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Zuozhen Tian,1 Frances S Shofer,1,2 Alec Z Sandroni,1 Lan Zhao,3 Carla R Scanzello,4,5 Yejia Zhang1,6 1Department of Physical Medicine & Rehabilitation, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 2Department of Emergency Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA; 4Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Section of Rheumatology, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA; 6Section of Rehabilitation Medicine, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USACorrespondence: Yejia Zhang, Department of Physical Medicine & Rehabilitation, Hospital of the University of Pennsylvania, Philadelphia, PA, USA, Email yejia.zhang@pennmedicine.upenn.edu; yejia.zhang@va.govObjective: To examine the effects of human interleukin (IL) 8 expression on mouse behavior.Methods: A mouse line expressing human IL8 in the intervertebral discs (IVD) and cartilaginous tissues (hIL8+) was generated. Mouse spontaneous behaviors, including locomotion, climbing, rearing, grooming, eating, drinking, and immobility were recorded with a fully automatic, non-invasive platform.Results: Distance traveled by the hIL8+ mice declined with age compared with control littermates, and male hIL8+ mice traveled a shorter distance than male controls and females of either genotype (p < 0.05). The hIL8+ mice also spent less time in locomotion than control mice (p < 0.01), and male hIL8+ mice spent the least amount of time and had lowest count in locomotion compared with the other 3 groups at 12 weeks of age or greater (p < 0.05). The hIL8+ mice spent less time climbing than controls, and male mice spent less time climbing than female mice of the same genotype (p < 0.01). The hIL8+ mice spent more time eating and less time drinking than controls, and all mice spent less time eating and more time drinking with increasing age. Finally, hIL8+ mice spent more time immobile than controls, and male hIL8+ mice spent more time immobile than any other group (p < 0.05).Conclusion: The hIL8+ mice, especially hIL8+ males, showed reduced ambulation and climbing. Mice showed age-related decrease in eating and increase in drinking and grooming time that was also influenced by expression of hIL8. These changes in natural behaviors in control mice are consistent with functional decline with age. Effects of hIL8 superimposed on the natural aging process could involve systemic (e.g., on the brain) and local (e.g., in the spine and joint tissues) mechanisms. Future exploration of these mechanisms might be productive.Keywords: interleukin (IL) 8, mouse, behavior, age, decline

Objective: We evaluated a behaviorally designed intervention utilizing gamification and social support to improve physical activity and reduce symptoms in patients with osteoarthritis of the knee (KOA)., Methods: Veterans with KOA, aged 40-80 years, were enrolled in this randomized controlled trial. Participants received a Fitbit and completed a 2- to 4-week baseline period. A Web-based platform administered biweekly surveys after randomization and tracked physical activity. Participants selected a daily step goal that was 33%, 40%, or 50% above their baseline. The intervention arm received game playing aspects and a social support partner to advance weekly step performance while the control arm only received weekly updates. The primary outcome was the change in steps per day averaged over 2-week intervals. We used mixed effects regression, adjusting for baseline step count. Secondary outcomes assessed the change in KOOS (Knee Injury and Osteoarthritis Outcome Score) over 32 weeks., Results: Thirty-one participants were included in the final analysis. Most participants were male (90.3%), Black (70.96%), had a mean (SD) age of 60 (13) years, and body mass index of 33.7 (5.9) kg/m2. Participants that received the intervention walked a total of 1119 (95% confidence interval: -562, 2799) more steps per day (p = 0.19). The effect was greatest in the first 6 months (1491 [-272, 3254], p = 0.10). Compared with controls, those that received the intervention had improvement over time in total KOOS (mean 2-week change +0.62 [0.031, 1.20] vs -0.38 [-1.04, 0.28], p = 0.02) and several subscales., Conclusions: This intervention demonstrated promise for promoting greater physical activity and improving symptoms in patients with KOA., Competing Interests: Conflicts of interest and sources of funding: Dr Baker would like to acknowledge funding through a Veterans Affairs Rehabilitation Research and Development (RR&D) SPiRE Award (I21 RX003157), an RR&D Merit Award (I01 RX003644), and Clinical Science Research and Development Career Merit Award (I01 CX001703). Dr Scanzello is supported by a Basic Laboratory Research and Development Merit Award (BX004912) and a RR&D Merit Award (RX003988). Dr Neogi is supported by a National Institutes of Health Mentoring Award (K24 AR070892). Dr Wysham is supported by a VA Career Development Award (CX002351). The contents of this work do not represent the views of the Department of the Veterans Affairs or the United States Government. The authors do not have any conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA., Methods: Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined., Results: There was acceptable to very good agreement when using 3-4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain., Conclusions: To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed "synovitis" score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered., Competing Interests: Declaration of Competing Interest The following authors declare no conflicts of interest: AMO, SYK, KGB, BH, SI, JL, RX. REM serves as an Associate Editor of Arthritis & Rheumatology. CBL serves as Deputy Editor for Osteoarthritis & Cartilage, received consulting fees from Fidia Farmaceutici and Rotapharm, and conducts contract research for various pharmaceutical companies. AMM received consulting fees from Asahi Kasei Pharma Corporation, Orion, and 23andMe, and serves as the co-Editor-in-Chief of Osteoarthritis and Cartilage. CRS and REM serve as Associate Editors for Arthritis & Rheumatology, and are on the Editorial Board of Osteoarthritis & Cartilage. In addition, CRS is named as inventor on provisional patent applications regarding a novel method of treatment for osteoarthritis., (Published by Elsevier Ltd.)

Objective: In the knee, synovial fibrosis after ligamentous injury is linked to progressive joint pain and stiffness. The objective of this study was to evaluate changes in synovial architecture, mechanical properties, and transcriptional profiles following naturally occurring cruciate ligament injury in canines and to test potential therapeutics that target drivers of synovial inflammation and fibrosis., Design: Synovia from canines with spontaneous cruciate ligament tears and from healthy knees were assessed via histology (n = 10/group) and micromechanical testing (n = 5/group) to identify changes in tissue architecture and stiffness. Additional samples (n = 5/group) were subjected to RNA-sequencing to define the transcriptional response to injury. Finally, synovial tissue samples from injured animals (n = 6 (IL1) or n = 8 (IL6)/group) were assessed in vitro for response to therapeutic molecules directed against interleukin (IL) signaling (IL1 or IL6)., Results: Cruciate injury resulted in increased synovial fibrosis, vascularity, inflammatory cell infiltration, and intimal hyperplasia. Additionally, the stiffness of both the intima and subintima regions were higher in diseased compared to healthy tissue. Differential gene expression analysis showed that diseased synovium had an upregulation of immune response and cell adhesion pathways and a downregulation of Rho protein transduction pathways. In vitro application of small molecule therapeutics targeting IL1 (anakinra) or IL6 (tocilizumab) dampened expression of inflammatory and matrix deposition mediators., Conclusion: Spontaneous cruciate ligament injury in canines is associated with synovial inflammation and fibrosis in a relevant model for testing emerging intra-articular treatments. Small molecule therapeutics targeting IL pathways may be ideal interventions for delivery to the joint space after injury., Competing Interests: Conflict of Interest The authors declare no competing interests associated with this manuscript., (Published by Elsevier Ltd.)

