Inhibitory effects of melatonin on titanium particle-induced inflammatory bone resorption and osteoclastogenesis via suppression of NF-κB signaling.
Ping Zichuan,Wang Zhirong,Shi Jiawei,Wang Liangliang,Guo Xiaobin,Zhou Wei,Hu Xuanyang,Wu Xiexing,Liu Yu,Zhang Wen,Yang Huilin,Xu Yaozeng,Gu Ye,Geng Dechun
Acta biomaterialia
Wear debris-induced peri-implant osteolysis challenges the longevity of implants. The host response to wear debris causes chronic inflammation, promotes bone resorption, and impairs bone formation. We previously demonstrated that melatonin enhances bone formation and attenuates wear debris-induced bone loss in vivo. However, whether melatonin inhibits chronic inflammation and bone resorption at sites of wear debris-induced osteolysis remains unclear. In this study, we examined the potential inhibitory effects of melatonin on titanium particle-induced inflammatory osteolysis in a murine calvarial model and on RANKL-induced osteoclastic formation in bone marrow-derived macrophages. We found that the exogenous administration of melatonin significantly inhibited wear debris-induced bone resorption and the expression of inflammatory cytokines in vivo. Additionally, melatonin inhibited RANKL-induced osteoclast differentiation, F-actin ring formation, and osteoclastic resorption in a concentration-dependent manner in vitro. We also showed that melatonin blocked the phosphorylation of IκB-α and p65, but not IKKα, and significantly inhibited the expression of NFATc1 and c-Fos. However, melatonin had no effect on MAPK or PI3K/AKT signaling pathways. These results provide novel mechanistic insight into the anti-inflammatory and anti-bone resorptive effects of melatonin on wear debris-induced bone loss and provide an evidence-based rationale for the protective effects of melatonin as a treatment for peri-implant osteolysis. STATEMENT OF SIGNIFICANCE:Wear debris-induced chronic inflammation, osteoclastic activation and osteoblastic inhibition have been identified as critical factors of peri-implant bone loss. We previously demonstrated that melatonin, a bioactive indolamine secreted mainly by the pineal gland, activates Wnt/β-catenin signaling pathway and enhances bone regeneration at osteolytic site in vivo. In the current study, we further demonstrated that melatonin significantly suppresses wear debris-induced bone resorption and inflammatory cytokine expression in vivo. In addition, melatonin inhibits receptor activator of nuclear factor kappa-B ligand induced osteoclast formation and osteoclastic bone resorption in vitro. Meanwhile, we found that melatonin mediates its anti-inflammation and anti-bone resorption effects by abrogating nuclear factor kappa-B activation. These results further support the protective effects of melatonin on wear debris-induced peri-implant bone loss, and strongly suggest that melatonin could be considered as a potential candidate for the prevention and treatment of wear debris-induced osteolysis and subsequent aseptic loosening.
10.1016/j.actbio.2017.08.046
Mechanism and Prevention of Titanium Particle-Induced Inflammation and Osteolysis.
Eger Michal,Hiram-Bab Sahar,Liron Tamar,Sterer Nir,Carmi Yaron,Kohavi David,Gabet Yankel
Frontiers in immunology
The worldwide number of dental implants and orthopedic prostheses is steadily increasing. Orthopedic implant loosening, in the absence of infection, is mostly attributable to the generation of wear debris. Dental peri-implantitis is characterized by a multifactorial etiology and is the main cause of implant failure. It consists of a peri-implant inflammatory lesion that often results in loss of supporting bone. Disease management includes cleaning the surrounding flora by hand instruments, ultrasonic tips, lasers, or chemical agents. We recently published a paper indicating that US scaling of titanium (Ti) implants releases particles that provoke an inflammatory response and osteolysis. Here we show that a strong inflammatory response occurs; however, very few of the titanium particles are phagocytosed by the macrophages. We then measured a dramatic Ti particle-induced stimulation of IL1β, IL6, and TNFα secretion by these macrophages using multiplex immunoassay. The particle-induced expression profile, examined by FACS, also indicated an M1 macrophage polarization. To assess how the secreted cytokines contributed to the paracrine exacerbation of the inflammatory response and to osteoclastogenesis, we treated macrophage/preosteoclast cultures with neutralizing antibodies against IL1β, IL6, or TNFα. We found that anti-TNFα antibodies attenuated the overall expression of both the inflammatory cytokines and osteoclastogenesis. On the other hand, anti-IL1β antibodies affected osteoclastogenesis but not the paracrine expression of inflammatory cytokines, whereas anti-IL6 antibodies did the opposite. We then tested these neutralizing antibodies using our mouse calvarial model of Ti particle-induced osteolysis and microCT analysis. Here, all neutralizing antibodies, administered by intraperitoneal injection, completely abrogated the particle-induced osteolysis. This suggests that blockage of paracrine inflammatory stimulation and osteoclastogenesis are similarly effective in preventing bone resorption induced by Ti particles. Blocking both the inflammation and osteoclastogenesis by anti-TNFα antibodies, incorporated locally into a slow-release membrane, also significantly prevented osteolysis. The osteolytic inflammatory response, fueled by ultrasonic scaling of Ti implants, results from an inflammatory positive feedback loop and osteoclastogenic stimulation. Our findings suggest that blocking IL1β, IL6, and/or TNFα systemically or locally around titanium implants is a promising therapeutic approach for the clinical management of peri-implant bone loss.
