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Cross-sectional and longitudinal associations between circulating leptin and knee cartilage thickness in older adults. Annals of the rheumatic diseases OBJECTIVE:To investigate cross-sectional and longitudinal associations between serum leptin levels and knee cartilage thickness in older adults. METHODS:A prospective cohort of 163 randomly selected subjects (mean 63 years, range 52-78, 46% women) was studied. Knee cartilage thickness at medial tibial, lateral tibial, femoral and patellar sites was determined using T1-weighted fat-suppressed MRI. Serum leptin levels were measured by radioimmunoassay. Radiographic osteoarthritis, body fat (%), trunk fat (%), weight and height were measured, and body mass index (BMI) was calculated. RESULTS:Cross-sectionally, serum levels of leptin were negatively associated with femoral (β: -0.013, 95% CI -0.022 to -0.003), medial tibial (β: -0.009, 95% CI -0.018 to -0.001), lateral tibial (β: -0.012, 95% CI -0.021 to -0.003) and patellar (β: -0.014, 95% CI -0.026 to -0.002) cartilage thickness after adjustment for covariates. Moreover, BMI, trunk fat and total body fat were negatively associated with cartilage thickness, and the significant associations disappeared after further adjustment for leptin. Longitudinally, both baseline leptin and change in leptin were associated with greater changes in medial tibial cartilage thickness (β: -0.004, 95% CI -0.007 to -0.001 and β: -0.009, 95% CI -0.018 to -0.001, respectively) in multivariable analyses. CONCLUSIONS:Serum levels of leptin are independently and consistently associated with reduced cartilage thickness cross-sectionally and longitudinally. In addition, the associations between adiposity measures and cartilage thickness are mediated by leptin, suggesting leptin may play a key role in cartilage thinning. 10.1136/annrheumdis-2013-203308
Metformin Ameliorates Senescence of Adipose-Derived Mesenchymal Stem Cells and Attenuates Osteoarthritis Progression via the AMPK-Dependent Autophagy Pathway. Oxidative medicine and cellular longevity Osteoarthritis (OA) is one of the most serious age-related diseases worldwide that drastically affects the quality of life of patients. Despite advancements in the treatment of arthritis, especially with adipose-derived mesenchymal stem cells (ADSCs), senescence-induced alterations in ADSCs negatively affect the treatment outcomes. This study was aimed at mechanistically exploring whether metformin could ameliorate the senescence of ADSCs and at exploring the effect of metformin-preconditioned ADSCs in an experimental OA mouse model. In this study, an HO-induced mouse ADSC senescent model was established. Cell proliferation, senescence, and autophagy were investigated in vitro. Moreover, the effects of intra-articular injection of metformin-preconditioned ADSCs were investigated in vivo. Metformin could promote autophagy and activate the AMPK/mTOR pathway in ADSCs. The metformin-enhanced autophagy could improve the survival and reduce the senescence of ADSCs. The protective effects of metformin against senescence were partially blocked by 3-methyladenine and compound C. Injection of metformin-preconditioned ADSCs slowed OA progression and reduced OA pain in mice. The results suggest that metformin activates the AMPK/mTOR-dependent autophagy pathway in ADSCs against HO-induced senescence, while metformin-preconditioned ADSCs can potentially inhibit OA progression. 10.1155/2022/4620254
Aging-related inflammation in osteoarthritis. Greene M A,Loeser R F Osteoarthritis and cartilage It is well accepted that aging is an important contributing factor to the development of osteoarthritis (OA). The mechanisms responsible appear to be multifactorial and may include an age-related pro-inflammatory state that has been termed "inflamm-aging." Age-related inflammation can be both systemic and local. Systemic inflammation can be promoted by aging changes in adipose tissue that result in increased production of cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (TNFα). Numerous studies have shown an age-related increase in blood levels of IL-6 that has been associated with decreased physical function and frailty. Importantly, higher levels of IL-6 have been associated with an increased risk of knee OA progression. However, knockout of IL-6 in male mice resulted in worse age-related OA rather than less OA. Joint tissue cells, including chondrocytes and meniscal cells, as well as the neighboring infrapatellar fat in the knee joint, can be a local source of inflammatory mediators that increase with age and contribute to OA. An increased production of pro-inflammatory mediators that include cytokines and chemokines, as well as matrix-degrading enzymes important in joint tissue destruction, can be the result of cell senescence and the development of the senescence-associated secretory phenotype (SASP). Further studies are needed to better understand the basis for inflamm-aging and its role in OA with the hope that this work will lead to new interventions targeting inflammation to reduce not only joint tissue destruction but also pain and disability in older adults with OA. 10.1016/j.joca.2015.01.008
Age-associated increases in the size of the infrapatellar fat pad in knee osteoarthritis as measured by 3T MRI. Chuckpaiwong Bavornrit,Charles Hal Cecil,Kraus Virginia B,Guilak Farshid,Nunley James A Journal of orthopaedic research : official publication of the Orthopaedic Research Society Obesity, as a primary risk factor for osteoarthritis (OA), has been shown to alter joint loading, but may also result in metabolic changes characterized by chronic, low-level inflammation due to increased circulating levels of adipose-derived cytokines, or "adipokines." The presence of the infrapatellar fat pad in the knee suggests that local changes in adipokine concentrations may influence knee OA. This study examined the hypotheses that the volume of the infrapatellar fat pad is correlated to the body mass index (BMI) of OA patients, and that fat pad volume is greater in subjects with OA. Fat pad volume was measured in sequential magnetic resonance (MR) images taken over one year in a cohort of 15 control and 15 knee OA subjects. No differences were observed in the fat pad volume between the two groups at baseline, 3, 6, or 12 months. In control subjects, no significant correlations were present between any parameters (age, BMI, weight, volume of fat pad at any time point). However, in the osteoarthritic group, fat pad volume was correlated with age at every time point. One possible explanation is that local factors related to knee OA may also induce enlargement of the fat pad with age. Alternatively, subjects who are prone to growth or enlargement of the fat pad may also be more prone to symptomatic OA. These findings provide intriguing preliminary data on the potential role of the infrapatellar fat pad in OA, although additional study is required to better understand the mechanisms of this relationship. 10.1002/jor.21125
Responsiveness of Infrapatellar Fat Pad Volume Change to Body Weight Loss or Gain: Data from the Osteoarthritis Initiative. Steidle-Kloc Eva,Dannhauer Torben,Wirth Wolfgang,Eckstein Felix Cells, tissues, organs Obesity is a potent risk factor for knee osteoarthritis (OA) that is driven by mechanical and potentially endocrine mechanisms, and it affects women more frequently than men. The infrapatellar fat pat (IPFP) represents a potential link between obesity, intra-articular inflammation and structural pathology. Here we investigate whether the IPFP is responsive to body weight loss/gain in women and how its responsiveness to weight change compares to that of subcutaneous fat (SCF) of the thigh. All female participants of the Osteoarthritis Initiative (OAI) with ≥10% weight loss/gain between baseline and a 2-year follow-up were included. Within-subject changes in IPFP volume and SCF cross-sectional areas (CSA) were determined from 3-T magnetic resonance imaging. Linear regression was used to assess the association between change in weight, IPFP volume, and SCF CSA. In the 38 participants with ≥10% weight loss over 2 years (age 59.3 ± 9.1 years, mean loss = 15.9%), there was a significant reduction in IPFP volume (-2.2%, p = 0.02) as well as in SCF CSA (-22%, p < 0.001). In the 34 participants with ≥10% gain (age 61.5 ± 8.7 years, mean gain = 15.9%), there was a significant increase in SCF CSA (+26%, p < 0.001) but not in IPFP volume (0.2%, p = 0.87). Weight change was significantly associated with SCF CSA change (r = 0.76, p < 0.001) but not with IPFP volume change (r = 0.11, p = 0.37). In this first longitudinal, observational study investigating the responsiveness of IPFP and SCF to weight change, IPFP morphology was found responsive to weight loss but not to weight gain. Overall, the responsiveness of the IPFP was substantially less than that of the SCF. 10.1159/000485833
Basic Properties of Adipose-Derived Mesenchymal Stem Cells of Rheumatoid Arthritis and Osteoarthritis Patients. Pharmaceutics Rheumatoid arthritis (RA) and osteoarthritis (OA) are destructive joint diseases, the development of which are associated with the expansion of pathogenic T lymphocytes. Mesenchymal stem cells may be an attractive therapeutic option for patients with RA or OA due to the regenerative and immunomodulatory abilities of these cells. The infrapatellar fat pad (IFP) is a rich and easily available source of mesenchymal stem cells (adipose-derived stem cells, ASCs). However, the phenotypic, potential and immunomodulatory properties of ASCs have not been fully characterised. We aimed to evaluate the phenotype, regenerative potential and effects of IFP-derived ASCs from RA and OA patients on CD4+ T cell proliferation. The MSC phenotype was assessed using flow cytometry. The multipotency of MSCs was evaluated on the basis of their ability to differentiate into adipocytes, chondrocytes and osteoblasts. The immunomodulatory activities of MSCs were examined in co-cultures with sorted CD4+ T cells or peripheral blood mononuclear cells. The concentrations of soluble factors involved in ASC-dependent immunomodulatory activities were assessed in co-culture supernatants using ELISA. We found that ASCs with PPIs from RA and OA patients maintain the ability to differentiate into adipocytes, chondrocytes and osteoblasts. ASCs from RA and OA patients also showed a similar phenotype and comparable abilities to inhibit CD4+ T cell proliferation, which was dependent on the induction of soluble factors The results of our study constitute the basis for further research on the therapeutic potential of ASCs in the treatment of patients with RA and OA. 10.3390/pharmaceutics15031003
Osteoarthritis: Inflammation and fibrosis in adipose tissue of osteoarthritic joints. Ioan-Facsinay Andreea,Kloppenburg Margreet Nature reviews. Rheumatology 10.1038/nrrheum.2017.53
Adipokines and inflammation: is it a question of weight? British journal of pharmacology Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders. 10.1111/bph.14181
Correlation of systemic metabolic inflammation with knee osteoarthritis. Hormones (Athens, Greece) PURPOSE:The aim of this study was to analyze local and systematic inflammatory status in knee osteoarthritis (KOA), focusing on intra-articular and remote adipose tissue depots, and to explore its potential association with metabolic syndrome (MetS). METHODS:Patients (n = 27) with end-stage KOA were enrolled in the study and samples from infrapatellar fat pad (IFP), synovium, subcutaneous adipose tissue (SAT), synovial fluid (SF), and serum were collected. In homogenates from the tissues, mRNA expression of developmental endothelial locus-1 (DEL-1) was determined. Interleukin 6 (IL-6) and interleukin 8 (IL-8) were measured in tissues and SF and serum samples by enzyme-linked immunosorbent assay. RESULTS:Fifteen patients fulfilled MetS criteria (w-MetS group) and 12 did not (non-MetS). In the entire population, IL-6 levels were significantly higher in IFP compared to synovium (median (interquartile range), 26.05 (26.16) vs. 15.75 (14.8) pg/mg of total protein, p = 0.043), but not to SAT (17.89 (17.9) pg/mg); IL-8 levels were significantly higher in IFP (17.3 (19.3) pg/mg) and SAT (24.2 (26) pg/mg) when compared to synovium (8.45 (6.17) pg/mg) (p = 0.029 and < 0.001, respectively). Significantly higher IL-6 concentrations in SF were detected in w-MetS patients compared to non-MetS (194.8 (299) vs. 64.1 (86.9) pg/ml, p = 0.027). Finally, DEL-1 mRNA expression was higher in IFP compared to synovium (eightfold, p = 0.019). CONCLUSIONS:Our findings support the critical role of IFP in knee joint homeostasis and progression of KOA. Furthermore, in KOA patients w-MetS, SAT is thought to play an important role in intra-knee inflammation via secretion of soluble inflammatory mediators, such as IL-6. 10.1007/s42000-022-00381-y
Inflammation of the infrapatellar fat pad. Eymard Florent,Chevalier Xavier Joint bone spine The infrapatellar fat pad (IFP) of Hoffa's fat pad is the main adipose structure within the knee joint. It is located between the joint capsule and the synovial membrane, which lines its posterior aspect. The IFP is composed chiefly of adipocytes and receives an abundant supply of blood vessels and nerves. Immune cells can infiltrate the IFP, which can become a major source of numerous proinflammatory mediators (cytokines and adipokines). The physiological role for the IFP remains unclear but may involve shock absorption and the protection of adjacent tissues. Hoffa's disease is characterized by inflammation, hypertrophy, and fibrosis of the pad in response to repetitive trauma. Anterior knee pain is the most common symptom. In advanced forms, metaplasia of the IFP may result in the development of a sometimes sizable osteochondroma. The IFP may also contribute to the pathophysiology of knee osteoarthritis, in particular via procatabolic and proinflammatory effects on its synovial lining. Finally, in patients with knee osteoarthritis, inflammation of the IFP may be a source of pain. 10.1016/j.jbspin.2016.02.016
Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Annals of the rheumatic diseases OBJECTIVE:To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis. METHODS:Study subjects were patients 45 years of age and older with symptomatic knee osteoarthritis from the Boston Osteoarthritis of the Knee Study. Baseline and follow-up assessments at 15 and 30 months included knee magnetic resonance imaging (MRI), BMI and pain assessment (VAS) over the last week. Synovitis was scored at 3 locations (infrapatellar fat pad, suprapatellar and intercondylar regions) using a semiquantitative scale (0-3) at all 3 time points on MRI. Scores at each site were added to give a summary synovitis score (0-9). RESULTS:We assessed 270 subjects whose mean (SD) age was 66.7 (9.2) years, BMI 31.5 (5.7) kg/m(2); 42% were female. There was no correlation of baseline synovitis with baseline pain score (r = 0.09, p = 0.17). The change in summary synovitis score was correlated with the change in pain (r = 0.21, p = 0.0003). An increase of one unit in summary synovitis score resulted in a 3.15-mm increase in VAS pain score (0-100 scale). Effusion change was not associated with pain change. Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change. Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment. CONCLUSIONS:Change in synovitis was correlated with change in knee pain, but not loss of cartilage. Treatment of pain in knee osteoarthritis (OA) needs to consider treatment of synovitis. 10.1136/ard.2006.067470
Infrapatellar fat pad maximal area and changes in knee symptoms: gender-related difference or gender difference in reporting? Annals of the rheumatic diseases 10.1136/annrheumdis-2015-208620
A longitudinal study of the association between infrapatellar fat pad maximal area and changes in knee symptoms and structure in older adults. Annals of the rheumatic diseases BACKGROUND:The infrapatellar fat pad (IPFP) is of uncertain significance for knee osteoarthritis. The aim of this study was to describe the longitudinal associations between baseline IPFP maximal area and changes in knee pain, knee cartilage volume and cartilage defects in older adults. METHODS:356 community-dwelling male and female adults aged 50-80 years were measured at baseline and approximately 2.6 years later. T1-weighted or T2-weighted fat-suppressed MRI was used to assess maximal IPFP area, cartilage volume and cartilage defects at baseline and/or follow-up. Knee pain was assessed by the self-administered Western Ontario McMaster Osteoarthritis Index questionnaire. RESULTS:After adjustment for confounders, IPFP maximal area in women was significantly and negatively associated with changes in knee pain (β: -0.18 to -0.86 for total knee pain, pain at night while in bed, pain when sitting/lying and pain when standing upright, all p<0.05) but not with other knee pain subscales. IPFP maximal area in women was beneficially associated with change in tibial cartilage volume per annum (β: +1.56% per cm(2) at medial site; +0.86% per cm(2) at lateral site, both p<0.05), but not with change in patellar cartilage volume. Further, it was significantly associated with reduced risks of increases in medial cartilage defects (relative risk: 0·46 at tibial site, relative risk: 0.59 at femoral site; both p<0.05) but not with increases at other sites in women. No significant associations were found in men. CONCLUSIONS:While the associations are not fully consistent, IPFP maximal area appears to have a protective role for knee symptoms and cartilage damage in older female adults. 10.1136/annrheumdis-2013-205108
Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study. Annals of the rheumatic diseases OBJECTIVE:To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults. METHODS:A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed. RESULTS:In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses. CONCLUSIONS:IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA. 10.1136/annrheumdis-2015-208360
Infrapatellar fat pad-derived mesenchymal stromal cells from osteoarthritis patients: In vitro genetic stability and replicative senescence. Neri Simona,Guidotti Serena,Lilli Nicoletta Libera,Cattini Luca,Mariani Erminia Journal of orthopaedic research : official publication of the Orthopaedic Research Society Different sources of mesenchymal stromal cells can be considered for regenerative medicine applications. Here we analyzed human adipose-derived stromal cells from infrapatellar fat pad (IFPSC) of osteoarthritis patients, representing a very interesting candidate for cartilage regeneration. No data are available concerning IFPSC stability after in vitro expansion. Indeed, replicative potential and multipotency progressively decrease during culture passages while DNA damage and cell senescence increase, thus possibly affecting clinical applications. To investigate whether in vitro expansion influences the genetic stability and replicative senescence of IFPSC, we performed long-term cultures and comparatively analyzed cells at different culture passages. Stromal vascular fraction was harvested from infrapatellar fat pad of 11 osteoarthritis patients undergoing knee replacement surgery. Cell recovery, growth kinetics, surface marker profile, and differentiation ability in inductive culture conditions were recorded. Genetic integrity maintenance was estimated by microsatellite instability analysis and mismatch repair gene expression, whereas telomere length and telomerase activity were assessed to evaluate replicative senescence. Anchorage-dependent growth was tested by soft agar culture. IFPSC displayed a phenotype similar to mesenchymal stromal cells from subcutaneous fat and showed differentiation ability. No microsatellite instability was documented even at advanced culture times in accordance to a sustained expression of mismatch repair genes, thus highlighting stability of short repeated sequences in the genome. No significant telomere attrition nor telomerase activity were documented during culture and cells did not lose anchorage-dependent growth ability. The presented data support the suitability and safety of in vitro expanded IFPSC from osteoarthritis patients for applications in regenerative medicine approaches. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1029-1037, 2017. 10.1002/jor.23349
[Indirect coculture of human infrapatellar fat pad-derived stem cells with osteoarthritic chondrocytes induces their chondrogenesis]. Yang Junjun,Chen Cheng,Yang Liu,Song Xiongbo,Xie Wenbin,Huang Shu,Liu Baorong Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology Objective:To promote phenotype recovery of osteoarthritic articular chondrocytes( OACs) and induce chondrogenic differentiation of infrapatellar fat pad-derived stem cells( IPFPSCs) by indirectly coculturing these two types of cells. Methods:The OACs and IPFPSCs were isolated and cultured in vitro. This experiment included single IPFPSCs group,single OACs group,and coculture group. After cells were cultured in vitro with chondrogenic medium for 21 days,the chondrocyte phenotypes were determined by HE staining( cell morphology),Alcian blue staining( glycosaminoglycan content) and immunofluorescence cytochemistry( collagen 1,collagen 2,collagen 3,aggrecan,SOX9). Results:In coculture group,the OACs aggregated into microspheres,and the IPFPSCs were oval in shape. In single culture groups,the OACs were less aggregated and the spheres were smaller; and the IPFPSCs were spindle in shape. HE staining showed that,in the coculture group,the nuclei of OACs spheres were dark,and the IPFPSCs were rich in cytoplasm; while in single culture groups,the nuclei of OAC spheres were less dark,and the IPFPSCs were less stained compared with the coculture group. Alcian blue staining indicated that glycosaminoglycan content was higher in the coculture group than in single culture groups. Immunofluorescent staining showed that the intensity of chondrogenic markers( collagen 2,aggrecan,and SOX9)was stronger,while the intensity of collagen 1 and collagen 10 was weaker in the coculture group as compared with single culture groups. Conclusion:The indirect coculture of IPFPSCs with OACs can contribute to the phenotype recovery of OACs and induce the chondrogenic differentiation of IPFPSCs.