As a leading global cause of musculoskeletal-related disability, osteoarthritis (OA) represents a public health urgency. Understanding of disease pathogenesis has advanced substantially in the past decade, yet no disease-modifying therapeutics have advanced to the clinic. To address this challenge, the CARE-AP (Cartilage Repair strategies to alleviate Arthritis Pain) collaborative research team was convened to bring together relevant multidisciplinary expertise and perspectives from across the VA research community nationwide. The first CARE-AP Annual Research Symposium took place (virtually) in February 2022 with roughly 90 participants. A number of innovative and therapeutic strategies were discussed, including siRNA approaches coupled with novel nanoparticle-based delivery systems, cellular engineering approaches to develop reparative cells that can probe the joint environment and respond to disease-specific cues, and novel biofabrication techniques to improve tissue engineering and effect "biological joint replacement." In addition, challenges and advances in rehabilitation approaches, imaging outcomes, and clinical studies were presented, which were integrated into a framework of recommendations for running "preclinical trials" to improve successful clinical translation., (© 2024 Orthopaedic Research Society.)

Purpose of the Review: Erosive hand osteoarthritis (EHOA) is an aggressive form of hand osteoarthritis that leads to significant disability, and recent data suggests that it is increasing in prevalence. This review provides an update of our current understanding of epidemiology, genetic associations, biomarkers, pathogenesis, and treatment of EHOA, with particular focus on studies published within the last 5 years., Recent Findings: New studies of EHOA have identified new genetic loci associated with disease, including variants in genes involved in inflammation and bone remodeling. Preclinical studies implicate pathways of innate immunity, including some that may be causal in the condition. Recent novel studies showed that inflammatory features identified by ultrasound and MRI are associated with development of erosive lesions over time on conventional radiography. In the future, these imaging modalities may be useful in identifying patients at risk of adverse outcomes. Promising new findings in genetics, biomarkers, and treatment targets will hopefully allow for future therapeutic options for this debilitating condition., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Fibroses are disorders linked to persistence of myofibroblasts due to biochemical (e.g., Transforming growth factor-β) and biophysical cues (e.g., a stiff microenvironment). In the context of osteoarthritis, fibrotic changes in the joint-lining synovium have been linked with disease progression. The objective of this study was to probe synovial fibroblast mechanobiology and how essential functions (i.e., lubrication) are altered in fibrotic environments., Design: Both ex vivo and in vitro synovium models were assessed for fibrotic and lubrication biomarkers to better understand the role of mechanobiology and lubrication. Additionally, in vitro, work on small molecules targeting mechanobiology was assessed., Results: Our results indicated that modulating mechanobiology could rescue the fibrotic phenotype instigated by stiffening microenvironment that resulted in altered lubricant expression. A small molecule therapeutic, fasudil, blocked ROCK-mediated contractility and this inhibition of the fibrotic mechano-response of synovial fibroblasts restored proper lubrication function, providing insight into mechanisms of disease progression as well as a new avenue for therapeutic development., Conclusion: This study identifies synovial fibrosis as a condition that potentially has joint-wide deficits through inhibiting lubrication. Additionally, modulating mechanobiology (i.e., ROCK-mediated contractility) may pose a potential target for small molecule therapies that can be delivered to the joint space., Classification: Applied Biological Sciences., Competing Interests: Declaration of Competing Interest The authors declare no competing interests associated with this manuscript., (Published by Elsevier Ltd.)

Objective: To develop an imaging mass cytometry method for identifying complex cell phenotypes, inter-cellular interactions, and population changes in the synovium and infrapatellar fat pad (IFP) of the mouse knee following a non-invasive compression injury., Design: Fifteen male C57BL/6 mice were fed a high-fat diet for 8 weeks prior to random assignment to sham, 0.88 ​mm, or 1.7 ​mm knee compression displacement at 24 weeks of age. 2-weeks after loading, limbs were prepared for histologic and imaging mass cytometry analysis, focusing on myeloid immune cell populations in the synovium and IFP., Results: 1.7 ​mm compression caused anterior cruciate ligament (ACL) rupture, development of post-traumatic osteoarthritis, and a 2- to 3-fold increase in cellularity of synovium and IFP tissues compared to sham or 0.88 ​mm compression. Imaging mass cytometry identified 11 myeloid cell subpopulations in synovium and 7 in IFP, of which approximately half were elevated 2 weeks after ACL injury in association with the vasculature. Notably, two monocyte/macrophage subpopulations and an MHC II hi population were elevated 2-weeks post-injury in the synovium but not IFP. Vascular and immune cell interactions were particularly diverse in the synovium, incorporating 8 unique combinations of 5 myeloid cell populations, including a monocyte/macrophage population, an MHC II hi population, and 3 different undefined F4/80 + myeloid populations., Conclusions: Developing an imaging mass cytometry method for the mouse enabled us to identify a diverse array of synovial and IFP vascular-associated myeloid cell subpopulations. These subpopulations were differentially elevated in synovial and IFP tissues 2-weeks post injury, providing new details on tissue-specific immune regulation., Competing Interests: CRS and TMG have filed provisional patent applications #63/479,605 and #63/484,099 entitled, “COMPOSITIONS AND METHODS FOR TREATING OSTEOARTHRITIS USING A CD14 INHIBITOR”.