10.3389/fimmu.2018.02963
Orthopaedic implant materials drive M1 macrophage polarization in a spleen tyrosine kinase- and mitogen-activated protein kinase-dependent manner.
Mahon Olwyn R,O'Hanlon Sarah,Cunningham Clare C,McCarthy Geraldine M,Hobbs Christopher,Nicolosi Valeria,Kelly Daniel J,Dunne Aisling
Acta biomaterialia
Total joint replacements (TJR) are costly procedures required to relieve pain and restore function in patients suffering from end-stage arthritis. Despite great progress in the development and durability of TJRs, the generation of prosthesis-associated wear particles over time leads to an inflammatory cascade which culminates in periprosthetic osteolysis. Studies suggest that wear particles drive the polarization/differentiation of immature macrophages towards a pro-inflammatory M1 phenotype rather than an anti-inflammatory M2 phenotype associated with normal bone and wound healing. This, in turn, contributes to the initiation of peri-implant inflammation. As a result, modulating M1 macrophage cytokine production has been recognised as a viable therapeutic option. The aim of this study was to examine the impact of hydroxyapatite (HA) and poly(methyl methacrylate) (PMMA) particles on human macrophage polarization by comparing their effect on M1/M2-associated gene expression using real-time PCR. Furthermore, using immunoblotting to assess kinase activation, we sought to identify the intracellular signalling molecules activated by PMMA/HA particles and to determine whether pharmacological blockade of these molecules impacts on macrophage phenotype and cytokine production as measured by ELISA. We report that wear particles preferentially polarize macrophages towards an M1 phenotype, an effect that is dependent on activation of the membrane proximal kinase, Syk and members of the mitogen-activated protein kinase (MAPK) family of signalling molecules. Pre-treatment of macrophages with Syk inhibitors (R788/piceatannol) or MAPK inhibitors (SB203580 and PD98059), not only prevents M1 polarization, but also attenuates production of key pro-inflammatory mediators that have been specifically implicated in periprosthetic osteolysis and osteoclast differentiation. STATEMENT OF SIGNIFICANCE:It is now well established that wear-debris particles from implanted materials drive deleterious inflammatory responses which can eventually lead to implant loosening. In this study, we provide further insight into the specific cellular pathways activated by wear particles in primary human immune cells. We demonstrate that PMMA bone cement and hydroxyapatite, a commonly used biomaterial, drive the polarization of macrophages towards an inflammatory phenotype and identify the specific signalling molecules that are activated in this process. Pre-treatment of macrophages with pharmacological inhibitors of these molecules in turn prevents macrophage polarization and dampens inflammatory cytokine production. Hence these signalling molecules represent potential therapeutic targets to treat or possibly prevent particulate induced osteolysis.
10.1016/j.actbio.2017.10.041
Osteopontin is essential for IL-1β production and apoptosis in peri-implantitis.