Between-group differences in infra-patellar fat pad size and signal in symptomatic and radiographic progression of knee osteoarthritis vs non-progressive controls and healthy knees - data from the FNIH Biomarkers Consortium Study and the Osteoarthritis Initiative. Ruhdorfer A,Haniel F,Petersohn T,Dörrenberg J,Wirth W,Dannhauer T,Hunter D J,Eckstein F Osteoarthritis and cartilage OBJECTIVE:To examine cross-sectional and longitudinal between-group differences of infra-patellar fat pad (IPFP) size and magnetic resonance imaging (MRI) signal from fat-suppressed intermediate-weighted images with clinically relevant symptomatic and radiographic progression of knee osteoarthritis (OA), vs healthy references. METHODS:We studied 110 case knees (Kellgren-Lawrence Grade [KLG1-3]) with radiographic (≥0.7 mm loss in joint space width [JSW]) and symptomatic progression (≥+9/100 units on the Western Ontario and McMasters Universities Osteoarthritis Index [WOMAC] knee pain subscale) vs 118 control knees without progression from the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium cohort. We further studied 88 knees from the Osteoarthritis Initiative (OAI) healthy reference cohort without (risk factors) of knee OA. The IPFP was manually segmented using baseline and year-2 sagittal fat-suppressed intermediate-weighted spin-echo 3 T MRIs. Baseline measures and longitudinal change in IPFP volume and 3D MRI signal (mean, standard deviation [SD]) were compared between groups. RESULTS:No statistically significant baseline differences in IPFP volume, 3D MRI signal mean or signal heterogeneity (SD) were observed between progressor and non-progressor OA knees. Yet, the IPFP 3D MRI signal SD, but not its volume, was statistically significantly greater in OA vs healthy knees. No statistically significant 2-year changes in IPFP volume were observed in either group, but the increase in 3D MRI signal heterogeneity (SD) was greater in progressor vs non-progressor knees, and was greater in OA vs healthy knees. CONCLUSION:Whereas IPFP-related morphometric measures did not statistically significantly differ between groups, a stronger increase in 3D IPFP MRI signal and signal heterogeneity may be associated with radiographic/symptomatic progression of OA, when compared to non-progressive OA or healthy knees. 10.1016/j.joca.2017.02.789
Impact of Diet and/or Exercise Intervention on Infrapatellar Fat Pad Morphology: Secondary Analysis from the Intensive Diet and Exercise for Arthritis (IDEA) Trial. Cells, tissues, organs OBJECTIVES:The infrapatellar fat pad (IPFP) represents intra-articular adipose tissue that may contribute to intra-articular inflammation and pain by secretion of proinflammatory cytokines. Here we examined the impact of weight loss by diet and/or exercise interventions on the IPFP volume. METHODS:Intensive Diet and Exercise for Arthritis (IDEA) was a single-blinded, single-center, 18-month, prospective, randomized controlled trial that enrolled 454 overweight and obese older adults with knee pain and radiographic osteoarthritis. Participants were randomized to 1 of 3 groups: exercise-only control (E), diet-induced weight loss (D), and diet-induced weight loss + exercise (D+E). In a subsample (n = 106; E: n = 36, D: n = 35, and D+E: n = 35), magnetic resonance images were acquired at baseline and at the 18-month follow-up, from which we analyzed IPFP volume, surface areas, and thickness in this secondary analysis. RESULTS:The average weight loss amounted to 1.0% in the E group, 10.5% in the D group, and 13.0% in the D+E group. A significant (p < 0.01) reduction in IPFP volume was observed in the E (2.1%), D (4.0%), and D+E (5.2%) groups. The IPFP volume loss in the D+E group was significantly greater than that in the E group (p < 0.05) when not adjusting for parallel comparisons. Across intervention groups, there were significant correlations between IPFP volume change, individual weight loss (r = 0.40), and change in total body fat mass (dual-energy X-ray absorptiometry; r = 0.44, n = 88) and in subcutaneous thigh fat area (computed tomography; r = 0.32, n = 82). CONCLUSIONS:As a potential link between obesity and knee osteoarthritis, the IPFP was sensitive to intervention by diet and/or exercise, and its reduction was correlated with changes in weight and body fat. 10.1159/000449407
Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients. Aikawa Jun,Uchida Kentaro,Takano Shotaro,Inoue Gen,Minatani Atsushi,Miyagi Masayuki,Iwase Dai,Sekiguchi Hiroyuki,Mukai Manabu,Takaso Masashi Journal of orthopaedic surgery and research BACKGROUND:The infrapatellar fat pad (IPFP) has been implicated as a possible source of osteoarthritis (OA) development and knee pain due to the production of inflammatory mediators and the existence of nerve fibers within this structure. Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that is localized to joint tissues and has recently been implicated in the development of knee OA and OA pain. To date, however, the expression levels of CGRP in the IPFP of human knee OA patients have not been examined. METHODS:IFFP and synovial (SYN) tissues were harvested from 100 individuals with radiographic knee OA (unilateral Kellgren/Lawrence [K/L] grades 2-4) during total knee arthroplasty and subjected to immunohistochemical analysis for CGRP localization. In addition, the messenger RNA (mRNA) expression levels of CGRP and cyclooxygenase-2 (COX-2) in the collected tissues were evaluated and compared using real-time PCR analysis of total RNA extracts. CGRP and COX-2 mRNA expression were also compared among individuals with K/L grades 2-4. RESULTS:CGRP-positive cells were detected in the capillaries within the IPFP and lining layer of SYN tissue. The expression levels of CGRP in the IPFP were positively correlated with COX-2 and were significantly higher than those in SYN tissue. CGRP expression in tissue from the KL4 group was twofold higher than that from the KL2 group. CONCLUSIONS:The IPFP of knee OA patients produces relatively high levels of CGRP, which may be regulated by COX-2 at the transcriptional level. Further studies are needed to determine if CGRP levels are directly linked to OA pathology. 10.1186/s13018-017-0568-1
Variance in infra-patellar fat pad volume: Does the body mass index matter?-Data from osteoarthritis initiative participants without symptoms or signs of knee disease. Burda Birgit,Steidle-Kloc Eva,Dannhauer Torben,Wirth Wolfgang,Ruhdorfer Anja,Eckstein Felix Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft The infra-patellar fat pad (IPFP) has been proposed to represent an endocrine link between obesity and knee osteoarthritis (OA). The purpose of the current study has been to explore the extent to which IPFP volume is related to body mass index (BMI). A total of 152 participants (age 56±7 years) without knee OA were studied. These consisted of 19 men and 19 women of normal weight (BMI 18.5-25), 19/19 pre-obese (BMI 25-30), 19/19 obese class I (BMI 30-35) and 19/19 obese class II (BMI 35-40), who were matched 1:1 for age and height. The IPFP volume was manually segmented from sagittal fat-suppressed magnetic resonance images (MRI). An ANOVA of repeated measures was used to assess whether IPFP volume was related to BMI. The IPFP volume differed significantly between the BMI strata (ANOVA: p=0.001): It was 27.1±6.7cm (mean±SD) in normal weight, 29.3±6.9cm in pre-obese, 31.0±6.9cm in obese class I, and 30.4±6.6cm in obese class II participants; the difference in IPFP volume (and body weight) relative to normal weight subjects was 10% (18%) in pre-obese, 17% (39%) in obese class I, and 15% (59%) in obese class II participants. Stratification by sex showed similar results. In conclusion, IPFP volume is shown to be related to BMI, albeit the relative increase (compared with normal weight) does not appear to be proportional to that in body weight. Nonetheless, these findings support the hypothesis that the IPFP may represent a potential endocrine link between obesity and OA, with more intra-articular adipose tissue potentially releasing greater amounts of adipokines. 10.1016/j.aanat.2017.04.004
Inflammatory features of infrapatellar fat pad in rheumatoid arthritis versus osteoarthritis reveal mostly qualitative differences. Annals of the rheumatic diseases 10.1136/annrheumdis-2017-211673
Regional differences between perisynovial and infrapatellar adipose tissue depots and their response to class II and III obesity in patients with osteoarthritis: comment on the article by Harasymowicz et al. Macchi Veronica,Porzionato Andrea,Rossato Marco,De Caro Raffaele Arthritis & rheumatology (Hoboken, N.J.) 10.1002/art.40241
Meniscus ECM-functionalised hydrogels containing infrapatellar fat pad-derived stem cells for bioprinting of regionally defined meniscal tissue. Romanazzo S,Vedicherla S,Moran C,Kelly D J Journal of tissue engineering and regenerative medicine Injuries to the meniscus of the knee commonly lead to osteoarthritis. Current therapies for meniscus regeneration, including meniscectomies and scaffold implantation, fail to achieve complete functional regeneration of the tissue. This has led to increased interest in cell and gene therapies and tissue engineering approaches to meniscus regeneration. The implantation of a biomimetic implant, incorporating cells, growth factors, and extracellular matrix (ECM)-derived proteins, represents a promising approach to functional meniscus regeneration. The objective of this study was to develop a range of ECM-functionalised bioinks suitable for 3D bioprinting of meniscal tissue. To this end, alginate hydrogels were functionalised with ECM derived from the inner and outer regions of the meniscus and loaded with infrapatellar fat pad-derived stem cells. In the absence of exogenously supplied growth factors, inner meniscus ECM promoted chondrogenesis of fat pad-derived stem cells, whereas outer meniscus ECM promoted a more elongated cell morphology and the development of a more fibroblastic phenotype. With exogenous growth factors supplementation, a more fibrogenic phenotype was observed in outer ECM-functionalised hydrogels supplemented with connective tissue growth factor, whereas inner ECM-functionalised hydrogels supplemented with TGFβ3 supported the highest levels of Sox-9 and type II collagen gene expression and sulfated glycosaminoglycans (sGAG) deposition. The final phase of the study demonstrated the printability of these ECM-functionalised hydrogels, demonstrating that their codeposition with polycaprolactone microfibres dramatically improved the mechanical properties of the 3D bioprinted constructs with no noticeable loss in cell viability. These bioprinted constructs represent an exciting new approach to tissue engineering of functional meniscal grafts. 10.1002/term.2602
Low-oxygen conditions promote synergistic increases in chondrogenesis during co-culture of human osteoarthritic stem cells and chondrocytes. Critchley Susan E,Eswaramoorthy Rajalakshmanan,Kelly Daniel J Journal of tissue engineering and regenerative medicine There has been increased interest in co-cultures of stem cells and chondrocytes for cartilage tissue engineering as there are the limitations associated with using either cell type alone. Drawbacks associated with the use of chondrocytes include the limited numbers of cells available for isolation from damaged or diseased joints, their dedifferentiation during in vitro expansion, and a diminished capacity to synthesise cartilage-specific extracellular matrix components with age and disease. This has motivated the use of adult stem cells with either freshly isolated or culture-expanded chondrocytes for cartilage repair applications; however, the ideal combination of cells and environmental conditions for promoting robust chondrogenesis remains unclear. In this study, we compared the effect of combining a small number of freshly isolated or culture-expanded human chondrocytes with infrapatellar fat pad-derived stem cells (FPSCs) from osteoarthritic donors on chondrogenesis in altered oxygen (5% or 20%) and growth factor supplementation (TGF-β3 only or TGF-β3 and BMP-7) conditions. Both co-cultures, but particularly those including freshly isolated chondrocytes, were found to promote cell proliferation and enhanced matrix accumulation compared to the use of FPSCs alone, resulting in the development of a tissue that was compositionally more similar to that of the native articular cartilage. Local oxygen levels were found to impact chondrogenesis in co-cultures, with more robust increases in proteoglycan and collagen deposition observed at 5% O . Additionally, collagen type I synthesis was suppressed in co-cultures maintained at low-oxygen conditions. This study demonstrates that a co-culture of freshly isolated human chondrocytes and FPSCs promotes robust chondrogenesis and thus is a promising cell combination for cartilage tissue engineering. 10.1002/term.2608
FABP4 as a biomarker for knee osteoarthritis. Zhang Chaofan,Li Teng,Chiu Kwong Yuen,Wen Chunyi,Xu Aimin,Yan Chun Hoi Biomarkers in medicine AIM:To explore the role of an adipokine-termed fatty acid-binding protein 4 (FABP4) in osteoarthritis (OA). METHODS:Patients with primary knee OA and non-OA controls were included. Paired tissues including plasma, synovial fluid (SF), subcutaneous fat and infrapatellar fat pad (IPFP) were harvested during surgery. FABP4 concentration was determined by ELISA. RESULTS:Plasma FABP4 increased significantly with OA stage (n = 263). OA patients (n = 38) had significantly higher plasma and SF FABP4 than non-OA patients (n = 29). FABP4 level of IPFP was positively correlated with SF FABP4. CONCLUSION:OA patients had significantly high systemic and local FABP4, and IPFP may be the main source of FABP4 in synovial cavity. FABP4 may be a promising biomarker for OA. 10.2217/bmm-2017-0207
Quantitative Signal Intensity Alteration in Infrapatellar Fat Pad Predicts Incident Radiographic Osteoarthritis: The Osteoarthritis Initiative. Wang Kang,Ding Changhai,Hannon Michael J,Chen Zhongshan,Kwoh C Kent,Hunter David J Arthritis care & research OBJECTIVE:To determine whether infrapatellar fat pad (IPFP) signal intensity measures are predictive of incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative study. METHODS:Case knees (n = 355), as defined by incident ROA, were matched 1:1 with control knees, according to sex, age, and radiographic status. T2-weighted magnetic resonance images were assessed at P0 (the visit when incident ROA was observed on a radiograph), P1 (1 year prior to P0), and baseline and used to assess IPFP signal intensity semiautomatically. Conditional logistic regression analyses were performed to assess the risk of incident ROA associated with IPFP signal intensity alteration, after adjustment for covariates. RESULTS:The mean age of the participants was 60.2 years, and most (66.7%) were female and overweight (mean body mass index 28.3 kg/m ). Baseline IPFP measures including the mean value and standard deviation of IPFP signal intensity, the mean value and standard deviation of IPFP high signal intensity, median and upper quartile values of IPFP high signal intensity, and the clustering effect of high signal intensity were associated with incident knee ROA over 4 years. All P1 IPFP measures were associated with incident ROA after 12 months. All P0 IPFP signal intensity measures were associated with ROA. CONCLUSION:The quantitative segmentation of high signal intensity in the IPFP observed in our study confirms the findings of previous work based on semiquantitative assessment, suggesting the predictive validity of semiquantitative assessment of IPFP high signal intensity. The IPFP high signal intensity alteration could be an important imaging biomarker to predict the occurrence of ROA. 10.1002/acr.23577
Association Between Quantitatively Measured Infrapatellar Fat Pad High Signal-Intensity Alteration and Magnetic Resonance Imaging-Assessed Progression of Knee Osteoarthritis. Han Weiyu,Aitken Dawn,Zheng Shuang,Wluka Anita E,Zhu Zhaohua,Blizzard Leigh,Winzenberg Tania,Cicuttini Flavia,Jones Graeme,Ding Changhai Arthritis care & research OBJECTIVE:To describe the cross-sectional and longitudinal associations between quantitative measures of infrapatellar fat pad (IPFP) signal-intensity alteration and knee structural abnormalities in patients with symptomatic knee osteoarthritis (OA). METHODS:A total of 261 patients (mean ± SD age 63.0 ± 7.2 years) with symptomatic knee OA were selected from a randomized controlled trial with a follow-up of 2 years. IPFP signal-intensity alterations at baseline were quantitatively measured on T2-weighted fat-saturated magnetic resonance imaging using MATLAB. These quantitative measures included the SD of whole IPFP signal intensity measurement, the upper quartile value of high signal intensity (UQ ), the ratio of volume of high signal-intensity alteration to volume of whole IPFP (percentage ), and the clustering effect of high signal intensity (clustering-factor ). Cartilage volume and defects and bone marrow lesions (BMLs) were assessed using validated measures. RESULTS:Higher baseline SD of the IPFP, UQ , and clustering-factor were associated with greater loss of tibial cartilage volume and larger increases in tibiofemoral cartilage defects over 2 years. Patients with high and medium tertiles of clustering-factor had greater loss of cartilage volume per annum compared with those with a low tertile (for high 4.9%, for medium 4.6%, and for low 3.3% annually). Baseline percentage and clustering-factor were positively and significantly associated with increases in tibiofemoral BMLs over 2 years. Cross-sectional associations between IPFP measures and knee structures were similar but more consistent. CONCLUSION:Quantitative measures of increased signal intensity in the IPFP were associated with knee structural abnormalities in the tibiofemoral compartment, suggesting that these measurements could be used as an additional entry criterion to enrich studies for faster progressors of knee OA. 10.1002/acr.23713
Quantitative MRI analysis of infrapatellar and suprapatellar fat pads in normal controls, moderate and end-stage osteoarthritis. Fontanella Chiara Giulia,Belluzzi Elisa,Rossato Marco,Olivotto Eleonora,Trisolino Giovanni,Ruggieri Pietro,Rubini Alessandro,Porzionato Andrea,Natali Arturo,De Caro Raffaele,Vettor Roberto,Ramonda Roberta,Macchi Veronica,Favero Marta Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft The aim of this study was to analyze the magnetic resonance imaging (MRI) volumetric and morphometric characteristics of the infrapatellar fat pad (IFP) and the suprapatellar fat pad (SFP) in normal controls, moderate and end-stage osteoarthritis (OA) patients. Forty-four MRI images of the three groups were collected: a) 17 patients undergoing meniscectomy with Outerbridge score 0 (control group); b) 15 patients undergoing meniscectomy with Outerbridge score 3/4 (moderate OA group); and c) 12 patients undergoing total knee replacement (end-stage OA group). Volume, depth, femoral and tibial arch lengths of IFP were quantified. The hypointense IFP signals were also scored. The SFP volume, oblique, antero-posterior and cranio-caudal lengths were determined. IFP and SFP characteristics were compared between groups. A decrease of IFP volume, depth, femoral, and tibial arch lengths in moderate and end-stage OA compared to controls were observed. A difference in IFP hypointense signal was found between groups. No differences were found in SFP characteristics between the groups. In controls and moderate OA patients, correlations were found among the different MRI characteristics of both IFP and SFP, while in the end-stage OA group correlations were found only in SFP. We evidenced differences of the IFP MRI morphometric characteristics between the groups analyzed, supporting an important role of IFP in OA pathology and progression. On the contrary, no differences were highlighted in SFP analysis suggesting that this fat pad is not clearly involved in OA, probably due to its peculiar localization and different function. 10.1016/j.aanat.2018.09.007
Effusion-synovitis and infrapatellar fat pad signal intensity alteration differentiate accelerated knee osteoarthritis. Davis Julie E,Ward Robert J,MacKay James W,Lu Bing,Price Lori Lyn,McAlindon Timothy E,Eaton Charles B,Barbe Mary F,Lo Grace H,Harkey Matthew S,Driban Jeffrey B Rheumatology (Oxford, England) OBJECTIVES:To determine whether greater effusion-synovitis volume and infrapatellar fat pad (IFP) signal intensity alteration differentiate incident accelerated knee OA (KOA) from a gradual onset of KOA or no KOA. METHODS:We classified three sex-matched groups of participants in the Osteoarthritis Initiative who had a knee with no radiographic KOA at baseline (recruited 2004-06; Kellgren-Lawrence <2; n = 125/group): accelerated KOA: ⩾1 knee progressed to Kellgren-Lawrence grade ⩾3 within 48 months; common KOA: ⩾1 knee increased in radiographic scoring within 48 months; and no KOA: both knees had the same Kellgren-Lawrence grade at baseline and 48 months. The observation period included up to 2 years before and after when the group criteria were met. Two musculoskeletal radiologists reported presence of IFP signal intensity alteration and independent readers used a semi-automated method to segment effusion-synovitis volume. We used generalized linear mixed models with group and time as independent variables, as well as testing a group-by-time interaction. RESULTS:Starting at 2 years before disease onset, adults who developed accelerated KOA had greater effusion-synovitis volume than their peers (accelerated KOA: 11.94 ± 0.90 cm3, KOA: 8.29 ± 1.19 cm3, no KOA: 8.14 ± 0.90 cm3) and have greater odds of having IFP signal intensity alteration than those with no KOA (odds ratio = 2.07, 95% CI = 1.14-3.78). Starting at 1 year prior to disease onset, those with accelerated KOA have greater than twice the odds of having IFP signal intensity alteration than those with common KOA. CONCLUSION:People with IFP signal intensity alteration and/or greater effusion-synovitis volume in the absence of radiographic KOA may be at high risk for accelerated KOA, which may be characterized by local inflammation. 10.1093/rheumatology/key305
Histopathological changes in the infrapatellar fat pad in an experimental rabbit model of early patellofemoral osteoarthritis. Wang Binggang,Lang Yanfei,Zhang Liu The Knee BACKGROUND:The purpose of this study was to characterise the histopathological changes in the infrapatellar fat pad (IPFP) in the early stage of patellofemoral osteoarthritis (PFOA). METHODS:Sixty-four New Zealand white rabbits were randomly divided into experimental (n = 24), sham (n = 16), and control groups (n = 24). In the experimental group, denoted as the patellar ligament uneven shortening group (US group), the patellar ligament (PL) was folded eight millimetres and sutured. After eight weeks, all animals were euthanised, and magnetic resonance imaging (MRI) evaluation, wet IPFP weight measurement, and histopathological and immunohistochemistry analysis were performed to analyse the histopathological changes in the IPFPs. RESULTS:The maximum cross-sectional area (CSA) of the IPFPs in the sagittal position of MRI in the control group, sham group, and US group were 45.50 ± 7.19 mm, 45.88 ± 6.60 mm (vs. control group, P = 0.907), and 53.83 ± 8.24 mm (vs. control group, P = 0.015; vs. sham group, P = 0.035), respectively. The MRI intensity of the IPFPs in the control group, sham group, and US group were 115.53 ± 28.85, 108.53 ± 26.73 (vs. control group, P = 0.589), and 154.52 ± 18.48 (vs. control group, P = 0.002; vs. sham group, P = 0.002), respectively. The wet weight of the IPFPs in the control group, sham group, and US group were 0.32 ± 0.05 g, 0.32 ± 0.04 g (vs. control group, P = 0.895), and 0.38 ± 0.06 g (vs. control group, P = 0.017; vs. sham group, P = 0.033), respectively. The Osteoarthritis Research Society International (OARSI) scores of the IPFPs in the US group were 6.00 ± 1.91, which was higher than the scores of 2.50 ± 2.02 (P < 0.001) in the control group and of 2.75 ± 1.67 (P = 0.001) in the sham group. CONCLUSIONS:The histopathological changes of the IPFPs as determined via MRI and microscopic structure appeared to occur much earlier than cartilage damage in PFOA. Furthermore, detecting and treating the IPFP changes may offer aid in the diagnosis and treatment of PFOA. 10.1016/j.knee.2018.06.010