Objective: To quantify the effect of corticosteroids compared to lidocaine-only injections over 12 weeks among patients with knee osteoarthritis (KOA)., Methods: Participants with KOA were randomized to receive a knee injection of methylprednisolone acetate 1 mL (40 mg) plus 2 mL lidocaine (1%) or 1 mL saline and 2 mL lidocaine. Participants and providers were blinded to treatment allocation using an opacified syringe. The outcome was the average change from baseline of the total Knee Injury and Osteoarthritis Outcome Score (KOOS) (range 0-100) assessed at 2-week intervals over 12 weeks. Participants received KOOS questionnaires on their smartphones through a web-based platform. We used linear mixed-effects regressions with robust variance estimators to evaluate the association between the intervention and change in KOOS total and subscales (ClinicalTrials.gov identifier NCT03835910; registered 2019-02-11)., Results: Of the 33 randomized participants, 31 were included in the final analysis. The predicted mean (SE) change in total KOOS over the 12-week follow-up was 9.4 (3.2) in the corticosteroids arm versus -1.3 (1.4) in the control arm (P = 0.003). Of participants, 47% achieved change as large as the minimal clinically important difference (16 units) in the intervention arm compared to 6% of participants in the lidocaine arm. Further, there were greater improvements in the intervention arm for KOOS subscales and for Patient Reported Outcomes Measurement Information System (PROMIS) assessments of pain intensity, behavior, and interference., Conclusion: Corticosteroid injections demonstrated clinically meaningful improvements in KOA symptoms over 12 weeks of follow-up. These data support larger studies to better quantify short-term benefits., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. We undertook this study to characterize age-associated changes in knee OA, pain-related behaviors, and dorsal root ganglion (DRG) molecular phenotypes in mice of both sexes., Methods: Male or female C57BL/6 mice 6 or 20 months of age were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 DRG immune characterization via flow cytometry. DRG gene expression in older mice and humans was also examined., Results: Male mice at 20 months of age had worse cartilage degeneration than 6-month-old mice. Older female mouse knees showed increased cartilage degeneration but to a lesser degree than those of male mice. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male mouse DRGs showed increased expression of Ccl2 and Ccl5, and older female mouse DRGs showed increased Cxcr4 and Ccl3 expression compared to 6-month-old mouse DRGs, among other differentially expressed genes. Human DRG analysis from 6 individuals >80 years of age revealed elevated CCL2 in men compared to women, whereas CCL3 was higher in DRGs from women., Conclusion: We found that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of OA therapies., (© 2023 American College of Rheumatology.)

Mucopolysaccharidosis I is a lysosomal storage disorder characterized by deficient alpha-L-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a critical need for improved understanding of joint disease pathophysiology in MPS I, including specific biomarkers to predict and monitor joint disease progression, and response to treatment. The objective of this study was to leverage the naturally-occurring MPS I canine model and undertake an unbiased proteomic screen to identify systemic biomarkers predictive of local joint disease in MPS I. Synovial fluid and serum samples were collected from MPS I and healthy dogs at 12 months-of-age, and protein abundance characterized using liquid chromatography tandem mass spectrometry. Stifle joints were evaluated postmortem using magnetic resonance imaging (MRI) and histology. Proteomics identified 40 proteins for which abundance was significantly correlated between serum and synovial fluid, including markers of inflammatory joint disease and lysosomal dysfunction. Elevated expression of three biomarker candidates, matrix metalloproteinase 19, inter-alpha-trypsin inhibitor heavy-chain 3 and alpha-1-microglobulin, was confirmed in MPS I cartilage, and serum abundance of these molecules was found to correlate with MRI and histological degenerative grades. The candidate biomarkers identified have the potential to improve patient care by facilitating minimally-invasive, specific assessment of joint disease progression and response to therapeutic intervention., Competing Interests: Declaration of Competing Interest LJS: Scientific Advisory Board, National MPS Society; Scientific Advisory Board, JOR Spine. GRD: Co-founder and CEO, Mechano-Therapeutics LLC. WM: Book royalties, “Diagnostic MRI in Dogs and Cats”, Taylor and Francis. RG: Consultant, Acorn Biolabs; Scientific Advisory Board, JOR Spine. MLC, CRS, CZ, ZJ, YKL, SYJ, LAS, HF: No relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human β-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4 mg/kg) or a high dose (20 mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6 months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6 months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6 months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs., Competing Interests: This study was funded in part by Ultragenyx Pharmaceutical, the company that produces vestronidase alfa (the drug that was evaluated). In addition, the drug used in the study was provided by the company at no cost to the investigators. Specific author conflicts: L.J.S., Research grant from Ultragenyx Pharmaceutical; Scientific Advisory Board, National MPS Society; Scientific Advisory Board, JOR Spine. G.R.D., co-founder and CEO, Mechano-Therapeutics LLC. W.M., book royalties, “Diagnostic MRI in Dogs and Cats,” Taylor & Francis. R.G., consultant, Acorn Biolabs; Scientific Advisory Board, JOR Spine. C.R.S., G.L., C.Z., Z.J., Y.K.L., S.S.S., S.Y.J., and K.A., no relevant disclosures., (© 2022 The Authors.)

Background: Knee osteoarthritis (KOA) is a high-priority problem among the aging population. While exercise has been shown to be beneficial in management of the disease, scalable and low-cost interventions to improve exercise in this population are lacking. Recent controversy over the value of corticosteroid injections for palliation has also arisen. Therefore, we designed a randomized, double-blind, placebo-controlled clinical trial with a 2-period crossover design to study (1) behavioral incentives to promote exercise and (2) corticosteroid injections to reduce pain and improve function in patients with KOA when compared to lidocaine only., Methods: The study design is a pragmatic factorial and crossover randomized clinical trial. Patients with KOA who are deemed eligible by their provider to receive knee injections and are able to walk without assistive devices will be recruited from clinical practices at four sites within the Veterans Affairs (VA) Health System in the USA. In total, 220 participants will be randomized to receive social incentives with gamification (i.e., incorporation of game elements) to promote exercise and compared to controls that receive a Fitbit but no incentive. Each patient will also be assigned to receive a blinded corticosteroid injection and a lidocaine-only injection in random order. The primary outcomes are the change in average daily step counts from baseline and the change in Knee Osteoarthritis Outcome Score (KOOS) from baseline. The study team will continuously collect step count, heart rate, and sleep data using activity monitors and patient-reported outcomes using the Way to Health (WTH) platform at two four-week intervals over eight months of follow-up. Mixed effects regression incorporating all available data points will be used for analysis., Discussion: The "Marching on for Veterans with Osteoarthritis of the Knee" (MOVE-OK) trial will take a pragmatic approach to evaluate (1) whether incentives based on behaviorally enhanced gamification can improve physical activity in this patient population and (2) whether corticosteroids injections reduce pain and disability in patients with KOA. Results of this trial will help to direct clinical practice and inform management guidelines., Trial Registration: ClinicalTrials.gov NCT05035810 . Registered on 5 September 2021., (© 2022. The Author(s).)

