PEA 300 mg, p < 0.0490; 600 mg PEA, p = 0.001) and in the WOMAC function score in the 600 mg PEA group (p = 0.033) compared to placebo. The NRS pain evaluations for "worst pain" and "least pain" were significantly reduced in the 300 mg PEA group (p < 0.001, p = 0.005) and the 600 mg PEA group (p < 0.001, p < 0.001) compared to placebo. There was a significant reduction in anxiety (DASS) in both active treatment groups (300 mg PEA, p = 0.042; 600 mg PEA group (p = 0.043) compared to placebo. There were no changes in the clinical markers and the product was well tolerated. CONCLUSIONS:The study demonstrated that palmitoylethanolamide may be a novel treatment for attenuating pain and reducing other associated symptoms of knee osteoarthritis. Further studies on the pharmacological basis of this anti-inflammatory effect are now required.
10.1007/s10787-019-00582-9
The chondroprotective agent ITZ-1 inhibits interleukin-1beta-induced matrix metalloproteinase-13 production and suppresses nitric oxide-induced chondrocyte death.
Kimura Haruhide,Yukitake Hiroshi,Suzuki Hirobumi,Tajima Yasukazu,Gomaibashi Koyo,Morimoto Shinji,Funabashi Yasunori,Yamada Kiyofumi,Takizawa Masayuki
Journal of pharmacological sciences
In a screening program aimed at discovering anti-osteoarthritis (OA) drugs, we identified an imidazo[5,1-c][1,4]thiazine derivative, ITZ-1, that suppressed both interleukin-1beta (IL-1beta)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1beta-induced cartilage proteoglycan degradation in rat knee joints. ITZ-1 did not inhibit enzyme activities of various matrix metalloproteinases (MMPs), which have pivotal roles in cartilage degradation, while it selectively inhibited IL-1beta-induced production of MMP-13 in human articular chondrocytes (HAC). IL-1beta-induced MMP production has been shown to be mediated by extracellular signal-regulated protein kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) family signal transduction molecules. An ERK-MAPK pathway inhibitor (U0126), but not a p38 kinase inhibitor (SB203580) or a JNK inhibitor (SP600125), also selectively inhibited IL-1beta-induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1beta-induced ERK activation without affecting p38 kinase and JNK activation, which may account for its selective inhibition of MMP-13 production. Inhibition of nitric oxide (NO)-induced chondrocyte apoptosis has been another area of interest as a therapeutic strategy for OA, and ITZ-1 also suppressed NO-induced death in HAC. These results suggest that ITZ-1 is a promising lead compound for a disease modifying anti-OA drug program.
Efficacy and safety of combination of curcuminoid complex and diclofenac versus diclofenac in knee osteoarthritis: A randomized trial.
Medicine
BACKGROUND:To compare the efficacy and safety of combination of curcuminoid complex and diclofenac vs diclofenac alone in the treatment of knee osteoarthritis (OA). METHODS:In this randomized trial, 140 patients of knee OA received either curcuminoid complex 500 mg (BCM-95) with diclofenac 50 mg 2 times daily or diclofenac 50 mg alone 2 times daily for 28 days. Patients were assessed at baseline, day 14 and day 28. Primary efficacy measures were Knee injury and OA outcome score (KOOS) subscale at day 14 and day 28. Anti-ulcer effect and patient-physician's global assessment of therapy at day 28 were included as secondary endpoints. Safety after treatment was evaluated by recording adverse events and laboratory investigations. RESULTS:Both treatment groups showed improvement in primary endpoints at each evaluation visit. Patients receiving curcuminoid complex plus diclofenac showed significantly superior improvement in KOOS subscales, viz. pain and quality of life at each study visit (P < .001) when compared to diclofenac. Less number of patients required rescue analgesics in curcuminoid complex plus diclofenac group (3%) compared to diclofenac group (17%). The number of patients who required histamine 2 (H2) blockers was significantly less in curcuminoid complex plus diclofenac group compared to diclofenac group (6% vs 28%, respectively; P < .001). Adverse effects were significantly less in curcuminoid complex plus diclofenac group (13% vs 38% in diclofenac group; P < .001). Patient's and physician's global assessment of therapy favored curcuminoid complex plus diclofenac than diclofenac. CONCLUSION:Combination of curcuminoid complex and diclofenac showed a greater improvement in pain and functional capacity with better tolerability and could be a better alternative treatment option in symptomatic management of knee OA. TRIAL REGISTRATION:ISRCTN, ISRCTN10074826.