TGFβi is involved in the chondrogenic differentiation of mesenchymal stem cells and is dysregulated in osteoarthritis. Ruiz M,Maumus M,Fonteneau G,Pers Y-M,Ferreira R,Dagneaux L,Delfour C,Houard X,Berenbaum F,Rannou F,Jorgensen C,Noël D Osteoarthritis and cartilage OBJECTIVE:Transforming growth factor-β (TGFβ) is a major regulator of cartilage homeostasis and its deregulation has been associated with osteoarthritis (OA). Deregulation of the TGFβ pathway in mesenchymal stem cells (MSCs) has been proposed to be at the onset of OA. Using a secretome analysis, we identified a member of the TGFβ family, TGFβ-induced protein (TGFβi or βIGH3), expressed in MSCs and we investigated its function and regulation during OA. DESIGN:Cartilage, bone, synovium, infrapatellar fat pad and bone marrow-MSCs were isolated from patients with OA or healthy subjects. Chondrogenesis of BM-MSCs was induced by TGFβ3 in micropellet culture. Expression of TGFβi was quantified by RT-qPCR, ELISA or immunohistochemistry. Role of TGFβi was investigated in gain and loss of function experiments in BM-MSCs and chondrocytes. RESULTS:TGFβi was up-regulated in early stages of chondrogenesis and its knock-down in BM-MSCs resulted in the down-regulation of mature and hypertrophic chondrocyte markers. It likely occurred through the modulation of adhesion molecules including integrin (ITG)β1, ITGβ5 and N-cadherin. We also showed that TGFβi was upregulated in vitro in a model of OA chondrocytes, and its silencing enhanced the hypertrophic marker type X collagen. In addition, TGFβi was up-regulated in bone and cartilage from OA patients while its expression was reduced in BM-MSCs. Similar findings were observed in a murine model of OA. CONCLUSIONS:Our results revealed a dual role of TGFβi during chondrogenesis and pointed its deregulation in OA joint tissues. Modulating TGFβi in BM-MSCs might be of interest in cartilage regenerative medicine. 10.1016/j.joca.2018.11.005
Time course analyses of structural changes in the infrapatellar fat pad and synovial membrane during inflammation-induced persistent pain development in rat knee joint. Inomata Kei,Tsuji Kunikazu,Onuma Hiroaki,Hoshino Takashi,Udo Mio,Akiyama Masako,Nakagawa Yusuke,Katagiri Hiroki,Miyatake Kazumasa,Sekiya Ichiro,Muneta Takeshi,Koga Hideyuki BMC musculoskeletal disorders BACKGROUND:Osteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model. METHODS:Wistar rats received single intra-articular injection of monoiodoacetic acid (MIA, 0.2 or 1.0 mg/30 μL) in the right knees or phosphate-buffered saline (PBS, 30 μL) as a control in the left knees. Pain avoidance behaviors (weight-bearing asymmetry and tactile hypersensitivity of the plantar surface of the hind paw) were evaluated on days 0, 1, 3, 5, 7, and 14 after injection. Histological assessments of the knee joint were performed on days 0, 1, 3, 5, and 7 after MIA injection. RESULTS:Weight-bearing asymmetry was observed along with the onset of acute inflammation in both the low- (0.2 mg) and high-dose (1.0 mg) groups. In the low-dose group, weight-bearing asymmetry was completely reversed on day 10, indicating that joint pain seemed to alleviate between days 7 and 10. In contrast, we observed persistent joint pain after day 10 in the high-dose group. Histological assessments of the high-dose group indicated that the initial sign of inflammatory responses was observed in the perivascular region inside the IFP. Inflammatory cell infiltration from the perivascular region to the parenchymal region of the IFP was observed on day 3 and reached the IFP surface (synovial membrane) on day 7. Extensive fibrosis throughout the IFP was observed between days 5 and 7 after MIA injection. CONCLUSION:Our data indicated that acute joint pain occurs along with the onset of acute inflammatory process. Irreversible structural changes in the IFP, such as extensive fibrosis, are observed prior to persistent pain development. Thus, we consider that this process may play important roles in persistent pain development. 10.1186/s12891-018-2391-1
Preservation vs. resection of the infrapatellar fat pad during total knee arthroplasty part II: A systematic review of published evidence. Nisar S,Lamb J N,Somashekar N,Pandit H,van Duren B H The Knee BACKGROUND:The management of the infrapatellar fat pad (IPFP) during total knee arthroplasty (TKA) is the subject of ongoing debate. In part 2 of this two part series the authors aimed to investigate if resection of the IPFP affects clinical outcomes. METHODS:A systematic search of CENTRAL Cochrane library, Medline, Embase and Web-of-science databases for the past 10 years was performed. Studies of patients undergoing primary TKA comparing outcomes between IPFP resection and preservation were included. The meta-analysis was performed with Review Manager 5.3. RESULTS:Seven studies, involving 2815 patients (3312 knees) were included in the systematic review, of which two were RCTs. Outcome measures included patellar tendon length (PTL), post-operative pain, Knee Society Scores (KSS) and Functional Scores. Meta-analysis identified a trend toward shortening of the patellar tendon with IPFP resection. Resection correlated with a lower incidence of post-operative pain at one to two months, however at three to six months pain scores were higher in this group. No statistical difference was found in KSS and Functional Scores. CONCLUSION:There is wide variation in practice with regard to the IPFP in TKA. The available literature with regard to resection or preservation of the IPFP is not conclusive. IMPLICATIONS:There is no clear consensus in the literature on the resection or preservation of the IPFP indicating a clear need for high quality studies in the future to provide meaningful answers. 10.1016/j.knee.2019.01.007
Preservation vs. resection of the infrapatellar fat pad during total knee arthroplasty Part I: A survey of current practice in the UK. van Duren B H,Lamb J N,Nisar S,Ashraf Y,Somashekar N,Pandit H The Knee BACKGROUND:The management of the infrapatellar fat pad (IPFP) during total knee arthroplasty (TKA) is the subject of ongoing debate. In part 1 of this two-part series, we present an overview of current practice regarding the management of the IPFP in elective TKA among surgeons in the UK. METHODS:A web-based survey was offered to 269 delegates of the BASK 2017 annual conference. RESULTS:The survey showed a large variation in practice. Of the 173 responders, 86.7% were consultants; 62.4% partially resected the IPFP; 23.1% totally resected the IPFP, and 9.8% preserved it. Forty percent felt that resection made a difference. Only 23% stated that they were aware of guidelines/evidence. CONCLUSION:There is wide variation in practice with regard to the IPFP in TKA. The available literature with regard to resection or preservation of the IPFP is not conclusive. IMPLICATIONS:There are no definitive guidelines available for the management of the IPFP in TKA resulting in a wide variation in practice amongst surgeons. 10.1016/j.knee.2018.12.010
Anterior cruciate ligament transection alters the n-3/n-6 fatty acid balance in the lapine infrapatellar fat pad. Mustonen Anne-Mari,Käkelä Reijo,Finnilä Mikko A J,Sawatsky Andrew,Korhonen Rami K,Saarakkala Simo,Herzog Walter,Paakkonen Tommi,Nieminen Petteri Lipids in health and disease BACKGROUND:The infrapatellar fat pad (IFP) of the knee joint has received lots of attention recently due to its emerging role in the pathogenesis of osteoarthritis (OA), where it displays an inflammatory phenotype. The aim of the present study was to examine the infrapatellar fatty acid (FA) composition in a rabbit (Oryctolagus cuniculus) model of early OA created by anterior cruciate ligament transection (ACLT). METHODS:OA was induced randomly in the left or right knee joint of skeletally mature New Zealand White rabbits by ACLT, while the contralateral knee was left intact. A separate group of unoperated rabbits served as controls. The IFP of the ACLT, contralateral, and control knees were harvested following euthanasia 2 or 8 weeks post-ACLT and their FA composition was determined with gas chromatography-mass spectrometry. RESULTS:The n-3/n-6 polyunsaturated FA (PUFA) ratio shifted in a pro-inflammatory direction after ACLT, already observed 2 weeks after the operation (0.20 ± 0.008 vs. 0.18 ± 0.009). At 8 weeks, the FA profile of the ACLT group was characterized with increased percentages of 20:4n-6 (0.44 ± 0.064 vs. 0.98 ± 0.339 mol-%) and 22:6n-3 (0.03 ± 0.014 vs. 0.07 ± 0.015 mol-%) and with decreased monounsaturated FA (MUFA) sums (37.19 ± 1.586 vs. 33.20 ± 1.068 mol-%) and n-3/n-6 PUFA ratios (0.20 ± 0.008 vs. 0.17 ± 0.008). The FA signature of the contralateral knees resembled that of the unoperated controls in most aspects, but had increased proportions of total n-3 PUFA and reduced MUFA sums. CONCLUSIONS:These findings provide novel information on the effects of early OA on the infrapatellar FA profile in the rabbit ACLT model. The reduction in the n-3/n-6 PUFA ratio of the IFP is in concordance with the inflammation and cartilage degradation in early OA and could contribute to disease pathogenesis. 10.1186/s12944-019-1008-5
In vivo articular cartilage regeneration through infrapatellar adipose tissue derived stem cell in nanofiber polycaprolactone scaffold. Vahedi Parviz,Jarolmasjed Seyedhosein,Shafaei Hajar,Roshangar Leila,Soleimani Rad Jafar,Ahmadian Elham Tissue & cell In this study, we report the development of a nanofiber polycaprolactone scaffold that can act as a stem cell carrier to induce chondrogenesis and promote cartilage repair in vivo. Infrapatellar fat pads were obtained from sheep knee and the stem cells were isolated and characterized by flow cytometry. Defects were created in sheep knee, two defects received adipose tissue derived stem cells (ASCs)-polycaprolactone construct, second group received polycaprolactone (PCL), the third group was chosen as the ASCs group and the fourth group was control group. Morphological evaluation showed that defects treated with ASCs-scaffold constructs were completely filled with cartilage-like tissue, while other groups revealed the formation of a thin layer of cartilage-like tissue in the defects. Real-Time RT-PCR showed the increase in collagen type 2 mRNA levels, aggrecan and Sox9 in ASCs/PCL groups in comparison with the other groups. Immunofluorescence and toluidine blue staining results showed the protein expression of collagen type 2 and formation of round and polygonal clusters of chondrocytes in ASCS/PCL group. According to our results nanofiber polycaprolactone promoted the chondrogenesis of infrapatellar adipose tissue derived stem cells in vivo and could offer significant promise in the biological functionality of stem cell tissue engineering in clinical practice. 10.1016/j.tice.2019.02.002
Contribution of Infrapatellar Fat Pad and Synovial Membrane to Knee Osteoarthritis Pain. Belluzzi Elisa,Stocco Elena,Pozzuoli Assunta,Granzotto Marnie,Porzionato Andrea,Vettor Roberto,De Caro Raffaele,Ruggieri Pietro,Ramonda Roberta,Rossato Marco,Favero Marta,Macchi Veronica BioMed research international Osteoarthritis (OA) is the most common form of joint disease and a major cause of pain and disability in the adult population. Interestingly, there are patients with symptomatic OA displaying pain, while patients with asymptomatic OA that do not experience pain but show radiographic signs of joint damage. Pain is a complex experience integrating sensory, affective, and cognitive processes related to several peripheral and central nociceptive factors besides inflammation. During the last years, the role of infrapatellar fat pad (IFP), other than the synovial membrane, has been investigated as a potential source of pain in OA. Interestingly, new findings suggest that IFP and synovial membrane might act as a functional unit in OA pathogenesis and pain. The present review discuss the role of IFP and synovial membrane in the development of OA, with a particular focus on pain onset and the possible involved mediators that may play a role in OA pathology and pain mechanisms. Inflammation of IFP and synovial membrane may drive peripheral and central sensitization in KOA. Since sensitization is associated with pain severity in knee OA and may potentially contribute to the transition from acute to chronic, persistent pain in knee OA, preventing sensitization would be a potentially effective and novel means of preventing worsening of pain in knee OA. 10.1155/2019/6390182
Cartilage tissue engineering combining microspheroid building blocks and microneedle arrays. Grogan Shawn P,Dorthé Erik W,Glembotski Nicholas E,Gaul Florian,D'Lima Darryl D Connective tissue research : Scaffold-free cartilage tissue engineering circumvents issues with scaffold seeding, potential toxicity response, and impaired host integration. However, precisely controlling and maintaining a scaffold-free construct shape have been challenging. We explored the feasibility of microneedle arrays to print tissue using cellular microspheroids as building blocks.: Human embryonic-derived mesenchymal stem cells or infrapatellar fat pad mesenchymal stem cells were used to create microspheroids of 500 µm in diameter, which were assembled on microneedle arrays in a predefined arrangement using a robotic system under computer vision. Microspheroids on microneedles were cultured to permit fusion into a tissue construct. Infrapatellar fat pad mesenchymal stem cell constructs were either implanted into chondral defects created in human osteoarthritic cartilage explants or maintained on the microneedle array for 3 weeks. Embryonic-derived mesenchymal stem cell constructs were designed to be press-fit into 3 mm subchondral defects in New Zealand White rabbits and maintained for up to 8 weeks to assess retention, early tissue repair, and more mature cartilage regeneration.: Microspheroids of both cell types fused together in culture to form neotissues of predefined shape and size. Infrapatellar fat pad mesenchymal stem cell neotissues expressed high levels of chondrogenic genes and integrated with the surrounding osteoarthritic host cartilage. Embryonic-derived mesenchymal stem cell constructs generated chondrogenic neotissue as early as 2 weeks and more mature tissue by 8 weeks with increased glycosaminoglycan deposition.: We constructed defined scaffold-free shapes by bioprinting and fusing microspheroids. Proof of concept was shown in the repair of osteoarthritic human cartilage and rabbit osteochondral (OC) defects. 10.1080/03008207.2019.1617280
Associations between serum IL-8 and knee symptoms, joint structures, and cartilage or bone biomarkers in patients with knee osteoarthritis. Ruan Guangfeng,Xu Jianhua,Wang Kang,Zheng Shuang,Wu Juan,Bian Fuqin,Chang Bingru,Zhang Yan,Meng Tao,Zhu Zhaohua,Han Weiyu,Ding Changhai Clinical rheumatology OBJECTIVE:The aim of this study was to investigate cross-sectional associations between serum levels of IL-8 and the above outcomes in patients with knee osteoarthritis (OA). METHODS:A total of 160 subjects with clinical knee OA were included. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and Lequesne index were used to assess the joint symptom. Magnetic resonance imaging was used to measure knee structural abnormalities including infrapatellar fat pad (IPFP) signal intensity alternation. Knee radiographic OA was assessed by radiography using the Kellgren-Lawrence (K-L) grading system. Enzyme-linked immunosorbent assay was used to measure the serum levels of IL-8 and cartilage or bone biomarkers. RESULTS:In multivariable analyses, serum IL-8 was positively associated with WOMAC weight-bearing pain (β 2.85, P = 0.028), WOMAC physical dysfunction (β 12.71, P = 0.048), and Lequesne index (β 1.65, P = 0.015), and had positive associations with IPFP signal intensity alteration (OR 3.18, P = 0.011) and serum levels of N-telopeptide of type I collagen (NTXI), N-terminal procollagen III propeptide (PIIINP), matrix metalloproteinase (MMP)3, and MMP13 (β 0.24-1.44, all P < 0.05) in patients with clinical knee OA. Furthermore, there were positive associations between IL-8 and WOMAC score (β 22.49, P = 0.037), K-L grades (OR 3.88, P = 0.013), and IPFP signal intensity alteration (OR 3.20, P = 0.033) in patients with radiographic OA. CONCLUSIONS:Serum levels of IL-8 were positively associated with increased knee symptoms, IPFP signal intensity alteration, and serum levels of bone and/or cartilage biomarkers, suggesting that IL-8 may have a role to play in knee OA.Key Point• This study systemically investigates the associations between serum IL 8 and knee symptoms, joint structures, and cartilage or bone biomarkers in patients with knee osteoarthritis, and some significant associations have been found, suggesting that IL 8 may have a role to play in knee OA. 10.1007/s10067-019-04718-8
Infrapatellar Fat Pad Resection or Preservation during Total Knee Arthroplasty: A Systematic Review. Yao Benjamin,Samuel Linsen T,Acuña Alexander J,Faour Mhamad,Roth Alexander,Kamath Atul F,Mont Michael A The journal of knee surgery Considerations of how to improve postoperative outcomes for total knee arthroplasty (TKA) have included preservation of the infrapatellar fat pad (IPFP). Although the IPFP is commonly resected during TKA procedures, there is controversy regarding whether resection or preservation should be implemented, and how this influences outcomes. Therefore, the purpose of this systematic review was to evaluate how IPFP resection and preservation impacts postoperative flexion, pain, Insall-Salvati Ratio (ISR), Knee Society Score (KSS), patellar tendon length (PTL), and satisfaction in primary TKA. PubMed, EBSCO host, and SCOPUS were queried to retrieve all reports evaluating IPFP resection or preservation during TKA, which resulted into 488 studies. Two reviewers independently reviewed these articles for eligibility based on pre-established inclusion and exclusion criteria. Eleven studies were identified for final analysis, which reported on 11,996 cases. Patient demographics, type of surgical intervention, follow-up duration, and clinical outcome measures were collected and analyzed. Complete resection was implemented in 3,723 cases (31%), partial resection in 5,458 cases (45.5%), and preservation of the IPFP in 2,815 cases (23.5%). Clinical outcome measures included PTL (5 studies), knee flexion (4 studies), pain (6 studies), KSS (3 studies), ISR (3 studies), and patient satisfaction (1 study). No differences were found following IPFP resection for patient satisfaction ( = 0.98), ISR (> 0.05), and KSS (> 0.05). There was mixed evidence for PTL, pain, and knee flexion following IPFP resection versus preservation. Studies of shorter follow-up intervals suggested improved pain following resection, while reports of longer follow-up times indicated that resection resulted in increased pain. Given the mixed data available from the current literature, we were unable to conclude that one surgical technique can definitively be considered superior over the other. More extensive research, including randomized controlled trials, is required to better elucidate potential differences between the surgical handling choices. Future studies should focus on patient conditions in which one technique would be best indicated to establish guidelines for best surgical outcomes in those patients. 10.1055/s-0039-1696692
Infrapatellar fat pad abnormalities are associated with a higher inflammatory synovial fluid cytokine profile in young adults following ACL tear. Osteoarthritis and cartilage OBJECTIVE:To evaluate the degree of knee fat pad abnormalities after acute anterior cruciate ligament (ACL) tear via magnetic resonance fat pad scoring and to assess cross-sectionally its association with synovial fluid biomarkers and with early cartilage damage as quantified via T1ρ and T2 relaxation time measurements. DESIGN:26 patients with acute ACL tears underwent 3T MR scanning of the injured knee prior to ACL reconstruction. The presence and degree of abnormalities of the infrapatellar (IPFP) and the suprapatellar (SPFP) fat pads were scored on MR images along with grading of effusion-synovitis and synovial proliferations. Knee cartilage composition was assessed by 3T MR T1ρ and T2 mapping in six knee compartments. We quantified concentrations of 20 biomarkers in synovial fluid aspirated at the time of ACL reconstruction. Spearman rank partial correlations with adjustments for age and gender were employed to evaluate correlations of MR, particularly cartilage composition and fat pad abnormalities, and biomarker data. RESULTS:The degree of IPFP abnormality correlated positively with the synovial levels of the inflammatory cytokine markers IFN-γ (ρ = 0.64, 95% CI (0.26-0.85)), IL-10 (ρ = 0.47, 95% CI (0.04-0.75)), IL-6 (ρ = 0.56, 95% CI (0.16-0.81)), IL-8 (ρ = 0.49, 95% CI (0.06-0.76)), TNF-α (ρ = 0.55, 95% CI (0.14-0.80)) and of the chondrodestructive markers MMP-1 and -3 (MMP-1: ρ = 0.57, 95% CI (0.17-0.81); MMP-3: ρ = 0.60, 95% CI (0.21-0.83)). IPFP abnormalities were significantly associated with higher T1ρ and T2 values in the trochlear cartilage (T1ρ: ρ = 0.55, 95% CI (0.15-0.80); T2: ρ = 0.58, 95% CI (0.18-0.81)) and with higher T2 values in the medial femoral, medial tibial as well as in patellar cartilage (0.45 ≤ ρ ≤ 0.59). Correlations between SPFP abnormalities and synovial markers were not significant except for IL-6 (ρ = 0.57, 95% CI (0.17-0.81)). CONCLUSIONS:This exploratory study suggests that acute ACL rupture can be associated with damage to knee tissues such as the inferior fat pad of the knee. Such fat pad injury could be partially responsible for the apparent post-injury pro-inflammatory response noted in ACL-injured individuals. However, future longitudinal studies are needed to link ACL-rupture associated fat pad injury with important patient outcomes such as the development of posttraumatic osteoarthritis. 10.1016/j.joca.2019.09.001
Role of infrapatellar fat pad in pathological process of knee osteoarthritis: Future applications in treatment. Jiang Li-Feng,Fang Jing-Hua,Wu Li-Dong World journal of clinical cases It has been found that obese people have a higher proportion in suffering from osteoarthritis (OA), not only in the weight-bearing joints like knee and hip joints, even in non-weight-bearing joints such as hand joints. One of the reasons is because the large amount of adipose tissue secretes some factors, which can promote the occurrence of arthritis. As an important structure of the knee joint, the infrapatellar fat pad (IPFP) is actually a piece of adipose tissue. The aim of this review is to offer a comprehensive view of the anatomy and physiological characteristics of IPFP and its relationship with the pathological process of OA, indicating the important function of IPFP in OA. At the same time, with the development of adipose derived stem cells in the treatment of OA, owing to its special advantages, the IPFP is becoming a kind of important, minimally invasive fat stem cell source, providing a new approach for the treatment of OA. We hope that this review will offer an overview of all published data regarding the IPFP and will indicate novel directions for future research. 10.12998/wjcc.v7.i16.2134
Genetic mapping of distal femoral, stifle, and tibial radiographic morphology in dogs with cranial cruciate ligament disease. Healey Eleni,Murphy Rachel J,Hayward Jessica J,Castelhano Marta,Boyko Adam R,Hayashi Kei,Krotscheck Ursula,Todhunter Rory J PloS one Cranial cruciate ligament disease (CCLD) is a complex trait. Ten measurements were made on orthogonal distal pelvic limb radiographs of 161 pure and mixed breed dogs with, and 55 without, cranial cruciate partial or complete ligament rupture. Dogs with CCLD had significantly smaller infrapatellar fat pad width, higher average tibial plateau angle, and were heavier than control dogs. The first PC weightings captured the overall size of the dog's stifle and PC2 weightings reflected an increasing tibial plateau angle coupled with a smaller fat pad width. Of these dogs, 175 were genotyped, and 144,509 polymorphisms were used in a genome-wide association study with both a mixed linear and a multi-locus model. For both models, significant (pgenome <3.46×10-7 for the mixed and< 6.9x10-8 for the multilocus model) associations were found for PC1, tibial diaphyseal length and width, fat pad base length, and femoral and tibial condyle width at LCORL, a known body size-regulating locus. Other body size loci with significant associations were growth hormone 1 (GH1), which was associated with the length of the fat pad base and the width of the tibial diaphysis, and a region on CFAX near IRS4 and ACSL4 in the multilocus model. The tibial plateau angle was associated significantly with a locus on CFA10 in the linear mixed model with nearest candidate genes BET1 and MYH9 and on CFA08 near candidate genes WDHD1 and GCH1. MYH9 has a major role in osteoclastogenesis. Our study indicated that tibial plateau slope is associated with CCLD and a compressed infrapatellar fat pad, a surrogate for stifle osteoarthritis. Because of the association between tibial plateau slope and CCLD, and pending independent validation, these candidate genes for tibial plateau slope may be tested in breeds susceptible to CCLD before they develop disease or are bred. 10.1371/journal.pone.0223094