Osteoarthritis (OA) most commonly affects knee joints, and the next most commonly affected sites are the hands and hips. Three distinct hand OA phenotypes have been described: erosive hand OA (EHOA), nodal hand OA - also known as non-erosive hand OA (non-EHOA) - and first carpometacarpal joint OA. EHOA predominantly affects women and is the most aggressive form of hand OA, characterized by a severe clinical onset and progression, leading to joint damage, disability and reduction of quality of life. Clinical signs of inflammation associated with EHOA include the acute onset of pain, swelling and redness. Moreover, EHOA is characterized by radiographic features such as central erosion, saw-tooth and gull-wing lesions and, rarely, ankylosis. The aim of this Review is to report the latest findings on epidemiology, clinical features, pathology and aetiopathogenesis, biomarkers, imaging modalities and treatments for EHOA. The ongoing development of new hand OA classification criteria should facilitate standardization between studies., (© 2022. Springer Nature Limited.)

Background: The corrective procedures for meniscal injury are dependent on tear type, severity, and location. Vertical longitudinal tears are common in young and active individuals, but their natural progression and impact on osteoarthritis (OA) development are not known. Root tears are challenging and they often indicate poor outcomes, although the timing and mechanisms of initiation of joint dysfunction are poorly understood, particularly in large-animal and human models., Purpose/hypothesis: In this study, vertical longitudinal and root tears were made in a large-animal model to determine the progression of joint-wide dysfunction. We hypothesized that OA onset and progression would depend on the extent of injury-based load disruption in the tissue, such that root tears would cause earlier and more severe changes to the joint., Study Design: Controlled laboratory study., Methods: Sham surgeries and procedures to create either vertical longitudinal or root tears were performed in juvenile Yucatan mini pigs through randomized and bilateral arthroscopic procedures. Animals were sacrificed at 1, 3, or 6 months after injury and assessed at the joint and tissue level for evidence of OA. Functional measures of joint load transfer, cartilage indentation mechanics, and meniscal tensile properties were performed, as well as histological evaluation of the cartilage, meniscus, and synovium., Results: Outcomes suggested a progressive and sustained degeneration of the knee joint and meniscus after root tear, as evidenced by histological analysis of the cartilage and meniscus. This occurred in spite of spontaneous reattachment of the root, suggesting that this reattachment did not fully restore the function of the native attachment. In contrast, the vertical longitudinal tear did not cause significant changes to the joint, with only mild differences compared with sham surgery at the 6-month time point., Conclusion: Given that the root tear, which severs circumferential connectivity and load transfer, caused more intense OA compared with the circumferentially stable vertical longitudinal tear, our findings suggest that without timely and mechanically competent fixation, root tears may cause irreversible joint damage., Clinical Relevance: More generally, this new model can serve as a test bed for experimental surgical, scaffold-based, and small molecule-driven interventions after injury to prevent OA progression., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by the Department of Veterans Affairs (I01 RX000174, IK6 RX003416, and I21 RX003293) and the National Institutes of Health (R01 EB002425, R01 AR056624, and T32 AR007132). Additional support was provided by a New Investigator Award from the Orthopaedic Research and Education Foundation and a pilot award from the Penn Center for Musculoskeletal Disorders (P30 AR069619). L.M.M. has received hospitality payments from Stryker. J.M.P. has received consulting fees from NovoPedics. M.H.Z. has received education payments from Arthrex and Liberty Surgical. C.R.S. has received consulting fees from Bayer. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Objective: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene ( IL15RA ) for an association with OA with radiographic severity and symptoms. Methods: Cartilage samples from donors ( n = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 in vitro using explant cultures. Data from two independent Nottinghamshire-based studies ( n = 795 and n = 613) were used to test genetic variants in the IL15RA gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. Results: IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the IL15RA gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 p < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 p < 0.01) but not with radiographic severity. Conclusions: In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although ex vivo cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between IL15RA variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA., (Copyright © 2020 Warner, Nair, Marpadga, Chubinskaya, Doherty, Valdes and Scanzello.)

We showed previously that inflammatory mediators, including IL8, in intervertebral disc tissues from patients with discogenic back pain may play a key role in back pain. To investigate the molecular mechanism of IL8 signaling in back pain, we generated a mouse model that conditionally expresses human (h) IL8. We hypothesized that hIL8 levels affect mouse activity and function. Briefly, hIL8 cDNA was inserted into the pCALL2 plasmid, linearized, and injected into mouse embryos. Resulting pCALL2-hIL8 mice were then bred with GDF5-Cre mice to express the transgene in cartilage and intervertebral disc (IVD) tissues. Functional capacities including nest-making and other natural behaviors were measured. Both male and female mice expressing hIL8 showed lower nesting scores than did littermates that did not express hIL8 ( n = 14 to 16 per group). At 28 wk of age, mice expressing hIL8 ( n = 35) spent more time immobile and eating during each night than littermate controls ( n = 33). Furthermore, hIL8-expressing mice traveled shorter distances and at a lower average speed than littermate controls. Thus, in an initial effort to investigate the relationship between this chemokine and mouse behavior, we have documented changes in normal activities in mice conditionally expressing hIL8.

Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.

Although osteoarthritis (OA) was historically referred to as the non-inflammatory arthritis, it is now considered a condition involving persistent low-grade inflammation and activation of innate inflammatory pathways. Synovitis increases the risk of OA onset and progression and involves the recruitment of monocytes, lymphocytes, and other leukocytes. In particular, macrophages are important mediators of synovial inflammatory activity and pathologic cartilage and bone responses that are characteristic of OA. Advances in understanding how damage-associated molecular patterns (DAMPs) trigger monocyte/macrophage recruitment and activation in joints provide opportunities for disease-modifying therapies. However, the complexity and plasticity of macrophage phenotypes that exist in vivo have thus far prevented the successful development of macrophage-targeted treatments. Current studies show that synovial macrophages are derived from distinct cellular lineages, which correspond to unique functional roles for maintaining joint homeostasis. An improved understanding of the aetiology of synovial inflammation in specific OA-subtypes, such as with obesity or genetic risk, is a potential strategy for developing patient selection criteria for future precision therapies.