10.1097/MD.0000000000019723
Double-blind parallel comparison of multiple doses of apraclonidine, clonidine, and placebo administered intra-articularly to patients undergoing arthroscopic knee surgery.
Tan Ping-Heng,Buerkle Hartmut,Cheng Jiin-Tsuey,Shih Hsun-Chang,Chou Wen-Ying,Yang Lin-Cheng
The Clinical journal of pain
OBJECTIVE:This clinical study assessed and compared the potential analgesic and adverse effect of IA apraclonidine with IA clonidine. METHODS:Eighty patients scheduled for arthroscopic knee surgery under general anesthesia were randomized to receive, in a double-blind manner, either IA normal saline (group 1), 50 microg IA apraclonidine (group 2), 150 microg IA apraclonidine (group 3), or 150 microg IA clonidine (group 4), all in a volume of 20 mL subsequent to surgery. Visual analog pain scores (VAS), the duration of analgesia as defined by the time to first demand for supplemental analgesics, the subsequent 24-hour consumption of postoperative supplementary analgesics, and patient adverse effects were evaluated. RESULTS:The patients from groups 3 and 4 demonstrated a longer duration of analgesia and used fewer analgesics in the first postoperative 24 hour period compared with group 1 and 2 patients (P < 0.05). The VAS scores corresponding to the periods 1, 2, and 4 hours postoperatively were significantly lower for group 3 than for group 1 patients. The VAS scores at 1 and 4 hours postoperatively were also lower for group 3 than for group 2 patients (P < 0.05). There was no significant difference in the incidence of side effects among the 4 groups. DISCUSSION:The IA application of 150 microg apraclonidine and 150 microg clonidine provide similar degree of postoperative analgesia following knee arthroscopic surgery without any difference in adverse events.
10.1097/00002508-200407000-00007
Effect of Methylprednisolone in Periarticular Infiltration for Primary Total Knee Arthroplasty on Pain and Rehabilitation.
Kulkarni Mahesh,Mallesh Mahadevappa,Wakankar Hemant,Prajapati Ravikumar,Pandit Hemant
The Journal of arthroplasty
BACKGROUND:Optimal pain management after total knee arthroplasty (TKA) is important to ensure timely rehabilitation and patient satisfaction. This study examines the efficacy of adding corticosteroid in periarticular infiltration cocktail with relation to postoperative pain management and rehabilitation in patients undergoing simultaneous bilateral TKA. METHODS:Fifty patients with symptomatic end-stage bilateral knee osteoarthritis undergoing bilateral TKA under the same anesthetic were recruited. More painful knee was operated first, and the study solution containing ropivacaine, clonidine, epinephrine, and ketorolac with methylprednisolone was infiltrated in one knee and an identical mixture but without methylprednisolone was infiltrated in the second knee. Outcome measures included comparison of visual analogue scale on movement of each knee and range of motion achieved during the first three days after surgery. RESULTS:Differences in visual analogue scale score and range of motion at day one and three between the two groups of knees were significant (P < .05). Postoperative inflammation and the ability to straight leg raise showed better trends in the knees receiving prednisolone although this did not reach statistical significance. CONCLUSION:Addition of methylprednisolone to periarticular infiltration cocktail for patients undergoing TKA has significant influence on reduction of pain in the early postoperative period and patients are able to regain knee flexion more quickly.
10.1016/j.arth.2019.04.060
METTL3-mediated mA modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression.