Point-of-Care Procedure for Enhancement of Meniscal Healing in a Goat Model Utilizing Infrapatellar Fat Pad-Derived Stromal Vascular Fraction Cells Seeded in Photocrosslinkable Hydrogel. Rothrauff Benjamin B,Sasaki Hiroshi,Kihara Shinsuke,Overholt Kalon J,Gottardi Riccardo,Lin Hang,Fu Freddie H,Tuan Rocky S,Alexander Peter G The American journal of sports medicine BACKGROUND:Large radial tears of the meniscus involving the avascular region can compromise meniscal function and result in poor healing and subsequent osteochondral degeneration. Augmentation of surgical repairs with adipose-derived stromal vascular fraction (SVF), which contains mesenchymal stromal cells, may improve meniscal healing and preserve function (ie, chondroprotection). PURPOSES:(1) To develop a goat model of a radial meniscal tear with resulting osteoarthritis and (2) to explore the efficacy of a 1-step procedure utilizing infrapatellar fat pad-derived SVF cells seeded in a photocrosslinkable hydrogel to enhance meniscal healing and mitigate osteochondral degeneration. STUDY DESIGN:Controlled laboratory study. METHODS:A full-thickness radial tear spanning 90% of the medial meniscal width was made at the junction of the anterior and middle bodies of the goat stifle joint. Tears received 1 of 3 interventions (n = 4 per group): untreated, repair, or repair augmented with photocrosslinkable methacrylated gelatin hydrogel containing 2.0 × 10 SVF cells/mL and 2.0 µg/mL of transforming growth factor β3. The contralateral (left) joint served as a healthy control. At 6 months, meniscal healing and joint health were evaluated by magnetic resonance imaging (MRI) and assessed by histological and macroscopic scoring. The Whole-Organ Magnetic Resonance Imaging Score and the presence of a residual tear, as evaluated with T2 MRI sequences, were determined by a single blinded orthopaedic surgeon. RESULTS:When compared with tears left untreated or repaired with suture alone, augmented repairs demonstrated increased tissue formation in the meniscal tear site, as seen on MRI and macroscopically. Likewise, the neotissue of augmented repairs possessed a histological appearance more similar, although still inferior, to healthy meniscus. Osteochondral degeneration in the medial compartment, as evaluated by the Whole-Organ Magnetic Resonance Imaging Score and Inoue (macroscopic) scale, revealed increased degeneration in the untreated and repair groups, which was mitigated in the augmented repair group. Histological evaluation with a modified Mankin score showed a similar trend. In all measures of osteochondral degeneration, the augmented repair group did not differ significantly from the uninjured control. CONCLUSION:A radial tear spanning 90% of the medial meniscal width in a goat stifle joint showed poor healing potential and resulted in osteochondral degeneration by 6 months, even if suture repair was performed. Augmentation of the repair with a photocrosslinkable hydrogel containing transforming growth factor β3 and SVF cells, isolated intraoperatively by rapid enzymatic digestion, improved meniscal healing and mitigated osteoarthritic changes. CLINICAL RELEVANCE:Repair augmentation with an SVF cell-seeded hydrogel may support successful repair of meniscal tears previously considered irreparable. 10.1177/0363546519880468
Osteoporosis and osteoarthritis are two sides of the same coin paid for obesity. Oliveira Marina C,Vullings Julia,van de Loo Fons A J Nutrition (Burbank, Los Angeles County, Calif.) Obesity is characterized by adipose tissue expansion and chronic low-grade inflammation. Among the inflammatory mediators related to obesity development are the adipokines. These cytokines are released from fatty tissues and act in an autocrine, paracrine, or endocrine manner. Adipocytes influence the comorbidities of obesity such as osteoporosis (OP) and osteoarthritis (OA). It is still controversial as to whether OP is associated with either a low or high body mass index, but it is quite clear that the latter condition increases the risk for OA development. Bone marrow adipocytes (BMAs) have the same precursors of osteoblasts, which are the primary cells involved in bone formation, and the amount of BMAs appears to be inversely related to bone mineral density. Although adipokines released by these adipocytes influence bone loss progress, their exact role remains controversial. Differently, the infrapatellar fat pad (IPFP) is indicated to protect the function of joint regarding OA. However, there is relatively limited information about the secretion of adipokines and other inflammatory mediators by the IPFP. Despite some inconsistencies, nutritional interventions targeting obesity may also benefit patients with OP and OA. The association among obesity, OP, and OA is quite complex, and many factors need to be explored that are mainly related to the role of adipokines derived locally rather than from visceral and subcutaneous adipose tissue. Also, nutritional intervention may affect fatty tissue mass and secretion of inflammatory mediators that may, at least in part, influence other tissues in the organism such as bone and articular cartilage. The aim of this review was to present the latest knowledge about the interrelationship between obesity and OA or OP and to discuss whether a dietary intervention for obesity will hold promise for patients with OA or OP. 10.1016/j.nut.2019.04.001
Native-Osteoarthritic Joint Resident Stem and Progenitor Cells for Cartilage Cell-Based Therapies: A Quantitative Comparison With Respect to Concentration and Biological Performance. Mantripragada Venkata P,Bova Wes A,Piuzzi Nicolas S,Boehm Cynthia,Obuchowski Nancy A,Midura Ronald J,Muschler George F The American journal of sports medicine BACKGROUND:Cell-based therapy for cartilage repair is a promising approach and is becoming an established technique. Yet, there is no consensus on the optimal cell source. PURPOSE:To provide a donor-matched quantitative comparison of the connective tissue progenitors (CTPs) derived from cartilage (Outerbridge grade 1-3 [G1-2-3]), bone marrow aspirate concentrate (BMC), infrapatellar fat pad (IPFP), synovium, and periosteum with respect to (1) cell concentration ([Cell], cells/mL), (2) CTP prevalence (P, colonies per million cells), and (3) biological performance based on in vitro proliferation potential (cells per colony) colony density, and differentiation potential (expression of negatively charged extracellular matrix: glycosaminoglycan-rich extra cellular matrix [GAG-ECM]). STUDY DESIGN:Descriptive laboratory study. METHODS:Tissues were obtained from 10 patients undergoing total knee arthroplasty (mean age, 59 years; women, n = 6). Automated quantitative colony-forming unit analysis was used to compare [Cell], P, and CTP biological performance across tissue sources. RESULTS:[Cell] was highest in grade 3 cartilage ( = .002) and BMC ( = .001). Median P was highest in IPFP ( = .001), synovium ( = .003), and G1-2 cartilage ( = .02). Proliferation was highest in synovium-derived CTPs ( < .001). Median colony density was highest in G1-2-3 ( < .001). Median GAG-ECM was highest in G1-2-3 ( < .001). Within each patient, CTPs derived from all tissues were highly heterogeneous in biological performance as determined by cells per colony, density, and GAG-ECM. CONCLUSION:Tissue sources differ in [Cell], P, and biological attributes. The data presented in this study suggest that cartilage (G1-2-3) is the preferred tissue source for cartilage repair based on P and GAG-ECM, followed by synovium, IPFP, BMC, and periosteum. However, due to the heterogeneous mixture of CTPs within each tissue source, there exists a subset of CTPs with biological performance similar to G1-2-3 cartilage, particularly in synovium and IPFP. Performance-based clonal selection and expansion of preferred CTPs and their progeny will potentially lead to improved cell population with predictive future. CLINICAL RELEVANCE:Optimal tissue regeneration strategies will require informed decisions regarding which of the available tissue sources to use. Optimizing cell sourcing in any tissue may require separation of CTPs with preferred attributes from those with less desirable attributes. The heterogeneity manifest in the early stage of colony formation represents an opportunity for performance-based clone selection for clinical cell processing and manufacturing. 10.1177/0363546519880905
Infrapatellar fat pad resection during total knee arthroplasty: yet another reason for? Annals of the rheumatic diseases 10.1136/annrheumdis-2018-213684
Fibrotic changes in the infrapatellar fat pad induce new vessel formation and sensory nerve fiber endings that associate prolonged pain. Onuma Hiroaki,Tsuji Kunikazu,Hoshino Takashi,Inomata Kei,Udo Mio,Nakagawa Yusuke,Katagiri Hiroki,Miyatake Kazumasa,Watanabe Toshifumi,Sekiya Ichiro,Muneta Takeshi,Koga Hideyuki Journal of orthopaedic research : official publication of the Orthopaedic Research Society The infrapatellar fat pad (IFP) contains nerve fiber endings and is considered to play an important role in the perception of knee pain. However, it is unclear whether and to what degree prolonged pain influences the nociceptive role of the IFP. To answer this question, we established a novel rat model of knee pain in which inflammation is restricted to the IFP. Rats received a single intra-IFP injection of monoiodoacetic acid (MIA) (0.2 mg/10 µL or 1.0 mg/10 µL) in the left knee and a phosphate-buffered saline (10 µL) injection in the right knee as a control. Pain-avoidance behavior and histological changes of the knee joint were measured at multiple time points up to 28 days after MIA injection. Histological analysis showed a transient inflammatory response in the IFP body in the 0.2-mg model, whereas prolonged inflammation followed by fibrotic changes was observed in the 1.0-mg model. Subtle histological alterations were observed in the articular cartilage and IFP surface regardless of the dose. The pain-avoidance behavior test indicated the development of prolonged knee pain throughout the experimental period in the 1.0-mg group. Histological assessments showed a significant increase in calcitonin gene-related peptide (CGRP)-positive nerve fiber endings inside IFPs with fibrosis in newly vascularized surrounding regions. These data suggest that irreversible fibrotic changes in the IFP induce the formation of new vessels and CGRP-positive nerve fiber endings that associate prolonged pain in the joint. 10.1002/jor.24580
Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis. Bian Fuqin,Ruan Guangfeng,Xu Jianhua,Wang Kang,Wu Juan,Ren Jiale,Chang Bingru,Ding Changhai International journal of rheumatic diseases OBJECTIVE:The aim of this study was to investigate cross-sectional associations between serum levels of citrate and knee structural changes and cartilage enzymes in patients with knee osteoarthritis (OA). METHOD:A total of 137 subjects with symptomatic knee OA (mean age 55.0 years, range 34-74, 84% female) were included. Knee radiography was used to assess knee osteophytes, joint space narrowing (JSN) and radiographic OA assessed by Kellgren-Lawrence (K-L) grading system. T2-weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI) was used to determine knee cartilage defects, bone marrow lesions (BMLs) and infrapatellar fat pad (IPFP) signal intensity alternations. Colorimetric fluorescence was used to measure the serum levels of citrate. Enzyme-linked immunosorbent assay was used to measure the serum cartilage enzymes including matrix metalloproteinase (MMP)-3 and MMP-13. RESULTS:After adjustment for potential confounders (age, sex, body mass index), serum citrate was negatively associated with knee osteophytes at the femoral site, cartilage defects at medial femoral site, total cartilage defects, and total BMLs (odds ratio [OR] 0.17-0.30, all P < .05). Meanwhile, serum citrate was negatively associated with IPFP signal intensity alteration (OR 0.30, P = .05) in multivariable analyses. Serum citrate was significantly and negatively associated with MMP-13 (β -3106.37, P < .05) after adjustment for potential confounders. However, citrate was not significantly associated with MMP-3 in patients with knee OA. CONCLUSION:Serum citrate was negatively associated with knee structural changes including femoral osteophytes, cartilage defects, and BMLs and also serum MMP-13 in patients with knee OA, suggesting that low serum citrate may be a potential indicator for advanced knee OA. 10.1111/1756-185X.13787
Quantitative DCE-MRI demonstrates increased blood perfusion in Hoffa's fat pad signal abnormalities in knee osteoarthritis, but not in patellofemoral pain. European radiology OBJECTIVE:Infrapatellar fat pad (IPFP) fat-suppressed T2 (T2) hyperintense regions on MRI are an important imaging feature of knee osteoarthritis (OA) and are thought to represent inflammation. These regions are also common in non-OA subjects, and may not always be linked to inflammation. Our aim was to evaluate quantitative blood perfusion parameters, as surrogate measure of inflammation, within T2-hyperintense regions in patients with OA, with patellofemoral pain (PFP) (supposed OA precursor), and control subjects. METHODS:Twenty-two knee OA patients, 35 PFP patients and 43 healthy controls were included and underwent MRI, comprising T2 and DCE-MRI sequences. T2-hyperintense IPFP regions were delineated and a reference region was drawn in adjacent IPFP tissue with normal signal intensity. After fitting the extended Tofts pharmacokinetic model, quantitative DCE-MRI perfusion parameters were compared between the two regions within subjects in each subgroup, using a paired Wilcoxon signed-rank test. RESULTS:T2-hyperintense IPFP regions were present in 16 of 22 (73%) OA patients, 13 of 35 (37%) PFP patients, and 14 of 43 (33%) controls. DCE-MRI perfusion parameters were significantly different between regions with and without a T2-hyperintense signal in OA patients, demonstrating higher Ktrans compared to normal IFPF tissue (0.039 min versus 0.025 min, p = 0.017) and higher Ve (0.157 versus 0.119, p = 0.010). For PFP patients and controls no significant differences were found. CONCLUSIONS:IPFP T2-hyperintense regions are associated with higher perfusion in knee OA patients in contrast to identically appearing regions in PFP patients and controls, pointing towards an inflammatory pathogenesis in OA only. KEY POINTS:• Morphologically identical appearing T2-hyperintense infrapatellar fat pad regions show different perfusion in healthy subjects, subjects with patellofemoral pain, and subjects with knee osteoarthritis. • Elevated DCE-MRI perfusion parameters within T2-hyperintense infrapatellar fat pad regions in patients with osteoarthritis suggest an inflammatory pathogenesis in osteoarthritis, but not in patellofemoral pain and healthy subjects. 10.1007/s00330-020-06671-6
Correlation network analysis shows divergent effects of a long-term, high-fat diet and exercise on early stage osteoarthritis phenotypes in mice. Griffin Timothy M,Batushansky Albert,Hudson Joanna,Lopes Erika Barboza Prado Journal of sport and health science Background:Obesity increases knee osteoarthritis (OA) risk through metabolic, inflammatory, and biomechanical factors, but how these systemic and local mediators interact to drive OA pathology is not well understood. We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice. We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups. Methods:Male C57BL/6J mice were fed a defined control (10% kcal fat) or high fat (HF) (60% kcal fat) diet from 6 to 37 weeks of age. At 25 weeks, one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study. Histology, micro computed tomography, and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology. These local variables were then compared to systemic metabolic (body mass, body fat, and glucose tolerance), inflammatory (serum adipokines and inflammatory mediators), and functional (mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis. Diet and exercise effects were evaluated by two-way analysis of variance. Results:An HF diet increased the infrapatellar fat pad size and posterior joint osteophytes, and wheel running primarily altered the subchondral cortical and trabecular bone. Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups. However, the coefficient of variation was ≥25% for many outcomes, and some mice in both diet groups developed moderate OA (≥33% maximum score). This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes. In wheel-running cohorts, an HF diet reduced the network size compared to the control diet group despite similar running distances, suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors. Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA. Conclusion:Despite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations, diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA. These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease. 10.1016/j.jshs.2019.05.008
Influence of Glucose Concentration on Colony-Forming Efficiency and Biological Performance of Primary Human Tissue-Derived Progenitor Cells. Cartilage OBJECTIVE:Glucose concentrations used in current cell culture methods are a significant departure from physiological glucose levels. The study focuses on comparing the effects of glucose concentrations on primary human progenitors (connective tissue progenitors [CTPs]) used for cartilage repair. DESIGN:Cartilage- (Outerbridge grade 1, 2, 3; superficial and deep zone cartilage), infrapatellar fatpad-, synovium-, and periosteum-derived cells were obtained from 63 patients undergoing total knee arthroplasty and cultured simultaneously in fresh chondrogenic media containing 25 mM glucose (HGL) or 5 mM glucose (NGL) for pairwise comparison. Automated ASTM-based quantitative image analysis was used to determine colony-forming efficiency (CFE), effective proliferation rates (EPR), and sulfated-proteoglycan (GAG-ECM) staining of the CTPs across tissue sources. RESULTS:HGL resulted in increased cell cultures with CFE = 0 compared with NGL in all tissue sources ( = 0.049). The CFE in NGL was higher than HGL for superficial cartilage ( < 0.001), and contrary for synovium-derived CTPs ( = 0.046) when CFE > 0. EPR of the CTPs did not differ between the media in the 6-day assay time period ( = 0.082). The GAG-ECM area of the CTPs and their progeny was increased in presence of HGL ( = 0.027). CONCLUSION:Glucose concentration is critical to progenitor's physiology and should be taken into account in the setting of protocols for clinical or cell expansion strategies. 10.1177/1947603520906605
Recent Advance in Source, Property, Differentiation, and Applications of Infrapatellar Fat Pad Adipose-Derived Stem Cells. Stem cells international Infrapatellar fat pad (IPFP) can be easily obtained during knee surgery, which avoids the damage to patients for obtaining IPFP. Infrapatellar fat pad adipose-derived stem cells (IPFP-ASCs) are also called infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs) because the morphology of IPFP-ASCs is similar to that of bone marrow mesenchymal stem cells (BM-MSCs). IPFP-ASCs are attracting more and more attention due to their characteristics suitable to regenerative medicine such as strong proliferation and differentiation, anti-inflammation, antiaging, secreting cytokines, multipotential capacity, and 3D culture. IPFP-ASCs can repair articular cartilage and relieve the pain caused by osteoarthritis, so most of IPFP-related review articles focus on osteoarthritis. This article reviews the anatomy and function of IPFP, as well as the discovery, amplification, multipotential capacity, and application of IPFP-ASCs in order to explain why IPFP-ASC is a superior stem cell source in regenerative medicine. 10.1155/2020/2560174
Intra-articular infiltration of adipose-derived stromal vascular fraction cells slows the clinical progression of moderate-severe knee osteoarthritis: hypothesis on the regulatory role of intra-articular adipose tissue. Lapuente Juan Pedro,Dos-Anjos Severiano,Blázquez-Martínez Alejandro Journal of orthopaedic surgery and research BACKGROUND:The infiltration of the stromal vascular fraction (SVF) of autologous adipose tissue to treat osteoarthritis has been used for several years demonstrating its safety and noticeable efficacy. This article presents clinical data from patients afftected by moderate and severe knee osteoarthritis demonstrating safety and clinical efficacy of the treatment when this autologous cell product is injected in the knee joint and patients evaluated post-operatively after 1 year. However, what do we know about the mechanism that underlies this clinical improvement? This article proposes, for the first time in our opinion, a hypothesis of the mode of action that involves structural and molecular interactions between SVF and infrapatellar fat pad (IFP). As consequence, there would be a re-education of intra-articular adipose tissue, which we consider a key player for the clinical effect observed in the mid and long term mainly due to immuno-regulatory mechanisms. METHODS:This is a retrospective and not controlled study that evaluated 50 patients (100 joints) ranging from 50 to 89 years old, separated by age cohorts. Clinical efficacy was assessed using the Lequesne, WOMAC, and VAS scales, by ultrasound control and quantification of the biochemical profiles of synovial fluid. RESULTS:There were no serious adverse effects. All the indexes studied showed a significant clinical improvement after 1-year follow-up for all ages and OA degree groups. This finding was correlated with the ultrasound observations and biochemical data, which show a marked decrease in catabolic and pro-inflammatory molecules (MMP-2, IL-1B, IL-6, and IL-8) and significant increase for anabolic and anti-inflammatory molecules (IGF-1 and IL-10). CONCLUSIONS:We conclude that intra-articular SVF infiltration for knee OA treatment is safe and effective during 1 year. We propose that applied SVF cells cause a cascade of molecular and structural events that, through complex interactions between IFP and SVF, re-educating the intra-articular fatty tissue towards a homeostatic, protective, and anti-inflammatory function, which will ultimately promote the restructuring and regeneration of damaged tissues. 10.1186/s13018-020-01664-z
Site-Dependent Lineage Preference of Adipose Stem Cells. Frontiers in cell and developmental biology Adult stem cells have unique properties in both proliferation and differentiation preference. In this study, we hypothesized that adipose stem cells have a depot-dependent lineage preference. Four rabbits were used to provide donor-matched adipose stem cells from either subcutaneous adipose tissue (ScAT) or infrapatellar fat pad (IPFP). Proliferation and multi-lineage differentiation were evaluated in adipose stem cells from donor-matched ScAT and IPFP. RNA sequencing (RNA-seq) and proteomics were conducted to uncover potential molecular discrepancy in adipose stem cells and their corresponding matrix microenvironments. We found that stem cells from ScAT exhibited significantly higher proliferation and adipogenic capacity compared to those from donor-matched IPFP while stem cells from IPFP displayed significantly higher chondrogenic potential compared to those from donor-matched ScAT. Our findings are strongly endorsed by supportive data from transcriptome and proteomics analyses, indicating a site-dependent lineage preference of adipose stem cells. 10.3389/fcell.2020.00237
Signature quality attributes of CD146 mesenchymal stem/stromal cells correlate with high therapeutic and secretory potency. Bowles Annie C,Kouroupis Dimitrios,Willman Melissa A,Perucca Orfei Carlotta,Agarwal Ashutosh,Correa Diego Stem cells (Dayton, Ohio) CD146 bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) play key roles in the perivascular niche, skeletogenesis, and hematopoietic support; however, comprehensive evaluation of therapeutic potency has yet to be determined. In this study, in vitro inflammatory priming to crude human BM-MSCs (n = 8) captured a baseline of signature responses, including enriched CD146 with coexpression of CD107a , CXCR4 , and LepR , transcriptional profile, enhanced secretory capacity, and robust immunomodulatory secretome and function, including immunopotency assays (IPAs) with stimulated immune cells. These signatures were significantly more pronounced in CD146 (POS)-sorted subpopulation than in the CD146 (NEG). Mechanistically, POS BM-MSCs showed a markedly higher secretory capacity with significantly greater immunomodulatory and anti-inflammatory protein production upon inflammatory priming compared with the NEG BM-MSCs. Moreover, IPAs with stimulated peripheral blood mononuclear cells and T lymphocytes demonstrated robust immunosuppression mediated by POS BM-MSC while inducing significant frequencies of regulatory T cells. in vivo evidence showed that POS BM-MSC treatment promoted pronounced M1-to-M2 macrophage polarization, ameliorating inflammation/fibrosis of knee synovium and fat pad, unlike treatment with NEG BM-MSCs. These data correlate the expression of CD146 with innately higher immunomodulatory and secretory capacity, and thus therapeutic potency. This high-content, reproducible evidence suggests that the CD146 (POS) MSC subpopulation are the mediators of the beneficial effects achieved using crude BM-MSCs, leading to translational implications for improving cell therapy and manufacturing. 10.1002/stem.3196