Che Chengye,Liu Jie,Yang Jianjun,Ma Lei,Bai Na,Zhang Qian
Clinical implant dentistry and related research
BACKGROUND AND PURPOSE:Peri-implantitis is caused by a cascade of host and microbial factors leading to an oral inflammatory disease. The inflammation proliferates into supporting tissues surrounding implants and may finally lead to a complete loss of osseointegration. Being a phosphorylated glycoprotein secreted by immunocompetent cells, osteopontin (OPN) is involved in the differentiation of odontoblast-like cells during pulpal healing following tooth transplantation and the secretion of type I collagen in reparative dentin. But the production and function of OPN in peri-implantitis has not been thoroughly evaluated. MATERIALS AND METHODS:Peri-implant crevicular fluid (PICF) was collected from 28 healthy implants patients and 28 peri-implantitis patients to determine the expression of OPN in response to the inflammation of peri-implantitis by Western-blot, Enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. THP-1 macrophages infected by Porphyromonas gingivalis were chosen to reveal the production and function of OPN in peri-implantitis by immunofluorescence staining, quantitative polymerase chain reaction (RT-PCR), and Western-blot. RESULTS:Results showed that OPN increased in most PICF of peri-implantitis patients and in THP-1 macrophages stimulated with P. gingivalis. The expression of OPN in response to P. gingivalis decreased at mRNA and protein levels when exposed to either the lectin-type oxidized LDL receptor 1 (LOX-1) neutralizing antibody or inhibitor pretreatment in THP-1 macrophages. P. gingivalis induces OPN through the Erk1/2 MAPK dependent pathway. OPN neutralization decreased interleukin 1 beta (IL-1β) expression on P. gingivalis infection, and the lower IL-1β mRNA and protein levels were rescued by human osteopontin recombinant protein (rhOPN) in THP-1 macrophages. RhOPN suppressed P. gingivalis induced apoptosis of the mitochondrial pathway in THP-1 macrophage. CONCLUSIONS:Overall, the results of this study provide insight into the essential roles of OPN for IL-1β production and apoptosis in peri-implantitis, as supported by the evidence from the study of patient's PICF and cell culture experiments.
10.1111/cid.12592
[Research progress in the function of monocyte/macrophage-lineage origin cells in the peri-implant osseointegration interface].
Zhao J,Huang X
Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology
Although many studies have focused on how material surface modifications can promote stem cell differentiation toward osteogenic osteoblasts, little is known about the reaction between material surface and other cells, including osteoclasts and foreign body giant cells. Dental implant osseointegration results from the functional coupling and equilibrium not only between osteoblasts and osteoclasts but also between bone tissue and immune system. Osteoclasts and foreign body giant cells share the same origin, monocyte/macrophage lineage cells, which have initially got concerns in the field of implant osseointegration with regard to their peri-implant distribution and biological functions. Up-to-date data has shown that cells of monocyte/macrophage lineage origin manifest key roles in the establishment of peri-implant osseointegration and the long-term maintenance of marginal bone level and the prevalence of peri-implantitis. However, preliminary progress has been made in the subtypes, phenotypes vs. genotypes, and functions of monocyte/macrophage-lineage-originated cells on the osseointegration interface, quite a lot of facts still remain unclear, especially the potential and the rapeutic targets which could coordinate the cellular peri-implant microenvironment and the implant osseointegrated interface in the short and long term. This review will focus on the current progress in the function of monocyte/macrophage-lineage origin cells on the peri-implant osseointegration interface.
10.3760/cma.j.issn.1002-0098.2018.01.014
Anti-inflammatory and macrophage polarization effects of Cranberry Proanthocyanidins (PACs) for periodontal and peri-implant disease therapy.