Annals of the rheumatic diseases
OBJECTIVE:The aim of the study was to investigate the role and regulatory mechanisms of fibroblast-like synoviocytes (FLSs) and their senescence in the progression of osteoarthritis (OA). METHODS:Synovial tissues from normal patients and patients with OA were collected. Synovium FLS senescence was analysed by immunofluorescence and western blotting. The role of methyltransferase-like 3 (METTL3) in autophagy regulation was explored using N6-methyladenosine (mA)-methylated RNA and RNA immunoprecipitation assays. Mice subjected to destabilisation of the medial meniscus (DMM) surgery were intra-articularly injected with or without pAAV9 loaded with small interfering RNA (siRNA) targeting METTL3. Histological analysis was performed to determine cartilage damage. RESULTS:Senescent FLSs were markedly increased with the progression of OA in patients and mouse models. We determined that impaired autophagy occurred in OA-FLS, resulting in the upregulation of senescence-associated secretory phenotype (SASP). Re-establishment of autophagy reversed the senescent phenotype by suppressing GATA4. Further, we observed for the first time that excessive mA modification negatively regulated autophagy in OA-FLS. Mechanistically, METTL3-mediated mA modification decreased the expression of autophagy-related 7, an E-1 enzyme crucial for the formation of autophagosomes, by attenuating its RNA stability. Silencing METTL3 enhanced autophagic flux and inhibited SASP expression in OA-FLS. Intra-articular injection of synovium-targeted METTL3 siRNA suppressed cellular senescence propagation in joints and ameliorated DMM-induced cartilage destruction. CONCLUSIONS:Our study revealed the important role of FLS senescence in OA progression. Targeted METTL3 inhibition could alleviate the senescence of FLS and limit OA development in experimental animal models, providing a potential strategy for OA therapy.
10.1136/annrheumdis-2021-221091
Neutrophil Recruitment and Articular Hyperalgesia in Antigen-Induced Arthritis are Modulated by the Cholinergic Anti-Inflammatory Pathway.
Kanashiro Alexandre,Talbot Jhimmy,Peres Raphael S,Pinto Larissa G,Bassi Gabriel S,Cunha Thiago M,Cunha Fernando Q
Basic & clinical pharmacology & toxicology
The cholinergic anti-inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuroimmune pathway on the progression of experimental arthritis. Using antigen-induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methylatropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed 1 week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur-tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis, providing a pre-clinical evidence of a potential therapeutic strategy for RA.
10.1111/bcpt.12611
Tapentadol prolonged release for severe chronic osteoarthritis pain in the elderly: improvements in daily functioning and quality of life.
Kern Kai-Uwe,Sohns Melanie,Heckes Birgit,Elling Christian
Pain management
Chronic osteoarthritis (OA) pain leads to severe impairments in physical functioning and quality of life. Data of patients with severe chronic knee and/or hip OA pain were extracted from the database of a prospective, noninterventional trial to assess the benefits of tapentadol prolonged release (PR) in elderly patients (>65 years of age; n = 1162) compared with younger patients (≤65 years of age; n = 498). Tapentadol PR treatment (up to 3 months) significantly reduced pain intensity and pain-related restrictions on daily functioning and significantly improved physical and mental quality of life in both patient groups. The incidence of adverse drug reactions was low. Tapentadol PR is a useful strong analgesic to improve pain intensity, physical functioning and quality of life in elderly OA patients.
10.2217/pmt-2019-0041
Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis.