3D printing of fibre-reinforced cartilaginous templates for the regeneration of osteochondral defects. Critchley Susan,Sheehy Eamon J,Cunniffe Gráinne,Diaz-Payno Pedro,Carroll Simon F,Jeon Oju,Alsberg Eben,Brama Pieter A J,Kelly Daniel J Acta biomaterialia Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fibre-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mechanically competent implants, we first compared a range of 3D printed fibre networks (PCL, PLA and PLGA) for their capacity to mechanically reinforce alginate hydrogels whilst simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mechanically reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and subcutaneous implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fibre-reinforced, bi-phasic cartilaginous templates were then evaluated in clinically relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was observed after 6 months in animals treated with bi-phasic constructs compared to animals treated with commercial control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. STATEMENT OF SIGNIFICANCE: Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fibre-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fibre networks to mechanically reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fibre-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine. 10.1016/j.actbio.2020.05.040
Serum adipokines/related inflammatory factors and ratios as predictors of infrapatellar fat pad volume in osteoarthritis: Applying comprehensive machine learning approaches. Scientific reports OBJECTIVE:The infrapatellar fat pad (IPFP) has been associated with knee osteoarthritis onset and progression. This study uses machine learning (ML) approaches to predict serum levels of some adipokines/related inflammatory factors and their ratios on knee IPFP volume of osteoarthritis patients. METHODS:Serum and MRI were from the OAI at baseline. Variables comprised the 3 main osteoarthritis risk factors (age, gender, BMI), 6 adipokines, 3 inflammatory factors, and their 36 ratios. IPFP volume was assessed on MRI with a ML methodology. The best variables and models were identified in Total-cohort (n = 678), High-BMI (n = 341) and Low-BMI (n = 337), using a selection approach based on ML methods. RESULTS:The best model for each group included three risk factors and adipsin/C-reactive protein combined for Total-cohort, adipsin/chemerin; High-BMI, chemerin/adiponectin HMW; and Low-BMI, interleukin-8. Gender separation improved the prediction (13-16%) compared to the BMI-based models. Reproducibility with osteoarthritis patients from a clinical trial was excellent (R: female 0.83, male 0.95). Pseudocodes based on gender were generated. CONCLUSION:This study demonstrates for the first time that the combination of the serum levels of adipokines/inflammatory factors and the three main risk factors of osteoarthritis could predict IPFP volume with high reproducibility, with the superior performance of the model accounting for gender separation. 10.1038/s41598-020-66330-0
Partial resection of the infrapatellar fat pad during anterior cruciate ligament reconstruction has no effect on clinical outcomes including anterior knee pain. Asai Kazuki,Nakase Junsuke,Oshima Takeshi,Shimozaki Kengo,Yoshimizu Rikuto,Tsuchiya Hiroyuki Archives of orthopaedic and trauma surgery BACKGROUND:Anterior knee pain (AKP) is a major complication that occurs after anterior cruciate ligament reconstruction (ACLR), even when hamstring tendon (HT) grafts are used. Damage to the infrapatellar fat pad (IPFP) during arthroscopy can cause AKP. The purpose of this study was to evaluate the influence of IPFP preservation on clinical outcomes, including AKP, in patients who underwent ACLR with HT autografts using the inside-out technique. METHODS:Forty-two patients who underwent primary ACLR with HT autografts were prospectively assessed for 2 years after surgery. They were randomly selected to undergo treatment with as much intercondylar IPFP preservation as possible or with intercondylar IPFP resection to confirm the ACL origin on the femoral and tibial sides, especially the femoral footprint in deep flexion of the knee joint. The total IPFP volume was calculated using sagittal MR images before and 6 months after surgery. The patients completed a subjective knee score questionnaire and were assessed for patellar tendon tenderness and pain with the half-squat test or single-leg hop test at 6 months and 2 years postoperatively. RESULTS:There were no differences in the patient characteristics, including age, sex, BMI, time from injury to surgery, and meniscus tear. The difference in the total size of the IPFP preserved was significant (P = 0.004). However, there were no significant differences in the subjective knee scores. Moreover, there were no differences in the clinical assessment parameters between the IPFP preservation and resection groups. CONCLUSIONS:The size of the IPFP decreased more in the resection group than in the preservation group at 6 months after surgery. However, partial IPFP resection, which was used to better visualize the origin of the ACL, had no effect on the clinical outcomes, including AKP. LEVEL OF EVIDENCE:Level II. 10.1007/s00402-020-03520-5
Association of infra-patellar fat pad size with age and body weight in children and adolescents. Ladenhauf H N,Schlattau A,Burda B,Wirth W,Eckstein F,Metzger R,Ruhdorfer A Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft BACKGROUND:The infra-patellar fat pad (IPFP) represents a potential mediator between obesity, low grade inflammation, and knee osteoarthritis via endocrine pathways. Yet, not only in adults, but also in childhood obesity negatively impacts knee structures. OBJECTIVE:The current study therefore investigated the sex-specific growth of the IPFP with age and body weight in healthy children and adolescents. MATERIALS AND METHODS:Thirty young healthy subjects (60% girls; age 4-17 years, body weight 14-90 kg in girls and 29-105 kg in boys; BMI 12.2-32.4 kg/m) without magnetic resonance imaging (MRI) knee pathology were studied. The IPFP volume was determined from sagittal T-1 weighted and proton-density spectral attenuated inversion recovery MRIs. The primary analysis focused on the sex-specific IPFP volume/body weight ratio as dependent, and age as independent variable, using linear regression models. A secondary analytic focus was the slope of the age-dependence of IPFP volume, without normalization to body weight. RESULTS:There was no statistically significant association of the IPFP volume/body weight ratio with age in girls (p = 0.57) or boys (p = 0.31), the R of ranging from -0.32 to 0.14. The ratio was greater in boys (0.54 ± 0.10 cm/kg) than in girls (0.45 ± 0.07 cm/kg) (p < 0.01). The IPFP volume increased by approx. 2 cm per annum in both girls and boys, without any indication of a non-linear relationship. CONCLUSION:Our findings reveal that the ratio of the IPFP volume and body weight remains constant between age 4 and 17 in both normal weight girls and boys, and that the IPFP volume increases linearly with age throughout this period. 10.1016/j.aanat.2020.151533
Systemic iron overload exacerbates osteoarthritis in the strain 13 guinea pig. Burton L H,Radakovich L B,Marolf A J,Santangelo K S Osteoarthritis and cartilage OBJECTIVE:Iron is emerging as a key player in aging-associated diseases due to its propensity for driving free radical formation. Studies examining the role of iron in the pathogenesis of primary osteoarthritis (OA) are limited. Our objective was to establish a direct relationship between excess iron and OA by administering iron dextran to a guinea pig strain with decreased propensity for developing this disease. DESIGN:Twenty, 12-week-old Strain 13 guinea pigs received either iron dextran or dextran control intraperitoneally once weekly for 4 weeks; termination occurred at 16 weeks of age. Iron levels were determined systemically (serum and liver) and within diarthrodial joints [femoral head articular cartilage and infrapatellar fat pads (IFPs) of knee joints]. One knee was collected to score structural changes associated with OA via microcomputed tomography (microCT) and histology using published grading schemes. Articular cartilage and IFPs were harvested from contralateral knees for gene expression analyses. RESULTS:Iron overload was confirmed systemically via increased serum iron and liver iron concentration. Articular cartilage and IFPs in the iron dextran group also had higher levels of iron. Excess iron worsened knee OA using both microCT and histologic scoring systems. Gene analyses revealed that exogenous iron altered the expression of iron trafficking proteins, select cytokines, and structural components of cartilage. CONCLUSION:These results demonstrate that systemic iron overload caused cellular iron accumulation in the knee joint. This excess iron is associated with increased expression of local inflammatory mediators and early onset and progression of knee joint OA in Strain 13 animals. 10.1016/j.joca.2020.06.005
A numerical investigation of the infrapatellar fat pad. Fontanella Chiara Giulia,Macchi Veronica,Porzionato Andrea,Arduino Alessandro,Fotso Fongang Joseph Vannel,De Caro Raffaele,Natali Arturo Nicola,Carniel Emanuele Luigi Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine The infrapatellar fat pad is an adipose tissue in the knee that facilitates the distribution of synovial fluid and absorbs impulsive actions generated through the joint. The correlation between morphological configuration and mechanical properties is analyzed by a computational approach. The microscopic anatomy of the infrapatellar fat pad is studied aiming to measure the dimension of adipose lobules and the thickness of connective septa. Results from histomorphometric investigations show that the infrapatellar fat pad is an inhomogeneous tissue, constituted by large lobules in the superficial part and smaller lobules in the deepest one. Finite element models of the infrapatellar fat pad are developed. The first model considers the inhomogeneous conformation of the infrapatellar fat pad, composed of micro- and macro-chambers, while the second model considers a homogeneous distribution of adipose lobules with similar dimensions. Computational analyses are performed considering the static standing configuration and the passive flexion-extension movement. The computational results allow us to identify the different stress and strain fields within the tissue and to appreciate the variation of the mechanical performance of the overall system considering the distribution of adipose lobules. Results show that the distribution of adipose lobules in macro- and micro-chambers allows major deformation of the infrapatellar fat pad, decreasing the stress inside the tissues. 10.1177/0954411920940839
Obese and overweight individuals have greater knee synovial inflammation and associated structural and cartilage compositional degeneration: data from the osteoarthritis initiative. Skeletal radiology OBJECTIVE:This work aims to study (i) the relationship between body mass index (BMI) and knee synovial inflammation using non-contrast-enhanced MRI and (ii) the association of synovial inflammation versus degenerative abnormalities and pain. MATERIALS AND METHODS:Subjects with risk for and mild to moderate radiographic osteoarthritis were selected from the Osteoarthritis Initiative. Subjects were grouped into three BMI categories with 87 subjects per group: normal weight (BMI, 20-24.9 kg/m), overweight (BMI, 25-29.9 kg/m), and obese (BMI, ≥ 30 kg/m), frequency matched for age, sex, race, Kellgren-Lawrence grade, and history of knee surgery and injury. Semi-quantitative synovial inflammation imaging biomarkers were obtained including effusion-synovitis, size and intensity of infrapatellar fat pad signal abnormality, and synovial proliferation score. Cartilage composition was measured using T relaxation time and structural abnormalities using the whole-organ magnetic resonance imaging score (WORMS). The Western Ontario and McMasters (WOMAC) Osteoarthritis Index was used for pain assessment. Intra- and inter-reader reproducibility was assessed by kappa values. RESULTS:Overweight and obese groups had higher prevalence and severity of all synovial inflammatory markers (p ≤ 0.03). Positive associations were found between synovial inflammation imaging biomarkers and average T values, WORMS maximum scores and total WOMAC pain scores (p < 0.05). Intra- and inter-reader kappa values for imaging biomarkers were high (0.76-1.00 and 0.60-0.94, respectively). CONCLUSION:Being overweight or obese was significantly associated with a greater prevalence and severity of synovial inflammation imaging biomarkers. Substantial reproducibility and high correlation with knee structural, cartilage compositional degeneration, and WOMAC pain scores validate the synovial inflammation biomarkers used in this study. 10.1007/s00256-020-03550-5
Adipose Tissue-Derived Stem Cells Retain Their Adipocyte Differentiation Potential in Three-Dimensional Hydrogels and Bioreactors . O'Donnell Benjamen T,Al-Ghadban Sara,Ives Clara J,L'Ecuyer Michael P,Monjure Tia A,Romero-Lopez Monica,Li Zhong,Goodman Stuart B,Lin Hang,Tuan Rocky S,Bunnell Bruce A Biomolecules Osteoarthritis (OA) is a common joint disorder with a significant economic and healthcare impact. The knee joint is composed of cartilage and the adjoining bone, a synovial capsule, the infrapatellar fat pad (IPFP), and other connective tissues such as tendons and ligaments. Adipose tissue has recently been highlighted as a major contributor to OA through strong inflammation mediating effects. In this study, methacrylated gelatin (GelMA) constructs seeded with adipose tissue-derived mesenchymal stem cells (ASCs) and cultured in a 3D printed bioreactor were investigated for use in microphysiological systems to model adipose tissue in the knee joint. Four patient-derived ASC populations were seeded at a density of 20 million cells/mL in GelMA. Live/Dead and boron-dipyrromethene/4',6-diamidino-2-phenylindole (BODIPY/DAPI) staining of cells within the constructs demonstrated robust cell viability after 28 days in a growth (control) medium, and robust cell viability and lipid accumulation in adipogenic differentiation medium. qPCR gene expression analysis and protein analysis demonstrated an upregulated expression of key adipogenesis-associated genes. Overall, these data indicate that ASCs retain their adipogenic potential when seeded within GelMA hydrogels and cultured within perfusion bioreactors, and thus can be used in a 3D organ-on-a-chip system to study the role of the IPFP in the pathobiology of the knee OA. 10.3390/biom10071070
Infrapatellar fat pad resection or preservation during total knee arthroplasty: a meta-analysis of randomized controlled trials. Sun Changjiao,Zhang Xiaofei,Lee Woo Guan,Tu Yan,Li Huimin,Cai Xu,Yang Huadong Journal of orthopaedic surgery and research BACKGROUND:The infrapatellar fat pad (IPFP) or Hoffa's fat pad is often resected during total knee arthroplasty in order to improve visibility. However, the management of the IPFP during total knee arthroplasty (TKA) is the subject of an ongoing debate that has no clear consensus. The purpose of this review was to appraise if resection of the IPFP affects clinical outcomes. METHODS:We conducted a meta-analysis to identify relevant randomized controlled trials involving infrapatellar fat pad resection and infrapatellar fat pad preservation during total knee arthroplasty in electronic databases, including Web of Science, Embase, PubMed, Cochrane Controlled Trials Register, Cochrane Library, Highwire, CBM, CNKI, VIP, and Wanfang database, up to March 2020. RESULTS:Nine randomized controlled trials, involving 783 TKAs (722 patients), were included in the systematic review. Outcome measures included patellar tendon length (PTL), Insall-Salvati ratio (ISR), rate of anterior knee pain, Knee Society Scores (KSS), and knee range of motion. The meta-analysis identified a trend toward the shortening of the patellar tendon with IPFP resection at 6 months (P = 0.0001) and 1 year (P = 0.001). We found no statistical difference in ISR (P = 0.87), rate of anterior knee pain within 6 months (p = 0.45) and 1 year (p = 0.38), KSS at 1 year (p = 0.77), and knee range of motion within 6 months (p = 0.61) and 1 year (0.46). CONCLUSION:Based on the available level I evidence, we were unable to conclude that one surgical technique of IPFP can definitively be considered superior over the other. More adequately powered and better-designed randomized controlled trial (RCT) studies with long-term follow-up are required to produce evidence-based guidelines regarding IPFP resection. 10.1186/s13018-020-01823-2
Can low-dose methotrexate reduce effusion-synovitis and symptoms in patients with mid- to late-stage knee osteoarthritis? Study protocol for a randomised, double-blind, and placebo-controlled trial. Zhu Zhaohua,Yu Qinghong,Leng Xiaomei,Han Weiyu,Li Zhanguo,Huang Cibo,Gu Jieruo,Zhao Yi,Wang Kang,Li Tianwang,Mei Yifang,Xu Jianhua,Zhang Zhiyi,Hunter David,Cicuttini Flavia,Zeng Xiaofeng,Ding Changhai Trials BACKGROUND:Osteoarthritis (OA) is a common chronic disease in older adults. Currently, there are no effective therapies to reduce disease severity and progression of knee OA (KOA), particularly in mid- to late-stages. This study aims to examine the effect of methotrexate (MTX) on knee effusion-synovitis and pain in symptomatic patients with mid- to late-stage KOA. METHODS/DESIGN:This protocol describes a multicentre randomised placebo-controlled clinical trial aiming to recruit 200 participants with mid- to late-stage symptomatic KOA and with effusion-synovitis grade of ≥ 2. Participants will be randomly allocated to the MTX group (start from 5 mg per week for the first 2 weeks and increase to 10 mg per week for the second 2 weeks and 15 mg per week for the remaining period if tolerated) or the placebo group. Primary outcomes are effusion-synovitis size measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS). Secondary outcomes are signal intensity alteration within infrapatellar fat pad (IPFP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and subscores, and the Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders. Both intention-to-treat and per-protocol analyses will be performed. DISCUSSION:If MTX intervention can relieve symptoms and reduce inflammation in patients with mid- to late-stage KOA, it has the potential for significant clinical and public health impact as this low-cost and commonly used intervention would delay the time to knee replacement, leading to substantial cost savings and improve quality of life. TRIAL REGISTRATION:ClinicalTrials.gov NCT03815448 . Registered on 21 January 2019. 10.1186/s13063-020-04687-3
Scaffold-Free Cartilage Construct from Infrapatellar Fat Pad Stem Cells for Cartilage Restoration. Tissue engineering. Part A Once damaged, the articular cartilage has a very limited intrinsic capacity for self-renewal due to its avascular nature. If left untreated, damaged cartilage can lead to progressive degeneration of bone and eventually causes pain. Infrapatellar fat pad adipose-derived mesenchymal stromal cells (IPFP-ASCs) has a potential role for cartilage restoration. However, the therapeutic role for IPFP-ASCs remains to be evaluated in an appropriate osteochondral defect model. Thus, this study aimed to investigate the potential of using a three-dimensional (3D) cartilage construct of IPFP-ASCs as a promising source of cells to restore articular cartilage and to attenuate pain associated with the cartilage defect in an osteochondral defect model. The chondrogenic differentiation potential of the 3D cartilage construct derived from IPFP-ASCs was determined before implantation and postimplantation by gene expression and immunohistochemistry analysis. Pain-related behavior was also assessed by using a weight-bearing test. A significant pain-associated with the osteochondral defect was observed in this model in all groups postinduction; however, this pain can spontaneously resolve within 3 weeks postimplantation regardless of implantation of IPFP-ASCs constructs. The expression of and genes in addition to protein expression were strongly expressed in 3D construct IPFP-ASCs. The existence of mature chondrocytes, along with significant ( < 0.05) positive immunostaining for type II collagen and aggrecan, were identified in the implanted site for up to 12 weeks compared with the untreated group, indicating hyaline cartilage regeneration. Taken together, this study demonstrated the successful outcome of osteochondral regeneration with scaffold-free IPFP-ASCs constructs in an osteochondral defect rat model. It provides novel and interesting insights into the current hypothesis that 3D construct IPFP-ASCs may offer potential benefits as an alternative approach to repair the cartilage defect. Impact statement This study provides evidence of using the human 3D scaffold-free infrapatellar fat pad adipose-derived mesenchymal stromal cells (IPFP-ASCs) construct to restore the full-thickness osteochondral defect in a rat model. This study showed that chondrogenic features of the construct could be retained for up to 12 weeks postimplantation. The results of this proof-of-concept study support that human 3D scaffold-free IPFP-ASCs construct has potential benefits in promoting the hyaline-like native cartilage restoration, which may be beneficial as a tissue-specific stem cell for cell-based cartilage therapy. There are several clinical advantages of IPFP-ASC including ease and minimal invasive harvesting, chondrogenic inducible property, and tissue-specific progenitors in the knee. 10.1089/ten.TEA.2020.0167
Matrix reverses immortalization-mediated stem cell fate determination. Biomaterials Primary cell culture in vitro suffers from cellular senescence. We hypothesized that expansion on decellularized extracellular matrix (dECM) deposited by simian virus 40 large T antigen (SV40LT) transduced autologous infrapatellar fat pad stem cells (IPFSCs) could rejuvenate high-passage IPFSCs in both proliferation and chondrogenic differentiation. In the study, we found that SV40LT transduced IPFSCs exhibited increased proliferation and adipogenic potential but decreased chondrogenic potential. Expansion on dECMs deposited by passage 5 IPFSCs yielded IPFSCs with dramatically increased proliferation and chondrogenic differentiation capacity; however, this enhanced capacity diminished if IPFSCs were grown on dECM deposited by passage 15 IPFSCs. Interestingly, expansion on dECM deposited by SV40LT transduced IPFSCs yielded IPFSCs with enhanced proliferation and chondrogenic capacity but decreased adipogenic potential, particularly for the dECM group derived from SV40LT transduced passage 15 cells. Our immunofluorescence staining and proteomics data identify matrix components such as basement membrane proteins as top candidates for matrix mediated IPFSC rejuvenation. Both cell proliferation and differentiation were endorsed by transcripts measured by RNASeq during the process. This study provides a promising model for in-depth investigation of the matrix protein influence on surrounding stem cell differentiation. 10.1016/j.biomaterials.2020.120387