Objective: CD14 is a monocyte/macrophage pattern-recognition receptor that modulates innate inflammatory signaling. Soluble CD14 levels in knee OA synovial fluids are associated with symptoms and progression of disease. Here we investigate the role of this receptor in development of OA using a murine joint injury model of disease., Methods: 10-week-old Male C57BL/6 (WT) and CD14-deficient (CD14-/-) mice underwent destabilization of the medial meniscus (DMM) surgery to induce OA. Joint histopathology was used to examine cartilage damage, and microCT to evaluate subchondral bone (SCB) remodeling at 6 and 19 weeks after surgery. Synovial and fat pad expression of macrophage markers (F4/80, CD11c, CD68, iNOS, CCR7, CD163 and CD206) was assessed by flow cytometry and droplet digital (dd)PCR. Changes in locomotive activity indicative of joint pain were evaluated longitudinally up to 16 weeks by automated behavioral analysis., Results: Early cartilage damage scores 6 weeks post-DMM were similar in both strains (Mean score ±SEM WT: 4.667±1.38, CD14-/-: 4.6±0.6), but at 19 weeks were less severe in CD14-/- (6.0±0.46) than in WT mice (13.44±2.5, p = 0.0002). CD14-/- mice were protected from both age-related and post-surgical changes in SCB mineral density and trabecular thickness. In addition, CD14-/- mice were protected from decreases in climbing activity (p = 0.015 vs. WT, 8 weeks) observed after DMM. Changes in synovial/fat pad expression of CCR7, a marker of M1 macrophages, were slightly reduced post-DMM in the absence of CD14, while expression of CD68 (pan-macrophage marker) and CD163 (M2 marker) were unchanged., Conclusion: CD14 plays an important role in progression of structural and functional features of OA in the DMM model, and may provide a new target for therapeutic development., Competing Interests: The authors have read the journal's policy and have the following competing interests: CRS reports research funding from Baxalta, Inc and consultant fees from Bayer, Inc., both unrelated to the work included in this manuscript. All other authors report no competing interests to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Elevated chemokine receptor Ccr7 is observed in knee osteoarthritis (OA) and associated with severity of symptoms. In this study, we confirmed that CCR7 protein expression is elevated in synovial tissue from OA patients by immunohistochemical staining. We then investigated whether Ccr7 deficiency impacted structural and functional joint degeneration utilizing a murine model of OA. OA-like disease was induced in male C57BL/6 and Ccr7-deficient (Ccr7 -/- ) mice by destabilization of the medial meniscus (DMM). Functional deficits were measured by computer integrated monitoring of spontaneous activity every 4 weeks after DMM surgery up 16 weeks. Joint degeneration was evaluated at 6 and 19 weeks post-surgery by histopathology, and subchondral bone changes analyzed by microCT. Results showed reduction in locomotor activities in DMM-operated C57BL/6 mice by 8 weeks, while activity decreases in Ccr7 -/- mice were delayed until 16 weeks. Histopathologic evaluation showed minimal protection from early cartilage degeneration (p = 0.06) and osteophytosis (p = 0.04) in Ccr7 -/- mice 6 weeks post-DMM compared to C57BL/6 controls, but not at 19 weeks. However, subchondral bone mineral density (p = 0.03) and histologic sclerosis (p = 0.02) increased in response to surgery in C57BL/6 mice at 6 weeks, while Ccr7 -/- mice were protected from these changes. Our results are the first to demonstrate a role for Ccr7 in early development of functional deficits and subchondral bone changes in the DMM model. Understanding the mechanism of Ccr7 receptor signaling in the initiation of joint pathology and disability will inform the development of innovative therapies to slow symptomatic OA development after injury. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 36:864-875, 2018., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Evidence has been building that the pathologic drive for development of osteoarthritis (OA) involves more than simple mechanical "wear and tear." Inflammatory mechanisms play an important role in the tissue response to joint injury, and are involved in development of post-traumatic OA. Inflammation also appears integral to the progression of OA, whether post-traumatic or spontaneous, contributing to the evolution of joint tissue degradation and remodeling as well as joint pain. Both patient-based studies and in vivo models of disease have shed light on a number of inflammatory pathways and mediators that impact various aspects of this disease, both structurally and symptomatically. Recent work in this field has implicated inflammatory chemokines in osteoarthritis pathogenesis. Expression of multiple chemokines and their receptors is modulated during disease in both patients and animal models. Although best known for their effects on leukocyte migration and trafficking within the immune system, chemokines can have a wide variety of effects on both motile and non-motile cell types, impacting proliferation, differentiation, and activation of cellular responses. Their role in OA models has also demonstrated diverse effects on disease that exemplify their wide-ranging effects. Understanding how these important mediators of inflammation impact joint disease, and whether they can be targeted therapeutically, is actively being investigated by many groups in this field. This narrative review focuses on evidence published within the last 5 years highlighting chemokine-mediated pathways with mechanistic involvement in osteoarthritis and joint tissue repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:735-739, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Purpose of Review: Inflammatory changes in joint tissues can be detected by modern imaging techniques in osteoarthritis patients, but may be clinically subtle compared with many other types of arthritis. These changes associate with disease progression and clinical severity, and many inflammatory mediators may have biomarker utility. Moreover, a number of inflammatory mechanisms play a role in animal models of disease, but it is still not clear which mechanisms predominate and might be therapeutically manipulated most effectively. This review highlights specific examples of recent advances published in the past 18 months that have advanced this field., Recent Findings: Clinical investigators now show that synovial inflammation is associated with pain sensitization, and similar to knee osteoarthritis, is a common and important feature of hand osteoarthritis. In addition, recent advances in basic studies demonstrate inflammatory markers and mechanisms related to leukocyte activity, innate immune mechanisms, and the chondrocyte-intrinsic inflammatory response that might provide better opportunities for early detection, prognosis, or therapeutic intervention., Summary: Inflammation plays a central role in osteoarthritis pathogenesis, but additional translational work in this field is necessary, as are more clinical trials of anti-inflammatory approaches.

Inflammation is a variable feature of osteoarthritis (OA), associated with joint symptoms and progression of disease. Signs of inflammation can be observed in joint fluids and tissues from patients with joint injuries at risk for development of post-traumatic osteoarthritis (PTOA). Furthermore, inflammatory mechanisms are hypothesized to contribute to the risk of OA development and progression after injury. Animal models of PTOA have been instrumental in understanding factors and mechanisms involved in chronic progressive cartilage degradation observed after a predisposing injury. Specific aspects of inflammation observed in humans, including cytokine and chemokine production, synovial reaction, cellular infiltration and inflammatory pathway activation, are also observed in models of PTOA. Many of these models are now being utilized to understand the impact of post-injury inflammatory response on PTOA development and progression, including risk of progressive cartilage degeneration and development of chronic symptoms post-injury. As evidenced from these models, a vigorous inflammatory response occurs very early after joint injury but is then sustained at a lower level at the later phases. This early inflammatory response contributes to the development of PTOA features including cartilage erosion and is potentially modifiable, but specific mediators may also play a role in tissue repair. Although the optimal approach and timing of anti-inflammatory interventions after joint injury are yet to be determined, this body of work should provide hope for the future of disease modification tin PTOA., (Published by Elsevier Ltd.)