Loeser Richard F,Yammani Raghunatha R,Carlson Cathy S,Chen Hong,Cole Ada,Im Hee-Jeong,Bursch Laura S,Yan Shi Du
Arthritis and rheumatism
OBJECTIVE:The receptor for advanced glycation end products (RAGE) binds multiple ligands, including S100 proteins, high mobility group box chromosomal protein 1 (HMGB-1), and AGEs, all of which are present in articular cartilage. Stimulation of RAGE signaling can lead to MAP kinase activation and increased NF-kappaB activity. The objective of the present study was to determine if chondrocytes express functional RAGE. METHODS:The presence of chondrocyte RAGE was analyzed by immunohistochemistry using normal and osteoarthritic (OA) cartilage from young and old monkeys and humans, immunoblotting of chondrocyte lysates and human cartilage extracts, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA from chondrocytes treated with interleukin-1 (IL-1) and fibronectin fragments. RAGE signaling was evaluated by stimulating chondrocytes with S100B and HMGB-1 and analyzing for activation of the ERK MAP kinase and NF-kappaB. The ability of S100B and HMGB-1 to stimulate matrix metalloproteinase 13 (MMP-13) production was also assessed. A pull-down assay using biotin-labeled S100B was used to demonstrate binding to RAGE. RESULTS:RAGE was detected in sections of monkey knee cartilage and human knee and ankle cartilage. Increased immunostaining for RAGE was noted in cartilage from older adult monkeys and humans and was further increased in OA tissue. RAGE was also detected by immunoblotting and by RT-PCR, where IL-1beta and fibronectin fragments were found to stimulate RAGE expression. Stimulation of chondrocytes with S100B or HMGB-1 increased phosphorylation of the ERK MAP kinase and the p65 subunit of NF-kappaB and increased the production of MMP-13. This signaling was inhibited in cells pretreated with soluble RAGE, and S100B was shown to bind to chondrocyte RAGE. CONCLUSION:Articular chondrocytes express functional RAGE. The increase in RAGE noted in OA cartilage and the ability of RAGE ligands to stimulate chondrocyte MAP kinase and NF-kappaB activity and to stimulate MMP-13 production suggests that chondrocyte RAGE signaling could play a role in OA.
10.1002/art.21199
Safety and efficacy of duloxetine treatment in older and younger patients with osteoarthritis knee pain: a post hoc, subgroup analysis of two randomized, placebo-controlled trials.
Micca Joseph L,Ruff Dustin,Ahl Jonna,Wohlreich Madelaine M
BMC musculoskeletal disorders
BACKGROUND:Osteoarthritis (OA) knee pain is common in older patients and contributes to decreased quality of life. Older patients are generally at higher risk of adverse drug reactions due to age-related changes in physiology that affect drug disposition, metabolism, and response. These analyses examined efficacy and safety outcomes of older (≥65 years) versus younger patients from clinical trials of duloxetine in the management of OA knee pain. METHODS:This is a post hoc analysis of two 13-week studies, in which patients were randomized to duloxetine 60 mg/day or placebo. Both studies allowed potential dose changes after 7 weeks of dosing, with Study I re-randomizing duloxetine treated patients to either stay on 60 mg/day or increase to 120 mg/day; while Study II more closely mimicked clinical practice by escalating only non-responding patients to 120 mg/day. For all analyses patients were subgrouped by age: older (≥65 years) and younger (40-64 years). Overall efficacy and safety age-group comparisons of duloxetine versus placebo were performed using pooled data from both studies with all duloxetine dose levels combined. Safety analyses included discontinuation rates, treatment-emergent adverse events, and serious adverse events. To evaluate the effects of increasing the dose in non-responding patients, only Study II data were evaluated. Treatment arms were defined post hoc as placebo, duloxetine 60 mg/day, and duloxetine 60/120 mg/day. RESULTS:At study end, patients in each age group who were treated with duloxetine versus placebo had significantly greater improvement in pain (both, p<.05), and there was no significant effect of age on treatment (p=.72). Increasing the dose to 120 mg in non-responding patients was not found to have a significant advantage. Among treatment-emergent adverse events with duloxetine treatment, only dizziness had a significantly differential treatment effect (p=.02) with greater incidence over placebo in younger patients (6.6% versus 0.6%, p=.02), but not in older patients (1.0% versus 3.2%, p=.29). CONCLUSIONS:Duloxetine was efficacious and generally well tolerated for management of symptomatic knee OA in both older and younger patients, but increasing the dose to 120 mg in non-responding patients did not provide additional benefit.
10.1186/1471-2474-14-137
Increased expression of dopamine receptors in synovial fibroblasts from patients with rheumatoid arthritis: inhibitory effects of dopamine on interleukin-8 and interleukin-6.