Effects of infrapatellar fat pad preservation versus resection on clinical outcomes after total knee arthroplasty in patients with knee osteoarthritis (IPAKA): study protocol for a multicentre, randomised, controlled clinical trial. Zhu Zhaohua,Han Weiyu,Lu Ming,Lin Jianhao,Yin Zongsheng,Shang Xifu,Weng Xisheng,Zha Zhengang,Tian Jin,Lei Guanghua,Hunter David J,Ding Changhai BMJ open INTRODUCTION:The infrapatellar fat pad (IPFP) is commonly resected during total knee arthroplasty (TKA) for better exposure. However, our previous studies have suggested that IPFP size was protective against, while IPFP signal intensity alteration was detrimental on knee symptoms and structural abnormalities. We hypothesise that an IPFP with normal qualities, rather than abnormal qualities, should be preserved during TKA. The aim of this study is to compare, over a 1-year period, the postoperative clinical outcomes of IPFP preservation versus resection after TKA in patients with normal or abnormal IPFP signal intensity alteration on MRI. METHODS AND ANALYSIS:Three hundred and sixty people with end-stage knee osteoarthritis and on the waiting list for TKA will be recruited and identified as normal IPFP quality (signal intensity alteration score ≤1) or abnormal IPFP quality (signal intensity alteration score ≥2). Patients in each hospital will then be randomly allocated to IPFP resection group or preservation group. The primary outcomes are the summed score of self-reported Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS subscales assessing function in daily activities and function in sport and recreation. Secondary endpoints will be included: KOOS subscales (pain, symptoms and quality of life), Knee Society Score, 100 mm Visual Analogue Scale (VAS) Pain, timed up-and-go test, patellar tendon shortening, 100 mm VAS self-reported efficacy of reduced pain and increased quality of life, and Insall-Salvati index assessed on plain X-ray. Adverse events will be recorded. Intention-to-treat analyses will be used. ETHICS AND DISSEMINATION:The study is approved by the local Medical Ethics Committee (Zhujiang Hospital Ethics Committee, reference number 2017-GJGBK-001) and will be conducted according to the principle of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard, and in compliance with the Medical Research Involving Human Subjects Act . Data will be published in peer-reviewed journals and presented at conferences, both nationally and internationally. TRIAL REGISTRATION NUMBER:This trial was registered at Clinicaltrial.gov website on 19 October 2018 with identify number NCT03763448. 10.1136/bmjopen-2020-043088
[Influence of retention or resection subpatellar fat pad on patella height during rheumatoid knee replacement]. Li Long-Jie,Zhang Hai-Sen,Chen Si,Liu Chang Zhongguo gu shang = China journal of orthopaedics and traumatology OBJECTIVE:To compare influence of retention or resection subpatellar fat pad on patella height during rheumatoid knee replacement. METHODS:Totally 48 patients with rheumatoid arthritis who underwent total knee replacement from October 2013 to October 2017 were retrospectively analyzed and divided into resection and retention subpatellar fat pad group. There were 23 patients in resection subpatellar fat pad group, including 9 males and 14 females aged from 48 to 69 years old with an average of(55.83±5.65) years old; subpatellar fat pad were resected during opertaion. There were 25 patients in retention subpatellar fat pad group, including 6 males and 19 femlaes aged from 49 to 70 years old with an average age of (55.52± 6.28) years old;subpatellar fat pad were retentedduring opertaion. Postopertaive complications were observed between two groups, visual analogue scale (VAS) and Hospital for Special Surgery (HSS) at 1 year after operation were used to evaluate relieve pain degree and clnical effect of knee joint, Insall-Salvati ratio(I-S ratio) was used to compare changes of postoperative patella height at 1 year after operation. RESULTS:All patients were followed up from 12 to 39 months with an average of (23.85± 8.82) months. The postoperative wound healed well without infection complications and no prosthetic loosening or revision. Postoperative VAS score at 1 year between two groups was lower than that of before opertaion(<0.05), but no statistical difference between two groups at 1 year after operation(>0.05). Postopertaive HSS score between two groups was higer than that of before operation(<0.05), while no difference in HSS score at 1 year after operation between two groups (>0.05). I-S ratio of subpatellar fat pad resection group (1.03±0.04) was lower than that of subpatellar fat pad retention group (1.06±0.06), and difference was statistically significant (<0.05). CONCLUSION:Resection or retention subpatellar fat pad in rheumatoid knee replacement have advantages of relieving postoperative pain and improving functional recovery, however, retention of infrapatellar fat pad is beneficial to restoration of patellar height. 10.12200/j.issn.1003-0034.2020.10.007
Unfavorable Contribution of a Tissue-Engineering Cartilage Graft to Osteochondral Defect Repair in Young Rabbits. Lu Zhihua,Zhou Sheng,Vaida Justin,Gao Gongming,Stewart Amanda,Parenti Joshua,Yan Lianqi,Pei Ming Frontiers in cell and developmental biology A stem cell-based tissue-engineering approach is a promising strategy for treatment of cartilage defects. However, there are conflicting data in the feasibility of using this approach in young recipients. A young rabbit model with an average age of 7.7 months old was used to evaluate the effect of a tissue-engineering approach on the treatment of osteochondral defects. Following evaluation of proliferation and chondrogenic capacity of infrapatellar fat pad-derived stem cells (IPFSCs) after expansion on either tissue culture plastic (TCP) or decellularized extracellular matrix (dECM), a premature tissue construct engineered from pretreated IPFSCs was used to repair osteochondral defects in young rabbits. We found that dECM expanded IPFSCs exhibited higher proliferation and chondrogenic differentiation compared to TCP expanded cells in both pellet and tissue construct culture systems. Six weeks after creation of bilateral osteochondral defects in the femoral trochlear groove of rabbits, the Empty group (left untreated) had the best cartilage resurfacing with the highest score in Modified O'Driscoll Scale (MODS) than the other groups; however, this score had no significant difference compared to that of 15-week samples, indicating that young rabbits stop growing cartilage once they reach 9 months old. Interestingly, implantation of premature tissue constructs from both dECM and TCP groups exhibited significantly improved cartilage repair at 15 weeks compared to those at six weeks (about 9 months old), indicating that a tissue-engineering approach is able to repair adult cartilage defects. We also found that implanted pre-labeled cells in premature tissue constructs were undetectable in resurfaced cartilage at both time points. This study suggests that young rabbits (less than 9 months old) might respond differently to the classical tissue-engineering approach that is considered as a potential treatment for cartilage defects in adult rabbits. 10.3389/fcell.2020.595518
Infrapatellar Fat Pads-Derived Stem Cell Is a Favorable Cell Source for Articular Cartilage Tissue Engineering: An and Study Based on 3D Organized Self-Assembled Biomimetic Scaffold. Cartilage OBJECTIVE:Adipose tissue-derived stem cells (ASCs) are a promising source of cells for articular cartilage regeneration. However, ASCs isolated from different adipose tissue depots have heterogeneous cell characterizations and differentiation potential when cultured in 3-dimensional (3D) niches. DESIGN:We compared the chondrogenicity of ASCs isolated from infrapatellar fat pads (IPFPs) and subcutaneous fat pads (SCFPs) in 3D gelatin-based biomimetic matrix. RESULTS:The IPFP-ASC-differentiated chondrocytes had higher , , , , , , and mRNA levels and lower and levels than the SCFP-ASCs in 3D matrix. The difference in mRNA profile may have contributed to activation of the Akt, p38, RhoA, and JNK signaling pathways in the IPFP-ASCs. The chondrocytes differentiated from IPFP-ASCs had pronounced glycosaminoglycan and collagen type II production and a high chondroitin-6-sulfate/chondroitin-4-sulfate ratio with less polymerization of β-actin filaments. In an mice model, magnetic resonance imaging revealed a shorter T2 relaxation time, indicating that more abundant extracellular matrix was secreted in the IPFP-ASC-matrix group. Histological examinations revealed that the IPFP-ASC matrix had higher chondrogenic efficacy of new cartilaginous tissue generation as evident in collagen type II and S-100 staining. Conclusion. ASCs isolated from IPFPs may be better candidates for cartilage regeneration, highlighting the translational potential of cartilage tissue engineering using the IPFP-ASC matrix technique. 10.1177/1947603520988153
Infrapatellar fat pad volume and Hoffa-synovitis after ACL reconstruction: Association with early osteoarthritis features and pain over 5 years. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Infrapatellar fat pad (IPFP) morphology and Hoffa-synovitis may be relevant to the development and progression of post-traumatic osteoarthritis (OA). We aimed to compare IPFP volume and Hoffa-synovitis in participants with anterior cruciate ligament reconstruction (ACLR) and uninjured controls, and to determine their association with prevalent and worsening early knee OA features and pain in participants post-ACLR. We assessed IPFP volume and Hoffa-synovitis from magnetic resonance imaging (MRI) in 111 participants 1-year post-ACLR and 20 uninjured controls. Patellofemoral and tibiofemoral cartilage and bone marrow lesions (BMLs) were assessed from MRIs at 1 and 5 years post-ACLR, and worsening defined as any longitudinal increase in lesion size/severity. IPFP volume and Hoffa-synovitis prevalence were compared between groups with analysis of covariance and χ tests, respectively. Generalized linear models assessed the relation of IPFP volume and Hoffa-synovitis to prevalent and worsening features of OA and knee pain (Knee injury and Osteoarthritis Outcome Score-Pain Subscale, Anterior Knee Pain Scale). No significant between-group differences were observed in IPFP volume (ACLR 34.39 ± 7.29cm , Control 34.27 ± 7.56cm ) and Hoffa-synovitis (ACLR 61%, Control 80%). Greater IPFP volume at 1-year post-ACLR was associated with greater odds of patellofemoral BMLs at 1-year (odds ratio [OR] [95% confidence intervals]: 1.104 [1.016, 1.200]) and worsening tibiofemoral cartilage lesions at 5-year post-ACLR (OR: 1.234 [1.026, 1.483]). Hoffa-synovitis at 1-year post-ACLR was associated with greater odds of worsening patellofemoral BMLs at 5-year post-ACLR (OR: 7.465 [1.291, 43.169]). In conclusion, IPFP volume and Hoffa-synovitis prevalence are similar between individuals 1-year post-ACLR and controls. Greater IPFP volume and Hoffa-synovitis appear to be associated with the presence and worsening of some early OA features in those post-ACLR, but not pain. 10.1002/jor.24987
Hypoxic Preconditioning Induces Neuronal Differentiation of Infrapatellar Fat Pad Stem Cells through Epigenetic Alteration. Radhakrishnan Subathra,Martin Catherine Ann,Dhayanithy Geethanjali,Reddy Mettu Srinivas,Rela Mohamed,Kalkura Subbaraya Narayana,Sellathamby Shanmugaapriya ACS chemical neuroscience Hypoxia is considered a key factor in cellular differentiation and proliferation, particularly during embryonic development; the process of early neurogenesis also occurs under hypoxic conditions. Apart from these developmental processes, hypoxia preconditioning or mild hypoxic sensitization develops resistance against ischemic stroke in deteriorating tissues. We therefore hypothesized that neurons resulting from hypoxia-regulated neuronal differentiation could be the best choice for treating brain ischemia, which contributes to neurodegeneration. In this study, infrapatellar fat pad (IFP), an adipose tissue present beneath the knee joint, was used as the stem cell source. IFP-derived stem cells (IFPSCs) are totally adherent and are mesenchymal stem cells. The transdifferentiation protocol involved hypoxia preconditioning, the use of hypoxic-conditioned medium, and maintenance in maturation medium with α-lipoic acid. The differentiated cells were characterized using microscopy, reverse transcription PCR, real time PCR, and immunocytochemistry. To evaluate the epigenetic reprogramming of IFPSCs to become neuron-like cells, methylation microarrays were performed. Hypoxia preconditioning stabilized and allowed for the translocation of hypoxia inducible factor 1α into the nucleus and induced achaete-scute homologue 1 and doublecortin expression. Following induction, the resultant cells expressed neuronal markers neuron-specific enolase, neurofilament-light chain, growth associated protein 43, synaptosome associated protein 25, and β-III tubulin. The differentiated neural-lineage cells had functional gene expression pertaining to neurotransmitters, their release, and their receptors. The molecular signaling mechanisms regulated developmental neurogenesis. Furthermore, the physiological condition regulated neurotransmitter respecification or switching during IFPSC differentiation to neurons. Thus, differentiated neurons were fabricated against the ischemic region to treat neurodegenerative diseases. 10.1021/acschemneuro.0c00728
The clinical efficacy of arthroscopic therapy with knee infrapatellar fat pad cell concentrates in treating knee cartilage lesion: a prospective, randomized, and controlled study. Zhou Yiqin,Li Haobo,Xiang Dong,Shao Jiahua,Fu Qiwei,Han Yaguang,Zhu Jun,Chen Yi,Qian Qirong Journal of orthopaedic surgery and research INTRODUCTION:To evaluate the clinical efficacy of arthroscopic therapy with infrapatellar fat pad cell concentrates in treating knee cartilage lesions, we conducted a prospective randomized single-blind clinical study of controlled method. METHODS:Sixty cases from Shanghai Changzheng Hospital from April 2018 to December 2019 were chosen and randomly divided into 2 groups equally. Patients in the experiment group were treated through knee arthroscopy with knee infrapatellar fat pad cell concentrates containing mesenchymal stromal cells, while patients in the control group were treated through regular knee arthroscopic therapy. VAS and WOMAC scores were assessed at pre-operation, and 6 weeks, 12 weeks, 6 months, and 12 months after intervention. MORCART scores were assessed at pre-operation and 12 months after intervention. RESULTS:Twenty-nine cases in the experiment group and 28 cases in the control group were followed up. No significant difference in VAS, WOMAC, and MOCART scores were found between the two groups before surgery (P > 0.05). The WOMAC total and WOMAC function scores of the experiment group were significantly lower than those of the control group 6 months and 12 months after surgery (P < 0.05). The VAS rest and VAS motion scores of the experiment group were found significantly lower than those of the control group 12 months after surgery (P < 0.05). The MOCART scores of the experiment group were found significantly higher compared with the control group 12 months after surgery (P < 0.05). No significant difference in WOMAC stiffness scores were found between the two groups. CONCLUSIONS:The short-term results of our study are encouraging and demonstrate that knee arthroscopy with infrapatellar fat pad cell concentrates containing mesenchymal stromal cells is safe and provides assistance in reducing pain and improving function in patients with knee cartilage lesions. TRIAL REGISTRATION:ChiCTR1800015379. Registered on 27 March 2018, http://www.chictr.org.cn/showproj.aspx?proj=25901 . 10.1186/s13018-021-02224-9
Validation of the 1,4-butanediol thermoplastic polyurethane as a novel material for 3D bioprinting applications. Bioengineering & translational medicine Tissue engineering (TE) seeks to fabricate implants that mimic the mechanical strength, structure, and composition of native tissues. Cartilage TE requires the development of functional personalized implants with cartilage-like mechanical properties capable of sustaining high load-bearing environments to integrate into the surrounding tissue of the cartilage defect. In this study, we evaluated the novel 1,4-butanediol thermoplastic polyurethane elastomer (b-TPUe) derivative filament as a 3D bioprinting material with application in cartilage TE. The mechanical behavior of b-TPUe in terms of friction and elasticity were examined and compared with human articular cartilage, PCL, and PLA. Moreover, infrapatellar fat pad-derived human mesenchymal stem cells (MSCs) were bioprinted together with scaffolds. in vitro cytotoxicity, proliferative potential, cell viability, and chondrogenic differentiation were analyzed by Alamar blue assay, SEM, confocal microscopy, and RT-qPCR. Moreover, in vivo biocompatibility and host integration were analyzed. b-TPUe demonstrated a much closer compression and shear behavior to native cartilage than PCL and PLA, as well as closer tribological properties to cartilage. Moreover, b-TPUe bioprinted scaffolds were able to maintain proper proliferative potential, cell viability, and supported MSCs chondrogenesis. Finally, studies revealed no toxic effects 21 days after scaffolds implantation, extracellular matrix deposition and integration within the surrounding tissue. This is the first study that validates the biocompatibility of b-TPUe for 3D bioprinting. Our findings indicate that this biomaterial can be exploited for the automated biofabrication of artificial tissues with tailorable mechanical properties including the great potential for cartilage TE applications. 10.1002/btm2.10192
Pore geometry influences growth and cell adhesion of infrapatellar mesenchymal stem cells in biofabricated 3D thermoplastic scaffolds useful for cartilage tissue engineering. Martínez-Moreno D,Jiménez G,Chocarro-Wrona C,Carrillo E,Montañez E,Galocha-León C,Clares-Naveros B,Gálvez-Martín P,Rus G,de Vicente J,Marchal J A Materials science & engineering. C, Materials for biological applications The most pressing need in cartilage tissue engineering (CTE) is the creation of a biomaterial capable to tailor the complex extracellular matrix of the tissue. Despite the standardized used of polycaprolactone (PCL) for osteochondral scaffolds, the pronounced stiffness mismatch between PCL scaffold and the tissue it replaces remarks the biomechanical incompatibility as main limitation. To overcome it, the present work was focused in the design and analysis of several geometries and pore sizes and how they affect cell adhesion and proliferation of infrapatellar fat pad-derived mesenchymal stem cells (IPFP-MSCs) loaded in biofabricated 3D thermoplastic scaffolds. A novel biomaterial for CTE, the 1,4-butanediol thermoplastic polyurethane (b-TPUe) together PCL were studied to compare their mechanical properties. Three different geometrical patterns were included: hexagonal (H), square (S), and, triangular (T); each one was printed with three different pore sizes (PS): 1, 1.5 and 2 mm. Results showed differences in cell adhesion, cell proliferation and mechanical properties depending on the geometry, porosity and type of biomaterial used. Finally, the microstructure of the two optimal geometries (T1.5 and T2) was deeply analyzed using multiaxial mechanical tests, with and without perimeters, μCT for microstructure analysis, DNA quantification and degradation assays. In conclusion, our results evidenced that IPFP-MSCs-loaded b-TPUe scaffolds had higher similarity with cartilage mechanics and T1.5 was the best adapted morphology for CTE. 10.1016/j.msec.2021.111933
Exosomes from Kartogenin-Pretreated Infrapatellar Fat Pad Mesenchymal Stem Cells Enhance Chondrocyte Anabolism and Articular Cartilage Regeneration. Shao Jiahua,Zhu Jun,Chen Yi,Fu Qiwei,Li Lexiang,Ding Zheru,Wu Jun,Han Yaguang,Li Haobo,Qian Qirong,Zhou Yiqin Stem cells international Objective:To evaluate the effect of Kartogenin-pretreated exosomes derived from infrapatellar fat pad mesenchymal stem cells on chondrocyte in vitro and articular cartilage regeneration in vivo. Methods:Infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs) were isolated from rabbits to harvest exosomes. After identification of mesenchymal stem cells and exosomes, rabbit chondrocytes were divided into three groups for further treatment: the EXO group (chondrocytes treated with exosomes isolated from infrapatellar fat pad mesenchymal stem cells), KGN-EXO group (chondrocytes treated with exosomes isolated from infrapatellar fat pad mesenchymal stem cells pretreated with KGN), and control group. After processing and proliferation, phenotypic changes of chondrocytes were measured. In the in vivo study, 4 groups of rabbits with articular cartilage injury were treated with KGN-EXO, EXO, IPFP-MSCs, and control. Macroscopic evaluation and histological evaluation were made to figure out the different effects of the 4 groups on cartilage regeneration in vivo. Results:The proliferation rate of chondrocytes in the EXO or KGN-EXO group was significantly higher than that in the control group ( < 0.05). The qRT-PCR results showed that the expression of Sox-9, Aggrecan, and Col II was the highest in the KGN-EXO group compared with the EXO group and the control group ( < 0.05). The results of Western blot were consistent with the results of qRT-PCR. In vivo, the cartilage defects in the KGN-EXO group showed better gross appearance and improved histological score than those in IPFP-MSC groups, EXO groups, and control groups ( < 0.05). At 12 weeks, the defect site in the KGN-EXO group was almost completely repaired with a flat and smooth surface, while a large amount of hyaline cartilage-like structures and no obvious cracks were observed. Conclusion:Our study demonstrates that the exosomes isolated from infrapatellar fat pad mesenchymal stem cells pretreated with KGN have potent ability to induce chondrogenic differentiation of stem cells, effectively promoting the proliferation and the expression of chondrogenic proteins and genes of chondrocytes. The KGN-EXO can also promote the repair of articular cartilage defects more effectively, which can be used as a potential therapeutic method in the future. 10.1155/2021/6624874
Hoffa's fat pad thickness: a measurement method with sagittal MRI sequences. La Radiologia medica BACKGROUND:Hoffa's fat pad is a structure located within the fibrous joint capsule of the knee joint, but outside the synovial cavity. It plays an important biomechanical and metabolic role in knee joint, reducing the impact of forces generated by loading and producing cytokines. Changes in its size can induce modifications in the knee homeostasis. However, a great variability exists regarding its measurements. This work aims to evaluate the reliability of a measurement method of Hoffa's fat pad dimensions through MRI. METHODS:3T sagittal IW 2D TSE fat-suppressed MRI sequences, taken from the OAI (Osteoarthritis initiative) database, of 191 male and female patients, aged between 40 and 80 years, were analysed; a manual measurement of the thickness of Hoffa's fat pad of each subject was then performed by two different readers. The interobserver reliability and intraobserver reliability of the measurements were described by coefficient of variation (CV), Pearson correlation and Bland-Altman plots. RESULTS:All statistical analyses have shown that not significant intra- or interobservers differences were evident (intraobserver CV % for the first observer was 2.17% for the right knee and 2.24% for the left knee, while for the second observer 2.31% for the right knee and 2.24% for the left knee; linear correlation was for the first observer r = 0.96 for the right knee and r = 0.96 for the left knee, while for the second observer r = 0.97 for the right knee and r = 0.96 for the left knee; in addition, the interobserver CV % was 1.25% for the right knee and 1.21% for the left knee and a high interobserver linear correlation was found: r = 0.97 for the right knee and r = 0.96 for the left knee). All results suggest that this manual measurement method of Hoffa's fat pad thickness can be performed with satisfactory intra- and interobserver reliability. CONCLUSIONS:Hoffa's fat pad thickness can be measured, using sagittal MRI images, with this manual method that represents, for his high reliability, an effective means for the study of this anatomical structure. 10.1007/s11547-021-01345-9