Objective: In patients with knee OA, synovitis is associated with knee pain and symptoms. We previously identified synovial mRNA expression of a set of chemokines (CCL19, IL-8, CCL5, XCL-1, CCR7) associated with synovitis in patients with meniscal tears but without radiographic OA. CCL19 and CCR7 were also associated with knee symptoms. This study sought to validate expression of these chemokines and association with knee symptoms in more typical patients presenting for meniscal arthroscopy, many who have pre-existing OA., Design: Synovial fluid (SF) and biopsies were collected from patients undergoing meniscal arthroscopy. Synovial mRNA expression was measured using quantitative RT-PCR. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was administered preoperatively. Regression analyses determined if associations between chemokine mRNA levels and KOOS scores were independent of other factors including radiographic OA. CCL19 in SF was measured by ELISA, and compared to patients with advanced knee OA and asymptomatic organ donors., Results: 90% of patients had intra-operative evidence of early cartilage degeneration. CCL19, IL-8, CCL5, XCL1, CCR7 transcripts were detected in all patients. Synovial CCL19 mRNA levels independently correlated with KOOS Activities of Daily Living (ADL) scores (95% CI [-8.071, -0.331], P = 0.036), indicating higher expression was associated with more knee-related dysfunction. SF CCL19 was detected in 7 of 10 patients, compared to 4 of 10 asymptomatic donors., Conclusion: In typical patients presenting for meniscal arthroscopy, synovial CCL19 mRNA expression was associated with knee-related difficulty with ADL, independent of other factors including presence of radiographic knee OA., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Fibronectin (FN) is a widely expressed molecule that can participate in development of osteoarthritis (OA) affecting cartilage, meniscus, and synovial membrane (SM). The alternatively spliced isoforms of FN in joint tissues other than cartilage have not been extensively studied previously. The present study compares FN splice variation in patients with varying degrees of osteoarthritic change. Joint tissues were collected from asymptomatic donors and patients undergoing arthroscopic procedures. Total RNA was amplified by PCR using primers flanking alternatively spliced Extra Domain A (EDA), Extra Domain B (EDB) and Variable (V) regions. EDB(+) , EDB(-) and EDA(-) and V(+) variants were present in all joint tissues, while the EDA(+) variant was rarely detected. Expression levels of EDB(+) and EDV(+) variants were similar in cartilage, synovium, and meniscal tissues. Synovial expression of V(+) FN in arthroscopy patients varied with degree of cartilage degeneration. Two V(-) isoforms, previously identified in cartilage, were also present in SM and meniscus. Fibronectin splicing in meniscus and SM bears striking resemblance to that of cartilage. Expression levels of synovial V(+) FN varied with degree of cartilage degeneration. V(+) FN should be investigated as a potential biomarker of disease stage or progression in larger populations., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of innate immune cells with a granulocyte-like or monocyte-like phenotype and a unique ability to suppress T-cell responses. MDSCs have been shown to accumulate in cancer patients, but recent studies suggest that these cells are also present in humans and animals suffering from autoimmune diseases. We previously identified MDSCs in the synovial fluid (SF) of mice with experimental autoimmune arthritis. The goal of the present study was to identify MDSCs in the SF of patients with rheumatoid arthritis (RA)., Methods: RA SF cells were studied by flow cytometry using antibodies to MDSC cell surface markers as well as by analysis of cell morphology. The suppressor activity of RA SF cells toward autologous peripheral blood T cells was determined ex vivo. We employed both antigen-nonspecific (anti-CD3/CD28 antibodies) and antigen-specific (allogeneic cells) induction systems to test the effects of RA SF cells on the proliferation of autologous T cells., Results: SF from RA patients contained MDSC-like cells, the majority of which showed granulocyte (neutrophil)-like phenotype and morphology. RA SF cells significantly suppressed the proliferation of anti-CD3/CD28-stimulated autologous T cells upon co-culture. When compared side by side, RA SF cells had a more profound inhibitory effect on the alloantigen-induced than the anti-CD3/CD28-induced proliferation of autologous T cells., Conclusion: MDSCs are present among RA SF cells that are commonly regarded as inflammatory neutrophils. Our results suggest that the presence of neutrophil-like MDSCs in the SF is likely beneficial, as these cells have the ability to limit the expansion of joint-infiltrating T cells in RA.

Objective: Synovitis is associated with pain and other symptoms in patients with knee osteoarthritis (OA), and in patients with meniscal tears even in the absence of radiographic OA. Patients undergoing arthroscopic partial meniscectomy were followed for 2 years to determine whether synovitis predicts post-operative symptoms., Design: Thirty-three patients scheduled for arthroscopy were recruited for this pilot study. Symptoms were assessed using a knee pain scale, the Lysholm score, and the short form-12 (SF-12(®)) pre-operatively and at 16 weeks, 1 year and 2 years post-operatively. Synovial inflammation and hyperplasia were graded on surgical biopsies. Linear mixed effects models were tested to determine whether inflammation or hyperplasia is associated with outcome scores over time., Results: Lysholm scores and SF-12(®) physical component sub-scores were worse pre-operatively in patients with inflammation (Lysholm: 52.42 [95% confidence interval (CI) 42.37, 62.47] vs 72.38 [66.03, 78.72], P < 0.001; SF-12: 36.81 [28.26, 45.37] vs 46.23 [40.14, 52.32], P < 0.05). Up to 2-years post-operatively, patients with inflammation achieved mean scores similar to those without inflammation. As a result, the mean improvement in Lysholm scores was 13.01 [1.48-24.53] points higher than patients without inflammation, P = 0.03. 33% (4/12) of patients with inflammation still had fair to poor Lysholm scores 2 years after surgery compared to 7% (1/15, P=0.14) without inflammation. No association between hyperplasia and symptoms was noted., Conclusions: In this pilot study of patients undergoing partial meniscectomy, synovial inflammation was associated with worse pre-operative symptoms, but not with poorer outcomes in the first 2 years post-arthroscopy. Larger cohorts and longer follow-up should be pursued to confirm this relationship, and determine if the initial response is sustained., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: The pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium., Methods: Age-matched knee SF samples from 10 control subjects, 10 patients with early-stage OA, and 10 patients with late-stage OA were compared using 2-dimensional difference-in-gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles., Results: Sixty-six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome., Conclusion: Proteins involved in the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted., (Copyright © 2013 by the American College of Rheumatology.)

Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but there is increasing recognition that OA affects all of the joint tissues, including the synovium (SM). Under normal physiological conditions the synovial lining consists of a thin layer of cells with phenotypic features of macrophages and fibroblasts. These cells and the underlying vascularized connective tissue stroma form a complex structure that is an important source of synovial fluid (SF) components that are essential for normal cartilage and joint function. The histological changes observed in the SM in OA generally include features indicative of an inflammatory "synovitis"; specifically they encompass a range of abnormalities, such as synovial lining hyperplasia, infiltration of macrophages and lymphocytes, neoangiogenesis and fibrosis. The pattern of synovial reaction varies with disease duration and associated metabolic and structural changes in other joint tissues. Imaging modalities including magnetic resonance (MRI) and ultrasound (US) have proved useful in detecting and quantifying synovial abnormalities, but individual studies have varied in their methods of evaluation. Despite these differences, most studies have concluded that the presence of synovitis in OA is associated with more severe pain and joint dysfunction. In addition, synovitis may be predictive of faster rates of cartilage loss in certain patient populations. Recent studies have provided insights into the pathogenic mechanisms underlying the development of synovitis in OA. Available evidence suggests that the inflammatory process involves engagement of Toll-like receptors and activation of the complement cascade by degradation products of extracellular matrices of cartilage and other joint tissues. The ensuing synovial reaction can lead to synthesis and release of a wide variety of cytokines and chemokines. Some of these inflammatory mediators are detected in joint tissues and SF in OA and have catabolic effects on chondrocytes. These inflammatory mediators represent potential targets for therapeutic interventions designed to reduce both symptoms and structural joint damage in OA. This article is part of a Special Issue entitled "Osteoarthritis"., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Synovial inflammation, a feature of both osteoarthritis (OA) and meniscal injury, is hypothesized to be triggered in part via stimulation of Toll-like receptors (TLRs). We undertook this study to test whether a TLR-2- or TLR-4-stimulating factor in synovial fluid (SF) from patients with early knee OA with meniscal injury could lead to inflammatory activation of synoviocytes., Methods: SF was obtained from patients with early OA cartilage damage undergoing arthroscopic meniscal procedures. SF was used to stimulate primary cultures of fibroblast-like synoviocytes (FLS) and cell lines transfected with TLR-2 or TLR-4. SF was used either alone or in combination with a TLR-2 stimulus (palmitoyl-3-cysteine-serine-lysine-4 [Pam3CSK4]) or a TLR-4 stimulus (lipopolysaccharide [LPS]). In blocking experiments, SF was preincubated with anti-CD14 antibody., Results: SF from these patients did not stimulate interleukin-8 (IL-8) release from TLR transfectants. Compared with SF on its own, SF (at concentrations of 0.09-25%) in combination with TLR-2 or TLR-4 ligands resulted in significant augmentation of IL-8 release from both transfectants and primary FLS. Soluble CD14 (sCD14), a coreceptor for TLRs, was measured in SF from patients with early OA at levels comparable to those in patients with advanced OA and patients with rheumatoid arthritis. Blockade with anti-CD14 antibody abolished the ability of SF to augment IL-8 production in response to LPS, and diminished Pam3CSK4 responses., Conclusion: SF augments FLS responses to TLR-2 and TLR-4 ligands. This effect was largely due to sCD14. Our results demonstrate that sCD14 in the setting of OA and meniscal injury sensitizes FLS to respond to inflammatory stimuli such as TLR ligands., (Copyright © 2012 by the American College of Rheumatology.)

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the third most common diagnosis in the elderly [1], causes significant pain leading to disability and decreased quality of life in subjects 65 years and older [2]. Traditionally, clinicians have relied heavily on the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat the pain of OA, as numerous studies have proven these agents to be effective. The cardiovascular, gastrointestinal, renal and hepatic toxicities of NSAIDs have limited their use, particularly in the elderly. Acetaminophen has been recommended as initial therapy due to relative safety. Several other topical, oral and intra-articular agents are available today, with use limited by efficacy and side effect profiles. Many non-pharmacologic approaches are available but underused, and may be attractive choices to avoid poly-pharmacy in older patients. We will attempt to highlight the evidence behind available non-surgical therapies for OA while paying specific attention to issues in geriatric patients.

Patients with rheumatoid arthritis, an inflammatory arthritis that can destroy joint structures, are often on multiple disease-modifying antirheumatic medications to control disease activity. These medications have significant toxicities, most notably immunosuppression leading to increased risk of infection. Furthermore, certain disease-modifying antirheumatic medications have been reported to affect the healing process. Over the course of their lifetime, patients with rheumatoid arthritis may undergo many surgical procedures, often orthopedic interventions, including total joint arthroplasty, reconstructive surgeries, or cervical stabilization. How to manage antirheumatic medications and their toxicities in the perioperative period is a challenging question, especially with regard to the biologic therapies such as antitumor necrosis factor alpha agents. We conducted a review of the available literature pertaining to the perioperative use of biologic agents used to treat rheumatoid arthritis. Although existing data directly addressing complications during specific orthopedic procedures are sparse, information on general surgical complications in rheumatic and other patient populations may be used as a basis for conservative recommendations., ((C) 2011 Lippincott Williams & Wilkins, Inc.)