Capellino Silvia,Cosentino Marco,Luini Alessandra,Bombelli Raffaella,Lowin Torsten,Cutolo Maurizio,Marino Franca,Straub Rainer H
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Observations in both animal models of arthritis and patients with rheumatoid arthritis (RA) suggest a role for dopamine and its receptors in RA. Because synovial fibroblasts (SFs) contribute to inflammation and joint destruction in RA, the aim of this study was to investigate dopaminergic pathways in SFs obtained from patients with RA and, for comparison, in SFs from patients with osteoarthritis (OA) undergoing knee joint replacement surgery. METHODS:The expression of all dopamine receptors (D1 -D5 ) and dopamine transporter was assessed by immunofluorescence and immunohistochemical staining. The levels of dopamine receptor and tyrosine hydroxylase messenger RNA were measured by real-time polymerase chain reaction. The intracellular content of dopamine, its precursor, and its main metabolites was assayed by high-performance liquid chromatography. The influence of dopamine on proinflammatory interleukin-6 (IL-6) and IL-8, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-2 was studied in SFs. RESULTS:SFs possess an intrinsic dopaminergic system, including dopamine receptors, dopamine transporter, and tyrosine hydroxylase, and contain dopamine, its precursor, and its main metabolites. SFs from patients with RA, in comparison with those from patients with OA, showed increased expression of dopamine receptors D1 and D5 , and exogenous dopamine strongly inhibited the production of IL-8 in patients with RA. CONCLUSION:SFs from patients with RA and patients with OA show a dopaminergic phenotype. The expression of D1-like dopamine receptors was higher in RASFs, and this increased expression may lead to antiinflammatory effects, as demonstrated by the expression of IL-8. Studies in animal models and patients with RA are needed to assess the therapeutic potential of endogenous, local production of dopamine in synoviocytes.
10.1002/art.38746
Motor event-related synchronization as an inhibitory biomarker of pain severity, sensitivity, and chronicity in patients with knee osteoarthritis.
Neurophysiologie clinique = Clinical neurophysiology
OBJECTIVE:The study aimed to examine the clinical and neurophysiological predictors of motor event-related desynchronization (ERD) and synchronization (ERS) in patients with chronic pain due to knee osteoarthritis (KOA). METHODS:We performed a cross-sectional analysis of our cohort study (DEFINE cohort), KOA arm, with 71 patients, including demographic, functionality, genetic and neurophysiological measures. ERD/ERS was evaluated during hand motor tasks (motor execution, active and passive observation, and imagery). Multivariate regression models were used to explore predictors of ERD/ERS. RESULTS:Although we found an altered ERD/ERS pattern during motor execution and active observation, the ERS pattern could only be clearly differentiated after passive observation.`. We found no predictors of ERD (excitatory biomarker). For ERS (inhibitory biomarker), our results showed that the main predictors differ across EEG frequency bands. Considering pain measures, we found that visual analogue scale (VAS, right knee) and chronicity of pain negatively predict low beta and high beta ERS, respectively. Pain threshold was positively correlated with alpha ERS, while 36-Item Short Form Survey (SF-36) emotional domain positively predicted beta ERS. Regarding transcranial magnetic stimulation (TMS) markers, intracortical inhibition (ICF) negatively predicted beta and low beta ERS, and left hemisphere cortical silent period (CSP) negatively predicted low beta ERS. CONCLUSION:Considering that higher power of ERS indicates a stronger cortical organization and inhibitory drive, our results show that limitation of activities due to emotional factors, lower pain threshold, higher VAS pain, and longer duration of pain are associated with lower ERS power (in alpha and beta frequencies), thus indicating a lower inhibitory drive. In the same direction, a lower inhibitory drive as indicated by higher ERS power is associated with higher ICF amplitude. Although there was a negative association between ERS and CSP, this may indicate that ICF values are adjusting CSP results. Our findings support the idea that a less organized cortical response as indicated by changes to the ERS is associated with higher pain correlates in subjects with KOA.
10.1016/j.neucli.2022.09.006