Changes in Infrapatellar Fat Pad Volume 6 to 12 Months After Anterior Cruciate Ligament Reconstruction and Associations With Patient-Reported Knee Function. Journal of athletic training CONTEXT:Hypertrophy of the infrapatellar fat pad (IFP) in idiopathic knee osteoarthritis has been linked to deleterious synovial changes and joint pain related to mechanical tissue impingement. Yet little is known regarding the IFP's volumetric changes after anterior cruciate ligament reconstruction (ACLR). OBJECTIVES:To examine changes in IFP volume between 6 and 12 months after ACLR and determine associations between patient-reported outcomes and IFP volume at each time point as well as the volume change over time. In a subset of individuals, we examined interlimb IFP volume differences 12 months post-ACLR. STUDY DESIGN:Prospective cohort study. SETTING:Laboratory. PATIENTS OR OTHER PARTICIPANTS:We studied 26 participants (13 women, 13 men, age = 21.88 ± 3.58 years, body mass index = 23.82 ± 2.21 kg/m2) for our primary aims and 13 of those participants (8 women, 5 men, age = 21.15 ± 3.85 years, body mass index = 23.01 ± 2.01 kg/m2) for our exploratory aim. MAIN OUTCOME MEASURE(S):Using magnetic resonance imaging, we evaluated the IFP volume change between 6 and 12 months post-ACLR in the ACLR limb and between-limbs differences at 12 months in a subset of participants. International Knee Documentation Committee subjective knee evaluation (IKDC) scores were collected at 6-month and 12-month follow-ups, and associations between IFP volume and patient-reported outcomes were determined. RESULTS:The IFP volume in the ACLR limb increased from 6 months (19.67 ± 6.30 cm3) to 12 months (21.26 ± 6.91 cm3) post-ACLR. Greater increases of IFP volume between 6 and 12 months were significantly associated with better 6-month IKDC scores (r = .44, P = .03). The IFP volume was greater in the uninjured limb (22.71 ± 7.87 cm3) than in the ACLR limb (20.75 ± 9.03 cm3) 12 months post-ACLR. CONCLUSIONS:The IFP volume increased between 6 and 12 months post-ACLR; however, the IFP volume of the ACLR limb remained smaller than that of the uninjured limb at 12 months. In addition, those with better knee function 6 months post-ACLR demonstrated greater increases in IFP volume between 6 and 12 months post-ACLR. This suggests that greater IFP volumes may play a role in long-term joint health after ACLR. 10.4085/1062-6050-0458.20
Total Infrapatellar Fat Pad Excision Leads to Worse Isokinetic Performance in Total Knee Arthroplasty: A Randomized Controlled Trial. The journal of knee surgery There are concerns that total infrapatellar fat pad (IPFP) excision in total knee arthroplasty (TKA) results in patellar tendon shortening due to ischemic contracture, but individual preference of the surgeon is still the main determinant between total or partial excision. The aim of this randomized controlled study was to compare isokinetic performance and clinical outcome of TKAs with total and partial excision of the IPFP. Seventy-two patients scheduled to undergo TKA for primary knee osteoarthritis by a single surgeon were randomly assigned to either total or partial excision group. Patients were evaluated preoperatively and at postoperative 1 year, with Knee Society Score (KSS) and isokinetic measurements. The physiatrist performing isokinetic tests and patients were blinded to the study. There were no significant differences between the groups in respect of age, body mass index, gender, and preoperative KSS and isokinetic performance. Postoperatively, both groups had improved KSS knee and KSS function scores, with no difference determined. Knee extension peak torque was significantly higher postoperatively in the partial excision group at postoperative 1 year ( = 0.036). However, there were no significant differences in knee flexion peak torque following TKA ( = 0.649). The results of this study demonstrated that total excision of the IPFP during TKA is associated with worse isokinetic performance, which is most likely due to changes in the knee biomechanics with the development of patella baja. Partial excision of the IPFP appears to be a valid alternative to overcome this potential detrimental effect without impeding exposure to the lateral compartment. This is a Level I, therapeutic study. 10.1055/s-0041-1727114
Effects of Diet Induced Weight Reduction on Cartilage Pathology and Inflammatory Mediators in the Joint Tissues. Sun Antonia RuJia,Wu Xiaoxin,Crawford Ross,Li Hongxing,Mei Lin,Luo Yong,Xiao Yin,Mao Xinzhan,Prasadam Indira Frontiers in medicine Obesogenic diets contribute to the pathology of osteoarthritis (OA) by altering systemic and local metabolic inflammation. Yet, it remains unclear how quickly and reproducibly the body responds to weight loss strategies and improve OA. In this study we tested whether switching obese diet to a normal chow diet can mitigate the detrimental effects of inflammatory pathways that contribute to OA pathology. Male C57BL/6 mice were first fed with obesogenic diet (high fat diet) and switched to normal chow diet (obese diet → normal diet) or continued obese diet or normal diet throughout the experiment. A mouse model of OA was induced by surgical destabilization of the medial meniscus (DMM) model into the knee joint. Outcome measures included changes in metabolic factors such as glucose, insulin, lipid, and serum cytokines levels. Inflammation in synovial biopsies was scored and inflammation was determined using FACs sorted macrophages. Cartilage degeneration was monitored using histopathology. Our results indicate, dietary switching (obese diet → normal diet) reduced body weight and restored metabolic parameters and showed less synovial tissue inflammation. Systemic blood concentrations of pro-inflammatory cytokines IL-1α, IL-6, IL-12p40, and IL-17 were decreased, and anti-inflammatory cytokines IL-4 and IL-13 were increased in dietary switch group compared to mice that were fed with obesogenic diet continuously. Although obese diet worsens the cartilage degeneration in DMM OA model, weight loss induced by dietary switch does not promote the histopathological changes of OA during this study period. Collectively, these data demonstrate that switching obesogenic diet to normal improved metabolic syndrome symptoms and can modulate both systemic and synovium inflammation levels. 10.3389/fmed.2021.628843
Biofunctionalized Structure and Ingredient Mimicking Scaffolds Achieving Recruitment and Chondrogenesis for Staged Cartilage Regeneration. Yang Zhen,Li Hao,Tian Yue,Fu Liwei,Gao Cangjian,Zhao Tianyuan,Cao Fuyang,Liao Zhiyao,Yuan Zhiguo,Liu Shuyun,Guo Quanyi Frontiers in cell and developmental biology It remains scientifically challenging to regenerate injured cartilage in orthopedics. Recently, an endogenous cell recruitment strategy based on a combination of acellular scaffolds and chemoattractants to specifically and effectively recruit host cells and promote chondrogenic differentiation has brought new hope for articular cartilage regeneration. In this study, a transforming growth factor-β3 (TGF-β3)-loaded biomimetic natural scaffold based on demineralized cancellous bone (DCB) and acellular cartilage extracellular matrix (ECM) was developed and found to improve chondral repair by enhancing cell migration and chondrogenesis. The DCB/ECM scaffold has porous microstructures (pore size: 67.76 ± 8.95 μm; porosity: 71.04 ± 1.62%), allowing the prolonged release of TGF-β3 (up to 50% after 42 days ) and infrapatellar fat pad adipose-derived stem cells (IPFSCs) that maintain high cell viability (>96%) and favorable cell distribution and phenotype after seeding onto the DCB/ECM scaffold. The DCB/ECM scaffold itself can also provide a sustained release system to effectively promote IPFSC migration (nearly twofold ). Moreover, TGF-β3 loaded on scaffolds showed enhanced chondrogenic differentiation (such as collagen II, ACAN, and SOX9) of IPFSCs after 3 weeks of culture. After implanting the composite scaffold into the knee joints of rabbits, enhanced chondrogenic differentiation was discovered at 1, 2, and 4 weeks post-surgery, and improved repair of cartilage defects in terms of biochemical, biomechanical, radiological, and histological results was identified at 3 and 6 months post-implantation. To conclude, our study demonstrates that the growth factor (GF)-loaded scaffold can facilitate cell homing, migration, and chondrogenic differentiation and promote the reconstructive effects of cartilage formation, revealing that this staged regeneration strategy combined with endogenous cell recruitment and pro-chondrogenesis is promising for articular cartilage regeneration. 10.3389/fcell.2021.655440
Macroporous scaffold surface modified with biological macromolecules and piroxicam-loaded gelatin nanofibers toward meniscus cartilage repair. International journal of biological macromolecules Meniscus cartilage has poor self-healing capacity in the inner zone and its damage leads to articular cartilage degeneration. Here we have developed hybrid constructs using polycaprolactone (PCL) and polyurethane (PU) surface modified by gelatin (G), chitosan (C), and hyaluronic acid (H) biomacromolecules and piroxicam-loaded gelatin nanofibers (PCL/PU/GCH/P). The surface of constructs was crosslinked using EDC and NHS. The scaffolds were investigated by SEM, FTIR spectroscopy, swelling test, degradation rate, mechanical tests, and in vitro piroxicam release assay. Furthermore, the cell-seeded scaffolds were evaluated by SEM, viability assay, dapi staining, cell migration, proliferation, and gene expression of chondrocytes within these scaffolds. Finally, the animal study was performed in a rabbit model. Chondrocyte and rabbit adipose-derived mesenchymal stem cells (ASCs) from the infrapatellar fat pad (Hoffa's fat pad) were used. Swelling and degradation rate were increased in the modified scaffolds. Tensile and compressive Young's modulus also were near to human native meniscus tissue. The highest expression level of chondrocyte marker genes was observed for the PCL/PU/GCH scaffold. A significant regeneration was obtained in rabbits treated with ASCs-loaded PCL/PU/GCH/P scaffold after 3 months. The surface-modified scaffolds with or without ASCs could successfully accelerate meniscus regeneration and exhibit potential application in meniscus tissue engineering. 10.1016/j.ijbiomac.2021.04.151
The infrapatellar fat pad produces interleukin-6-secreting T cells in response to a proteoglycan aggrecan peptide and provides dominant soluble mediators different from that present in synovial fluid. Sae-Jung Thitiya,Leearamwat Nitigorn,Chaiseema Nichakarn,Sengprasert Panjana,Ngarmukos Srihatach,Yuktananda Pongsak,Tanavalee Aree,Hirankarn Nattiya,Reantragoon Rangsima International journal of rheumatic diseases OBJECTIVE:The purpose of this study was to investigate the effects of osteoarthritis (OA) peripheral blood mononuclear cell (PBMC) -stimulating proteoglycan aggrecan peptides on T cells present in infrapatellar fat pads (IPFPs) and synovial tissues, and to correlate these findings with mediators present in synovial fluid of OA patients. METHODS:We tested for interleukin-6 (IL-6) -producing T cells in IPFPs of patients with knee OA using ELISPOT. Cytokine and cytotoxic mediator production from OA PBMCs, IPFPs, synovial tissues, and synovial fluids in response to proteoglycan aggrecan peptides were quantified by cytometric bead array. Patterns of cytokine and cytotoxic mediator production were analyzed and compared. RESULTS:T cells from IPFPs elicited strong responses towards the p263-280 peptide by secreting IL-6. In addition, there was a trend that the p263-280 peptide stimulated higher production of cytokines/cytotoxic mediators than other proteoglycan aggrecan peptides, although this was not statistically significant. In patients with knee OA, a group of cytotoxic mediators (sFas, perforin, granzyme A, and granulysin) and IL-6 were detectable at high levels from the synovial fluid. In addition, inflammation in patients with knee OA was more pronounced in joint-surrounding tissues than levels in circulating peripheral blood. CONCLUSION:Our data suggest that T cells responding to the p263-280 peptide contribute to the secretion of various soluble mediators that are found within the synovial fluid. We also identified potential new candidates that may serve as biomarkers of knee OA. 10.1111/1756-185X.14126
Age-Dependent Remodeling in Infrapatellar Fat Pad Adipocytes and Extracellular Matrix: A Comparative Study. Frontiers in medicine The infrapatellar fat pad (IFP) is actively involved in knee osteoarthritis (OA). However, a proper description of which developmental modifications occur in the IFP along with age and in absence of joint pathological conditions, is required to adequately describe its actual contribution in OA pathophysiology. Here, two IFP sources were compared: (a) IFP from healthy young patients undergoing anterior-cruciate ligament (ACL) reconstruction for ACL rupture ( = 24); (b) IFP from elderly cadaver donors ( = 23). After histopathological score assignment to confirm the absence of inflammatory features (i.e., inflammatory infiltrate and increased vascularity), the adipocytes morphology was determined; moreover, extracellular matrix proteins were studied through histology and Second Harmonic Generation approach, to determine collagens content and orientation by Fast Fourier Transform and OrientationJ. The two groups were matched for body mass index. No inflammatory signs were observed, while higher area, perimeter, and equivalent diameter and volume were detected for the adipocytes in the elderly group. Collagen III displayed higher values in the young group and a lower total collagen deposition with aging was identified. However, collagen I/III ratio and the global architecture of the samples were not affected. A higher content in elastic fibers was observed around the adipocytes for the ACL-IFPs and in the septa cadaver donor-IFPs, respectively. Age affects the characteristics of the IFP tissue also in absence of a pathological condition. Variable mechanical stimulation, depending on age-related different mobility, could be speculated to exert a role in tissue remodeling. 10.3389/fmed.2021.661403
Measuring and Modeling Oxygen Transport and Consumption in 3D Hydrogels Containing Chondrocytes and Stem Cells of Different Tissue Origins. Carroll Simon F,Buckley Conor T,Kelly Daniel J Frontiers in bioengineering and biotechnology Understanding how the local cellular environment influences cell metabolism, phenotype and matrix synthesis is crucial to engineering functional tissue grafts of a clinically relevant scale. The objective of this study was to investigate how the local oxygen environment within engineered cartilaginous tissues is influenced by factors such as cell source, environmental oxygen tension and the cell seeding density. Furthermore, the subsequent impact of such factors on both the cellular oxygen consumption rate and cartilage matrix synthesis were also examined. Bone marrow derived stem cells (BMSCs), infrapatellar fat pad derived stem cells (FPSCs) and chondrocytes (CCs) were seeded into agarose hydrogels and stimulated with transforming growth factor-β3 (TGF- β3). The local oxygen concentration was measured within the center of the constructs, and numerical modeling was employed to predict oxygen gradients and the average oxygen consumption rate within the engineered tissues. The cellular oxygen consumption rate of hydrogel encapsulated CCs remained relatively unchanged with time in culture. In contrast, stem cells were found to possess a relatively high initial oxygen consumption rate, but adopted a less oxidative, more chondrocyte-like oxygen consumption profile following chondrogenic differentiation, resulting in net increases in engineered tissue oxygenation. Furthermore, a greater reduction in oxygen uptake was observed when the oxygen concentration of the external cell culture environment was reduced. In general, cartilage matrix deposition was found to be maximal in regions of low oxygen, but collagen synthesis was inhibited in very low (less than 2%) oxygen regions. These findings suggest that promoting an oxygen consumption profile similar to that of chondrocytes might be considered a key determinant to the success of stem cell-based cartilage tissue engineering strategies. 10.3389/fbioe.2021.591126
Comparison between Intra-Articular Injection of Infrapatellar Fat Pad (IPFP) Cell Concentrates and IPFP-Mesenchymal Stem Cells (MSCs) for Cartilage Defect Repair of the Knee Joint in Rabbits. Han Yaguang,Li Haobo,Zhou Rong,Wu Jun,Liu Ziye,Wang Huan,Shao Jiahua,Chen Yi,Zhu Jun,Fu Qiwei,Qian Qirong,Zhou Yiqin Stem cells international Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic method in regenerative medicine. Our previous research adopted a simple nonenzymatic strategy for the preparation of a new type of ready-to-use infrapatellar fat pad (IPFP) cell concentrates. The aim of this study was to compare the therapeutic efficacy of intra-articular (IA) injection of autologous IPFP cell concentrates and allogeneic IPFP-MSCs obtained from these concentrates in a rabbit articular cartilage defect model. IPFP-MSCs sprouting from the IPFP cell concentrates were characterized via flow cytometry as well as based on their potential for differentiation into adipocytes, osteoblasts, and chondrocytes. In the rabbit model, cartilage defects were created on the trochlear groove, followed by treatment with IPFP cell concentrates, IPFP-MSCs, or normal saline IA injection. Distal femur samples were evaluated at 6 and 12 weeks posttreatment via macroscopic observation and histological assessment based on the International Cartilage Repair Society (ICRS) macroscopic scoring system as well as the ICRS visual histological assessment scale. The macroscopic score and histological score were significantly higher in the IPFP-MSC group compared to the IPFP cell concentrate group at 12 weeks. Further, both treatment groups had higher scores compared to the normal saline group. In comparison to the latter, the groups treated with IPFP-MSCs and IPFP cell concentrates showed considerably better cartilage regeneration. Overall, IPFP-MSCs represent an effective therapeutic strategy for stimulating articular cartilage regeneration. Further, due to the simple, cost-effective, nonenzymatic, and safe preparation process, IPFP cell concentrates may represent an effective alternative to stem cell-based therapy in the clinic. 10.1155/2021/9966966
Sulfated carboxymethylcellulose conjugated electrospun fibers as a growth factor presenting system for tissue engineering. Bhutada Sarang S,Sriram M,Katti Dhirendra S Carbohydrate polymers Inspired by the natural electrostatic interaction of cationic growth factors with anionic sulfated glycosaminoglycans in the extracellular matrix, we developed electrospun poly(hydroxybutyrate)/gelatin (PG) fibers conjugated with anionic sulfated carboxymethylcellulose (sCMC) to enable growth factor immobilization via electrostatic interaction for tissue engineering. The fibrous scaffold bound cationic molecules, was cytocompatible and exhibited a remarkable morphological and functional stability. Transforming growth factor-β1 immobilized on the sCMC conjugated fibers was retained for at least 4 weeks with negligible release (3%). Immobilized fibroblast growth factor-2 and connective tissue growth factor were bioactive and induced proliferation and fibrogenic differentiation of infrapatellar fat pad derived mesenchymal stem cells respectively with efficiency similar to or better than free growth factors. Taken together, our studies demonstrate that sCMC conjugated PG fibers can immobilize and retain function of cationic growth factors and hence show potential for use in various tissue engineering applications. 10.1016/j.carbpol.2021.118256
Tissue Collection and RNA Extraction from the Human Osteoarthritic Knee Joint. Wilson Thomas,Kaur Navdeep,Davis Jason,Ali Shabana Amanda Journal of visualized experiments : JoVE Osteoarthritis (OA) is a chronic and degenerative joint disease most often affecting the knee. As there is currently no cure, total knee arthroplasty (TKA) is a common surgical intervention. Experiments using primary human OA tissues obtained from TKA provide the capability to investigate disease mechanisms ex vivo. While OA was previously thought to impact mainly the cartilage, it is now known to impact multiple tissues in the joint. This protocol describes patient selection, sample processing, tissue homogenization, RNA extraction, and quality control (based on RNA purity, integrity, and yield) from each of seven unique tissues to support disease mechanism investigation in the knee joint. With informed consent, samples were obtained from patients undergoing TKA for OA. Tissues were dissected, washed, and stored within 4 h of surgery by flash freezing for RNA or formalin fixation for histology. Collected tissues included articular cartilage, subchondral bone, meniscus, infrapatellar fat pad, anterior cruciate ligament, synovium, and vastus medialis oblique muscle. RNA extraction protocols were tested for each tissue type. The most significant modification involved the method of disintegration used for low-cell, high-matrix, hard tissues (considered as cartilage, bone, and meniscus) versus relatively high-cell, low-matrix, soft tissues (considered as fat pad, ligament, synovium, and muscle). It was found that pulverization was appropriate for hard tissues, and homogenization was appropriate for soft tissues. A proclivity for some subjects to yield higher RNA integrity number (RIN) values than other subjects consistently across multiple tissues was observed, suggesting that underlying factors such as disease severity may impact RNA quality. The ability to isolate high-quality RNA from primary human OA tissues provides a physiologically relevant model for sophisticated gene expression experiments, including sequencing, that can lead to clinical insights that are more readily translated to patients. 10.3791/62718
Inability of Low Oxygen Tension to Induce Chondrogenesis in Human Infrapatellar Fat Pad Mesenchymal Stem Cells. Frontiers in cell and developmental biology OBJECTIVE:Articular cartilage of the knee joint is avascular, exists under a low oxygen tension microenvironment, and does not self-heal when injured. Human infrapatellar fat pad-sourced mesenchymal stem cells (IFP-MSC) are an arthroscopically accessible source of mesenchymal stem cells (MSC) for the repair of articular cartilage defects. Human IFP-MSC exists physiologically under a low oxygen tension (i.e., 1-5%) microenvironment. Human bone marrow mesenchymal stem cells (BM-MSC) exist physiologically within a similar range of oxygen tension. A low oxygen tension of 2% spontaneously induced chondrogenesis in micromass pellets of human BM-MSC. However, this is yet to be demonstrated in human IFP-MSC or other adipose tissue-sourced MSC. In this study, we explored the potential of low oxygen tension at 2% to drive the chondrogenesis of IFP-MSC. We hypothesized that 2% O will induce stable chondrogenesis in human IFP-MSC without the risk of undergoing endochondral ossification at ectopic sites of implantation. METHODS:Micromass pellets of human IFP-MSC were cultured under 2% O or 21% O (normal atmosphere O) in the presence or absence of chondrogenic medium with transforming growth factor-β3 (TGFβ3) for 3 weeks. Following chondrogenesis, the resulting pellets were implanted in immunodeficient athymic nude mice for 3 weeks. RESULTS:A low oxygen tension of 2% was unable to induce chondrogenesis in human IFP-MSC. In contrast, chondrogenic medium with TGFβ3 induced chondrogenesis. All pellets were devoid of any evidence of undergoing endochondral ossification after subcutaneous implantation in athymic mice. 10.3389/fcell.2021.703038
Decellularized extracellular matrix loaded with IPFP-SC for repairing rabbit osteochondral defects. Li Lexiang,Chen Yi,Fu Qiwei,Wu Haishan,Zhou Yiqin,Shao Jiahua,Wu Jun,Han Yaguang,Qian Qirong American journal of translational research BACKGROUND:Tissue engineering is widely applied to treat osteochondral damage in osteoarthritis (OA). However, the superposition of seed cells, material scaffolds, inducing factors, and microenvironmental factors limit their practical application. We intended to develop a novel tissue engineering method for improving the repairment of osteochondral damage and to discuss its effect on repairing osteochondral defects. METHODS:The combined decellularization methods of physics, chemistry and enzymes were used to decellularize rabbit rib cartilage and articular cartilage, and rabbit decellularizated osteochondral composite scaffolds were prepared. The structure and organization of the scaffolds were analyzed. We extracted and identified infrapatellar fat pad stem cells (IPFP-SCs) from healthy rabbits and OA rabbit, which were different in viability, migration, osteogenic and chondrogenic differentiation. Finally, a variety of decellularizated bone cartilage composite scaffolds were loaded with rabbit IPFP-SC for and studies. RESULTS:The decellularization effect was strong, and the organic ingredients were lost. The layered scaffold showed lower density, greater porosity, larger pore size and water absorption than the whole scaffold, but the mechanical properties of the two scaffolds were low. IPFP-SCs were successfully extracted, and the migration and cartilage ability of IPFP-SCs in OA group were weak. The decellularized scaffold showed a high biocompatibility. The structure and composition of osteochondral promoted osteogenic differentiation and chondrogenic differentiation of IPFP-SCs. Moreover, the decellularized extracellular matrix loaded with IPFP-SC had the strongest repairing effect. CONCLUSION:The decellularized extracellular matrix loaded with IPFP-SC showed a better repair effect on rabbit osteochondral defects.