Objective: Traumatic and degenerative meniscal tears have different anatomic features and different proposed etiologies, yet both are associated with the development or progression of osteoarthritis (OA). In established OA, synovitis is associated with pain and progression, but a relationship between synovitis and symptoms in isolated meniscal disease has not been reported. Accordingly, we sought to characterize synovial pathology in patients with traumatic meniscal injuries and determine the relationships between inflammation, meniscal and cartilage pathology, and symptoms., Methods: Thirty-three patients without evidence of OA who were undergoing arthroscopic meniscectomy for meniscal injuries were recruited. Pain and function were assessed preoperatively; meniscal and cartilage abnormalities were documented at the time of surgery. Inflammation in synovial biopsy specimens was scored, and associations between inflammation and clinical outcomes were determined. Microarray analysis of synovial tissue was performed, and gene expression patterns in patients with and those without inflammation were compared., Results: Synovial inflammation was present in 43% of the patients and was associated with worse preoperative pain and function scores, independent of age, sex, or cartilage pathology. Microarray analysis and real-time polymerase chain reaction revealed a chemokine signature in synovial biopsy specimens with increased inflammation scores., Conclusion: Our findings indicate that in patients with traumatic meniscal injury undergoing arthroscopic meniscectomy without radiographic evidence of OA, synovial inflammation occurs frequently and is associated with increased pain and dysfunction. Synovia with increased inflammation scores exhibit a unique chemokine signature. Chemokines may contribute to the development of synovial inflammation in patients with meniscal pathology; they also represent potential therapeutic targets for reducing inflammatory symptoms., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Much of what is known about the inflammatory response in the synovial membrane (SM) of patients with osteoarthritis (OA) comes from studies of synovial tissues from end-stage disease. In this study, we sought to better characterize the inflammatory infiltrate in symptomatic patients with early signs of knee OA, and to determine how inflammatory cell populations relate to the pattern of cytokine and degradative enzyme production., Methods: Study populations comprised patients with degenerative meniscal tears and early cartilage thinning undergoing arthroscopic procedures (early OA) and patients undergoing total knee replacement for end-stage OA. Quantitative real-time polymerase chain reaction (PCR) was used to measure expression of SM cytokines and enzymes implicated in the pathogenesis of inflammatory arthritis and OA, as well as cell lineage-specific markers. We quantified synovial fluid (SF) cytokines and enzymes by enzyme-linked immunosorbent assay (ELISA) and SM cell populations by immunohistochemistry., Results: We found increased levels of SF interleukin-15 (IL-15) protein in the early knee OA patients when compared to end-stage OA. Both SF IL-15 protein and numbers of CD8 cells within SM correlated with matrix metalloproteinase-1 (MMP-1) and three levels. TNF-alpha, IL-6 and IL-21 were also detectable in the SF of the majority of patients, and IL-15 levels were associated with IL-6 levels., Conclusion: IL-15 is elevated in early knee OA, suggesting activation of an innate immune response in the SM. The association of IL-15 expression with CD8 transcripts and MMPs implicates this cytokine in OA pathogenesis and as a candidate therapeutic target.

Traditionally, clinicians have relied heavily on the use of NSAIDs to treat the pain of osteoarthritis, as numerous studies have proven these agents effective. However, controversy has arisen regarding their use as first-line therapy, due to increasing awareness of their cardiovascular risks. One of these agents, rofecoxib, was withdrawn from the market in 2004 due to these concerns. Since that time, numerous studies have illustrated that many of the NSAIDs, both the selective cyclooxygenase-2 inhibitors and the traditional nonselective agents, may confer similar risks of cardiovascular toxicity. Although these agents may still be useful in many patients, concerns over side effects have begun to limit their use, and patients and clinicians are reaching for alternate agents. This review highlights the evidence behind the effectiveness of other, non-NSAID pharmacologic options in the treatment of pain and inflammation in osteoarthritis.

Traditionally, clinicians have relied heavily on the use of NSAIDs to treat the pain of osteoarthritis, as numerous studies have proven these agents effective. However, controversy has arisen regarding their use as first-line therapy, due to increasing awareness of their cardiovascular risks. One of these agents, rofecoxib, was withdrawn from the market in 2004 due to these concerns. Since that time, numerous studies have illustrated that many of the NSAIDs, both the selective cyclooxygenase-2 inhibitors and the traditional non-selective agents, may confer similar risks of cardiovascular toxicity. Although these agents may still be useful in many patients, concerns over side effects have begun to limit their use, and patients and clinicians are reaching for alternate agents. This review highlights the evidence behind the effectiveness of other, non-NSAID pharmacologic options in the treatment of pain and inflammation in osteoarthritis.

Objective: C-reactive protein (CRP) has been associated with disease progression in patients with osteoarthritis (OA), but the reasons for this remain unclear. We hypothesized that higher CRP would be related to local inflammatory findings in the joints of patients with OA., Methods: Plasma and synovial membrane specimens from 54 OA patients undergoing total hip or knee arthroplasty or arthroscopy were obtained. Synovial fluid was obtained from 25 of these patients. Hematoxylin and eosin stained synovial membrane sections were scored for degree of inflammatory cell infiltration. Plasma high-sensitivity CRP (hsCRP) levels, and serum and synovial fluid interleukin (IL)-6 and IL-1beta levels were measured by enzyme-linked immunosorbent assay., Results: Fifty-seven percent of patients with idiopathic OA had inflammatory infiltrates within the synovial membrane. The mean hsCRP level in patients with inflammatory infiltrates was significantly higher than those without inflammation (4.7 +/- 5.0 mg/L vs 1.7 +/- 3.6 mg/L, P = 0.003). There were significant correlations between hsCRP levels and synovial fluid IL-6 (r = 0.64, P = 0.0006), degree of synovial inflammatory infiltration (r = 0.43, P = 0.002), and body mass index (r = 0.31, P = 0.02). Multivariate analysis indicated that only degree of inflammatory infiltrate was significantly associated with hsCRP level (P = 0.026)., Conclusion: These results suggest that systemic hsCRP levels reflect synovial inflammation in OA patients, perhaps by means of synovial IL-6 production. Future studies are needed to clarify how these infiltrates and their products may contribute to disease pathogenesis.

Patients with rheumatoid arthritis (RA), an inflammatory arthritis that can destroy joint structures, are often on multiple medications to control disease activity. These medications may have significant toxicities and side effects. Over the course of their lifetime, patients with this disease often require orthopedic procedures, including total joint arthroplasty, and the medications they are taking present management issues specific to the perioperative period. As many of these medications are immunosuppressive, the concern for postoperative infection and delayed wound healing are particularly worrisome. We conducted a review of the available literature pertaining to the perioperative use of the most commonly prescribed medications for RA. Although the existing data directly addressing perioperative complications in orthopedic surgery is sparse, information on relevant complications resulting from the general use of these drugs may be used as a basis for conservative recommendations.

Thrombotic thrombocytopenic purpura (TTP) causes significant morbidity and mortality, and may be associated with connective tissue diseases (CTD). Some cases are refractory to plasma exchange and require immunosuppressive therapy. We describe 2 patients with CTD who had refractory TTP treated successfully with rituximab. Both patients also developed heparin-induced thrombocytopenia (HIT). The propensity of a patient with a CTD to develop autoantibodies to ADAMTS-13 and platelets likely explains the association of such a disease with TTP and HIT. Rituximab should be considered in this complex clinical setting, because it may decrease the production of multiple pathogenic autoantibodies.