Galarraga-Vinueza Maria Elisa,Dohle Eva,Ramanauskaite Ausra,Al-Maawi Sara,Obreja Karina,Magini Ricardo,Sader Robert,Ghanaati Shahram,Schwarz Frank
Journal of periodontal research
BACKGROUND AND OBJECTIVE:Macrophages' cytokine expression and polarization play a substantial role in the host's "destructive" inflammatory response to periodontal and peri-implant pathogens. This study aimed to evaluate cell viability, anti-inflammatory activity, and macrophage polarization properties of different cranberry concentrates. METHODS:THP-1 cells (monocytic line) were treated with phorbol myristic acid to induce macrophage differentiation. Human gingival fibroblasts (HFIB-G cell line), osteosarcoma-derived osteoblasts (SAOS-2 cell line), and induced macrophages were treated with cranberry concentrates at 25, 50, and 100 µg/mL for 120 seconds, 1 hour and 24 hours. Untreated cells at the same time points served as controls. For anti-inflammatory analysis, induced macrophages exposed to cranberry concentrates (A-type PACs) were stimulated with lipopolysaccharides (LPS) derived from E coli for 24 hours. Cell viability, interleukin (IL)-8, IL-1 ß, IL-6, and IL-10 expression of LPS-stimulated macrophages, and macrophage polarization markers were evaluated through determination of live-cell protease activity, enzyme-linked immunosorbent assay, and immunofluorescence staining semi-quantification. RESULTS:Cranberry concentrates (A-type PACs) did not reduce HGF, SAOS-2, and macrophage viability after 24 hours of exposure. Pro-inflammatory cytokine expression (ie IL-8 and IL-6) was downregulated in LPS-stimulated macrophages by cranberry concentrates at 50 and 100 µg/mL. Anti-inflammatory IL-10 expression was significantly upregulated in LPS-stimulated macrophages by cranberry concentrates at 100 µg/mL after 24 hours of exposure. M1 polarization significantly decreased when LPS-stimulated macrophages were exposed to cranberry concentrates. High levels of positive M1 macrophages were present in all untreated control groups. M2 polarization significantly increased at all LPS-stimulated macrophages exposed to cranberry concentrates for 1 and 24 hours. CONCLUSION:Cranberry-derived proanthocyanidins may have the potential to act as an anti-inflammatory component in the therapy of periodontal and peri-implant diseases.
10.1111/jre.12773
Primary prevention of peri-implantitis: managing peri-implant mucositis.
Jepsen Søren,Berglundh Tord,Genco Robert,Aass Anne Merete,Demirel Korkud,Derks Jan,Figuero Elena,Giovannoli Jean Louis,Goldstein Moshe,Lambert France,Ortiz-Vigon Alberto,Polyzois Ioannis,Salvi Giovanni E,Schwarz Frank,Serino Giovanni,Tomasi Cristiano,Zitzmann Nicola U
Journal of clinical periodontology
AIMS:Over the past decades, the placement of dental implants has become a routine procedure in the oral rehabilitation of fully and partially edentulous patients. However, the number of patients/implants affected by peri-implant diseases is increasing. As there are--in contrast to periodontitis--at present no established and predictable concepts for the treatment of peri-implantitis, primary prevention is of key importance. The management of peri-implant mucositis is considered as a preventive measure for the onset of peri-implantitis. Therefore, the remit of this working group was to assess the prevalence of peri-implant diseases, as well as risks for peri-implant mucositis and to evaluate measures for the management of peri-implant mucositis. METHODS:Discussions were informed by four systematic reviews on the current epidemiology of peri-implant diseases, on potential risks contributing to the development of peri-implant mucositis, and on the effect of patient and of professionally administered measures to manage peri-implant mucositis. This consensus report is based on the outcomes of these systematic reviews and on the expert opinion of the participants. RESULTS:Key findings included: (i) meta-analysis estimated a weighted mean prevalence for peri-implant mucositis of 43% (CI: 32-54%) and for peri-implantitis of 22% (CI: 14-30%); (ii) bleeding on probing is considered as key clinical measure to distinguish between peri-implant health and disease; (iii) lack of regular supportive therapy in patients with peri-implant mucositis was associated with increased risk for onset of peri-implantitis; (iv) whereas plaque accumulation has been established as aetiological factor, smoking was identified as modifiable patient-related and excess cement as local risk indicator for the development of peri-implant mucositis; (v) patient-administered mechanical plaque control (with manual or powered toothbrushes) has been shown to be an effective preventive measure; (vi) professional intervention comprising oral hygiene instructions and mechanical debridement revealed a reduction in clinical signs of inflammation; (vii) adjunctive measures (antiseptics, local and systemic antibiotics, air-abrasive devices) were not found to improve the efficacy of professionally administered plaque removal in reducing clinical signs of inflammation. CONCLUSIONS:Consensus was reached on recommendations for patients with dental implants and oral health care professionals with regard to the efficacy of measures to manage peri-implant mucositis. It was particularly emphasized that implant placement and prosthetic reconstructions need to allow proper personal cleaning, diagnosis by probing and professional plaque removal.
10.1111/jcpe.12369