Single-Cell RNA-Sequencing Identifies Infrapatellar Fat Pad Macrophage Polarization in Acute Synovitis/Fat Pad Fibrosis and Cell Therapy. Kouroupis Dimitrios,Best Thomas M,Kaplan Lee D,Correa Diego,Griswold Anthony J Bioengineering (Basel, Switzerland) The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the initiation and progression of joint inflammation and can be potentially altered with mesenchymal stem cell (MSC) therapy. In an acute synovial/IFP inflammation rat model a single intra-articular injection of IFP-MSC was performed, having as controls (1) diseased rats not receiving IFP-MSC and (2) non-diseased rats. After 4 days, cell specific transcriptional profiling via single-cell RNA-sequencing was performed on isolated IFP tissue from each group. Eight transcriptomically distinct cell populations were identified within the IFP across all three treatment groups with a noted difference in the proportion of myeloid cells across the groups. Largely myeloid cells consisted of macrophages (>90%); one M1 sub-cluster highly expressing pro-inflammatory markers and two M2 sub-clusters with one of them expressing higher levels of canonical M2 markers. Notably, the diseased samples (11.9%) had the lowest proportion of cells expressing M2 markers relative to healthy (14.8%) and MSC treated (19.4%) samples. These results suggest a phenotypic polarization of IFP macrophages towards the pro-inflammatory M1 phenotype in an acute model of inflammation, which are alleviated by IFP-MSC therapy inducing a switch towards an alternate M2 status. Understanding the IFP cellular heterogeneity and associated transcriptional programs may offer insights into novel therapeutic strategies for disabling joint disease pathologies. 10.3390/bioengineering8110166
Layer-specific stem cell differentiation in tri-layered tissue engineering biomaterials: Towards development of a single-stage cell-based approach for osteochondral defect repair. Levingstone Tanya J,Moran Conor,Almeida Henrique V,Kelly Daniel J,O'Brien Fergal J Materials today. Bio Successful repair of osteochondral defects is challenging, due in part to their complex gradient nature. Tissue engineering approaches have shown promise with the development of layered scaffolds that aim to promote cartilage and bone regeneration within the defect. The clinical potential of implanting these scaffolds cell-free has been demonstrated, whereby cells from the host bone marrow MSCs infiltrate the scaffolds and promote cartilage and bone regeneration within the required regions of the defect. However, seeding the cartilage layer of the scaffold with a chondrogenic cell population prior to implantation may enhance cartilage tissue regeneration, thus enabling the treatment of larger defects. Here the development of a cell seeding approach capable of enhancing articular cartilage repair without the requirement for expansion of the cell population is explored. The intrinsic ability of a tri-layered scaffold previously developed in our group to direct stem cell differentiation in each layer of the scaffold was first demonstrated. Following this, the optimal chondrogenic cell seeding approach capable of enhancing the regenerative capacity of the tri-layered scaffold was demonstrated with the highest levels of chondrogenesis achieved with a co-culture of rapidly isolated infrapatellar fat pad MSCs (FPMSCs) and chondrocytes (CCs). The addition of FPMSCs to a relatively small number of CCs led to a 7.8-fold increase in the sGAG production over chondrocytes in mono-culture. This cell seeding approach has the potential to be delivered within a single-stage approach, without the requirement for costly expansion of harvested cells, to achieve rapid repair of osteochondral defects. 10.1016/j.mtbio.2021.100173
Characterization and differentiation potential of mesenchymal stem cells isolated from multiple canine adipose tissue sources. Rashid Usman,Yousaf Arfan,Yaqoob Muhammad,Saba Evelyn,Moaeen-Ud-Din Muhammad,Waseem Shahid,Becker Sandra K,Sponder Gerhard,Aschenbach Jörg R,Sandhu Mansur Abdullah BMC veterinary research BACKGROUND:Mesenchymal stem cells (MSCs) are undifferentiated cells that can give rise to a mesoderm lineage. Adipose-derived MSCs are an easy and accessible source for MSCs isolation, although each source of MSC has its own advantages and disadvantages. Our study identifies a promising source for the isolation and differentiation of canines MSCs. For this purpose, adipose tissue from inguinal subcutaneous (SC), perirenal (PR), omental (OM), and infrapatellar fat pad (IPFP) was isolated and processed for MSCs isolation. In the third passage, MSCs proliferation/metabolism, surface markers expression, in vitro differentiation potential and quantitative reverse transcription PCR (CD73, CD90, CD105, PPARγ, FabP4, FAS, SP7, Osteopontin, and Osteocalcin) were evaluated. RESULTS:Our results showed that MSCs derived from IPFP have a higher proliferation rate, while OM-derived MSCs have higher cell metabolism. In addition, MSCs from all adipose tissue sources showed positive expression of CD73 (NT5E), CD90 (THY1), CD105 (ENDOGLIN), and very low expression of CD45. The isolated canine MSCs were successfully differentiated into adipogenic and osteogenic lineages. The oil-red-O quantification and adipogenic gene expression (FAS, FabP4, and PPARγ) were higher in OM-derived cells, followed by IPFP-MSCs. Similarly, in osteogenic differentiation, alkaline phosphatase activity and osteogenic gene (SP7 and Osteocalcin) expression were higher in OM-derived MSCs, while osteopontin expression was higher in PR-derived MSCs. CONCLUSION:In summary, among all four adipose tissue sources, OM-derived MSCs have better differentiation potential toward adipo- and osteogenic lineages, followed by IPFP-MSCs. Interestingly, among all adipose tissue sources, MSCs derived from IPFP have the maximum proliferation potential. The characterization and differentiation potential of canine MSCs isolated from four different adipose tissue sources are useful to assess their potential for application in regenerative medicine. 10.1186/s12917-021-03100-8
Restoring Osteochondral Defects through the Differentiation Potential of Cartilage Stem/Progenitor Cells Cultivated on Porous Scaffolds. Wang Hsueh-Chun,Lin Tzu-Hsiang,Hsu Che-Chia,Yeh Ming-Long Cells Cartilage stem/progenitor cells (CSPCs) are cartilage-specific, multipotent progenitor cells residing in articular cartilage. In this study, we investigated the characteristics and potential of human CSPCs combined with poly(lactic-co-glycolic acid) (PLGA) scaffolds to induce osteochondral regeneration in rabbit knees. We isolated CSPCs from human adult articular cartilage undergoing total knee replacement (TKR) surgery. We characterized CSPCs and compared them with infrapatellar fat pad-derived stem cells (IFPs) in a colony formation assay and by multilineage differentiation analysis in vitro. We further evaluated the osteochondral regeneration of the CSPC-loaded PLGA scaffold during osteochondral defect repair in rabbits. The characteristics of CSPCs were similar to those of mesenchymal stem cells (MSCs) and exhibited chondrogenic and osteogenic phenotypes without chemical induction. For in vivo analysis, CSPC-loaded PLGA scaffolds produced a hyaline-like cartilaginous tissue, which showed good integration with the host tissue and subchondral bone. Furthermore, CSPCs migrated in response to injury to promote subchondral bone regeneration. Overall, we demonstrated that CSPCs can promote osteochondral regeneration. A monophasic approach of using diseased CSPCs combined with a PLGA scaffold may be beneficial for repairing complex tissues, such as osteochondral tissue. 10.3390/cells10123536
Mechanical behavior of infrapatellar fat pad of patients affected by osteoarthritis. Fontanella Chiara Giulia,Belluzzi Elisa,Pozzuoli Assunta,Favero Marta,Ruggieri Pietro,Macchi Veronica,Carniel Emanuele Luigi Journal of biomechanics The infrapatellar fat pad (IFP) is an adipose tissue present in the knee that lies between the patella, femur, meniscus and tibia, filling the space between these structures. IFP facilitates the distribution of the synovial fluid and may act to absorb impulsive actions generated through the joint. IFP in osteoarthritis (OA) pathology undergoes structural changes characterized by inflammation, hypertrophy and fibrosis. The aim of the present study is to analyze the mechanical behavior of the IFP in patients affected by end-stage OA. A specific test fixture was designed and indentation tests were performed on IFP specimens harvested from OA patients who underwent total knee arthroplasty. Experiments allowed to assess the typical features of mechanical response, such as non-linear stress-strain behavior and time-dependent effects. Results from mechanical experimentations were implemented within the framework of a visco-hyperelastic constitutive theory, with the aim to provide data for computational modelling of OA IFP role in knee mechanics. Initial and final indentation stiffness were calculated for all subjects and statistical results reveled that OA IFP mechanics was not significantly influenced by gender, BMI and sample preparation. OA IFP mechanical behavior was also compared to that of other adipose tissues. OA IFP appeared to be a stiffer adipose tissue compared to subcutaneous, visceral adipose tissues and heel fat pads. It is reasonable that fibrosis induces a modification of the tissue destabilizing the normal distribution of forces in the joint during movement, causing a worsening of the disease. 10.1016/j.jbiomech.2021.110931
Phenotypic and functional properties of dedifferentiated fat cells derived from infrapatellar fat pad. Regenerative therapy INTRODUCTION:Mature adipocyte-derived dedifferentiated fat cells (DFATs) are mesenchymal stem cell (MSC)-like cells with high proliferative ability and multilineage differentiation potential. In this study, we first examined whether DFATs can be prepared from infrapatellar fat pad (IFP) and then compared phenotypic and functional properties of IFP-derived DFATs (IFP-DFATs) with those of subcutaneous adipose tissue (SC)-derived DFATs (SC-DFATs). METHODS:Mature adipocytes isolated from IFP and SC in osteoarthritis patients (n = 7) were cultured by ceiling culture method to generate DFATs. Obtained IFP-DFATs and SC-DFATs were subjected to flow cytometric and microarray analysis to compare their immunophenotypes and gene expression profiles. Cell proliferation assay and adipogenic, osteogenic, and chondrogenic differentiation assays were performed to evaluate their functional properties. RESULTS:DFATs could be prepared from IFP and SC with similar efficiency. IFP-DFATs and SC-DFATs exhibited similar immunophenotypes (CD73, CD90, CD105, CD31, CD45, HLA-DR) and tri-lineage (adipogenic, osteogenic, and chondrogenic) differentiation potential, consistent with the minimal criteria for defining MSCs. Microarray analysis revealed that the gene expression profiles in IFP-DFATs were very similar to those in SC-DFATs, although there were certain number of genes that showed different levels of expression. The proliferative activity in IFP-DFATs was significantly (p < 0.05) higher than that in the SC-DFATs. IFP-DFATs showed higher chondrogenic differentiation potential than SC-DFATs in regard to production of soluble galactosaminogalactan and gene expression of type II collagen. CONCLUSIONS:IFP-DFATs showed higher cellular proliferative potential and higher chondrogenic differentiation capacity than SC-DFATs. IFP-DFAT cells may be an attractive cell source for chondrogenic regeneration. 10.1016/j.reth.2021.12.006
Quantitative MR evaluation of the infrapatellar fat pad for knee osteoarthritis: using proton density fat fraction and T2* relaxation based on DIXON. European radiology OBJECTIVES:To investigate the efficacy of fat fraction (FF) and T2* relaxation based on DIXON in the assessment of infrapatellar fat pad (IFP) for knee osteoarthritis (KOA) progression in older adults. METHODS:Ninety volunteers (age range 51-70 years, 65 females) were enrolled in this study. Participants were grouped based on the Kellgren-Lawrence grading (KLG). The FF and T2* values were measured based on the 3D-modified DXION technique. Cartilage defects, bone marrow lesions, and synovitis were assessed based on a modified version of whole-organ magnetic resonance imaging score (WORMS). Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaire. The differences of FF and T2* measurement and the correlation with WORMS and WOMAC assessments were analyzed. Diagnostic efficiency was analyzed by using receiver operating characteristic (ROC) curves. RESULTS:A total of 60 knees were finally included (n = 20 in each group). The values were 82.6 ± 3.7%, 74.7 ± 5.4%, and 60.5 ± 14.1% for FF is the no OA, mild OA, and advanced OA groups, and were 50.7 ± 6.6 ms, 44.1 ± 6.6 ms, and 39.1 ± 4.2 ms for T2*, respectively (all p values < 0.001). The WORMS assessment and WOMAC pain assessment showed negative correlation with FF and T2* values. The ROC showed the area under the curve (AUC), sensitivity, and specificity for diagnosing OA were 0.93, 77.5%, and 100% using FF, and were 0.86, 75.0%, and 90.0% using T2*, respectively. CONCLUSIONS:FF and T2* alternations in IFP are associated with knee structural abnormalities and clinical symptoms cross-sectionally and may have the potential to predict the severity of KOA. KEY POINTS:• Fat fraction (FF) and T2* relaxation based on DIXON imaging are novel methods to quantitatively assess the infrapatellar fat pad for knee osteoarthritis (KOA) progression in older adults. • The alterations of FF and T2* using mDIXON technique in IFP were associated with knee structural abnormalities and clinical symptoms. • FF and T2* alternations in IFP can serve as the new imaging biomarkers for fast, simple, and noninvasive assessment in KOA. 10.1007/s00330-022-08561-5
High glucose stimulating ECM remodeling and an inflammatory phenotype in the IPFP via upregulation of MFAP5 expression. Biochemical and biophysical research communications Extracellular matrix (ECM) remodeling and inflammation in the infrapatellar fat pad (IPFP) are associated with cartilage degeneration and the severity of osteoarthritis (OA). Diabetes is associated with the progression of OA. However, it is still unclear whether diabetes can promote osteoarthritis by targeting the IPFP. In this study, we established a high-fat diet/streptozotocin (HFD/STZ)-induced diabetes mouse model. We found that fibrosis and inflammation were more severe in the IPFP in diabetic mice. Transcriptomic profiling showed that MFAP5 expression was upregulated in IPFPs collected from diabetic mice compared to IPFPs collected from normal mice. We identified that Pdgfrα(+) progenitors were the primary source of MFAP5 in the IPFP under diabetic conditions. In addition, high glucose promoted the expression of MFAP5 in Pdgfrα(+) progenitors by stimulating the translocation of Yap1. Overexpression of MFAP5 in Pdgfrα(+) progenitors promoted fibrogenic differentiation and the production of IL-6. Knocking down the expression of MFAP5 efficiently prevented fibrosis and decreased the level of IL-6 in the IPFP and attenuated cartilage degeneration. Together, these results suggest that MFAP5 may be a potential novel therapeutic target for the treatment of diabetes-induced OA. 10.1016/j.bbrc.2022.02.077
An Open Debate on the Morphological Measurement Methodologies of the Infrapatellar Fat Pad to Determine Its Association with the Osteoarthritis Process. Current rheumatology reports INTRODUCTION:Knee osteoarthritis (OA) is a disease affecting all the neighboring articular tissues including the infrapatellar fat pad (IPFP). Although not yet as widely studied as other tissues in the knee, the IPFP has been recognized to have important metabolic activities and is a key player in OA. METHODS:In this commentary, we will briefly describe the different methodologies employed for the MRI morphological measurement of this tissue and depict the findings in regard to OA. RESULTS:The morphology of this tissue, monitored mainly with the use of magnetic resonance imaging (MRI), demonstrates changes during OA. However, studies of the IPFP morphological alterations and their association with the OA process have shown conflicting results, including a detrimental or beneficial role or no role at all. Although many reasons could explain such mixed findings, one might be the different methodologies used for the MRI measurement of area, volume, or signal intensity. In addition, several techniques are also employed for measuring the volume and signal intensity. An additional level of complexity is related to the presence within the IPFP of two different types of signal intensities, hyper-intensity, and hypo-intensity. CONCLUSION:A consensus of a procedure to measure the morphology of the IPFP is urgently needed to fully appreciate the role of this tissue in the pathology of OA, as well as its uses for clinical decision-making. 10.1007/s11926-022-01057-7
Longitudinal association of infrapatellar fat pad signal intensity alteration with biochemical biomarkers in knee osteoarthritis. Rheumatology (Oxford, England) OBJECTIVE:To explore the longitudinal association of quantitative infrapatellar fat pad (IPFP) signal intensity alteration with OA-related biomarkers. METHODS:Eighteen OA-related biochemical biomarkers of 600 knee OA participants in the Foundation for the National Institutes of Health OA Biomarkers Consortium (FNIH) study were extracted. The quantitative IPFP signal intensity measures were acquired based on magnetic resonance imaging, including mean value [Mean (IPFP)] and standard deviation [sDev (IPFP)] of the whole IPFP signal intensity, median value [Median (H)] and upper quartile value [UQ (H)] of high signal intensity, the ratio of volume of high signal intensity to volume of whole IPFP signal intensity [Percentage (H)] and Clustering factor (H). The linear mixed-effect model was applied to determine the longitudinal associations between IPFP signal intensity alteration and biochemical biomarkers over 2 years. RESULTS:All IPFP measures except for Clustering factor (H) were positively associated with urine collagenase-cleaved type II collagen neoepitope (uC2C), urine C-terminal cross-linked telopeptide of type II collagen (uCTX-II), urine C-terminal cross-linked telopeptide of type I collagen-α (uCTX-Iα) and urine N-terminal cross-linked telopeptide of type I collagen (uNTX-I). Mean (IPFP), Median (H) and Percentage (H) were positively associated with the nitrated form of an epitope located in the triple helix of type II collagen (Coll2-1 NO2). Mean (IPFP), Median (H) and UQ (H) were positively associated with sCTX-I and uCTX-Iβ. Positive associations between sDev (IPFP), Percentage (H) and serum hyaluronic acid (sHA) were found. CONCLUSION:Our results suggest a role of IPFP signal intensity alteration in joint tissue remodelling on a molecular level. 10.1093/rheumatology/keac214
Comparing the chondrogenic potential of rabbit mesenchymal stem cells derived from the infrapatellar fat pad, periosteum & bone marrow. The Indian journal of medical research Background & objectives:Rabbit model is commonly used to demonstrate the proof of concept in cartilage tissue engineering. However, limited studies have attempted to find an ideal source of rabbit mesenchymal stem cells (MSCs) for cartilage repair. This study aimed to compare the in vitro chondrogenic potential of rabbit MSCs isolated from three sources namely infrapatellar fat pad (IFP), periosteum (P) and bone marrow (BM). Methods:Rabbit MSCs from three sources were isolated and characterized using flow cytometry and multi-lineage differentiation assay. Cell proliferation was assessed using trypan blue dye exclusion test; in vitro chondrogenic potential was evaluated by histology and gene expression and the outcomes were compared amongst the three MSC sources. Results:MSCs from three sources shared similar morphology and expressed >99 per cent positive for CD44 and CD81 and <3 per cent positive for negative markers CD34, CD90 and human leukocyte antigen - DR isotype (HLA-DR). The BM-MSCs and IFP-MSCs showed significantly higher cell proliferation (P<0.001) than the P-MSCs from passage 4. Histologically, BM-MSCs formed a thicker cartilage pellet (P<0.01) with abundant matrix deposition than IFP and P-MSCs during chondrogenic differentiation. The collagen type 2 staining was significantly (P<0.05) higher in BM-MSCs than the other two sources. These outcomes were further confirmed by gene expression, where the BM-MSCs demonstrated significantly higher expression (P<0.01) of cartilage-specific markers (COL2A1, SOX9 and ACAN) with less hypertrophy. Interpretation & conclusions:This study demonstrated that BM-MSCs had superior chondrogenic potential and generated better cartilage than IFP and P-MSCs in rabbits. Thus, BM-MSCs remain a promising candidate for rabbit articular cartilage regeneration. 10.4103/ijmr.IJMR_93_19
Morphological characteristics of the infrapatellar fat pad. Scientific reports The relationship between the morphological characteristics of the infrapatellar fat pad (IFP) and joint deformity has yet to be fully elucidated. Therefore, the purpose of this study was to clarify the morphological characteristics of the IFP and to identify the relationships between morphological characteristics of the IFP and degenerative grade of the articular surface of the patella. This investigation examined 41 legs from 25 Japanese cadavers. The IFP length, width, and volume were measured. It was categorized into three types: Type I, IFP proximal located on medial and lateral sides of the patella; Type II, the IFP proximal only located medially; and Type III, absence of the IFP proximal. Articular surfaces were graded as macroscopically intact or mildly altered (Grade I), moderately (Grade II), or severely (Grade III). Grade III was significantly more frequent than Grades I or II in Type III. IFP volume was significantly larger in Type I than in Types II or III. A negative correlation was found between the degenerative grade of the articular surface of the patella and IFP volume. It was suggested that a relationship between the degenerative grade of the articular surface of the patella and the IFP volume. 10.1038/s41598-022-12859-1
MRI-based Texture Analysis of Infrapatellar Fat Pad to Predict Knee Osteoarthritis Incidence. Radiology Background Infrapatellar fat pad (IPFP) quality has been implicated as a marker for predicting knee osteoarthritis (KOA); however, no valid quantification for subtle IPFP abnormalities has been established. Purpose To investigate whether MRI-based three-dimensional texture analysis of IPFP abnormalities could help predict incident radiographic KOA. Materials and Methods In this prospective nested case-control study, 690 participants whose knees were at risk for KOA were included from the Pivotal Osteoarthritis Initiative MRI Analyses incident osteoarthritis cohort. All knees had a Kellgren-Lawrence grade of 1 or less at baseline. During the 4-year follow-up, case participants were matched 1:1 to control participants, with incident radiographic KOA as the outcome. MRI scans were segmented at the incident time point of KOA (hereafter, P0), 1 year before P0 (hereafter, P-1), and baseline. MRI-based three-dimensional texture analysis was performed to extract IPFP texture features. Least absolute shrinkage and selection operator and multivariable logistic regressions were applied in the development cohort and evaluated in the test cohort. The area under the receiver operating characteristic curve (AUC) was used to evaluate the discriminative value of the clinical score, IPFP texture score, and MRI Osteoarthritis Knee Score. Results Participants were allocated to development ( = 500, 340 women; mean age, 60 years) and test ( = 190, 120 women; mean age, 61 years) cohorts. In both cohorts, IPFP texture scores (AUC ≥0.75 for all) showed greater discrimination than clinical scores (AUC ≤0.69 for all) at baseline, P-1, and P0, with significant differences in pairwise comparisons ( ≤ .002 for all). Greater predictive and concurrent validities of IPFP texture scores (AUC ≥0.75 for all) compared with MRI Osteoarthritis Knee Scores (AUC ≤0.66 for all) were also demonstrated ( < .001 for all). Conclusion MRI-based three-dimensional texture of the infrapatellar fat pad was associated with future development of knee osteoarthritis. ClinicalTrials.gov registration no.: NCT00080171 © RSNA, 2022 See also the editorial by Fischer in this issue. 10.1148/radiol.212009
From Morphology to Biomarker: Quantitative Texture Analysis of the Infrapatellar Fat Pad Reliably Predicts Knee Osteoarthritis. Radiology 10.1148/radiol.221094
Aberrant Expression of and in Infrapatellar Fat Pad-Derived ASCs from Pre-Diabetic Donors. Cells Osteoarthritis (OA) is a degenerative joint disease resulting in limited mobility and severe disability. Type II diabetes mellitus (T2D) is a weight-independent risk factor for OA, but a link between the two diseases has not been elucidated. Adipose stem cells (ASCs) isolated from the infrapatellar fat pad (IPFP) may be a viable regenerative cell for OA treatment. This study analyzed the expression profiles of inflammatory and adipokine-related genes in IPFP-ASCs of non-diabetic (Non-T2D), pre-diabetic (Pre-T2D), and T2D donors. Pre-T2D ASCs exhibited a substantial decrease in levels of mesenchymal markers CD90 and CD105 with no change in adipogenic differentiation compared to Non-T2D and T2D IPFP-ASCs. In addition, Cyclooxygenase-2 (), Forkhead box G1 () expression and prostaglandin E2 (PGE) secretion were significantly increased in Pre-T2D IPFP-ASCs upon stimulation by interleukin-1 beta (IL-1β). Interestingly, M1 macrophages exhibited a significant reduction in expression of pro-inflammatory markers and when co-cultured with Pre-T2D IPFP-ASCs. These data suggest that the heightened systemic inflammation associated with untreated T2D may prime the IPFP-ASCs to exhibit enhanced anti-inflammatory characteristics via suppressing the IL-6/COX-2 signaling pathway. In addition, the elevated production of PGE by the Pre-T2D IPFP-ASCs may also suggest the contribution of pre-diabetic conditions to the onset and progression of OA. 10.3390/cells11152367