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Synovitis, inflammation of the synovial membrane, is a common manifestation of osteoarthritis (OA) and is recognized to play a role in the complex pathophysiology of OA. Increased recognition of the importance of synovitis in the OA disease process and its potential as a target for treatment has increased the need for noninvasive detection and characterization of synovitis using medical imaging. Numerous imaging methods can assess synovitis involvement in OA with varying sensitivity, specificity, and complexity. This article reviews the role of contrast-enhanced MRI, conventional MRI, novel unenhanced MRI, gray-scale ultrasound (US), and power Doppler US in the assessment of synovitis in patients with OA. The role of imaging in disease evaluation and the challenges of conventional imaging methods are discussed. We also provide an overview of the potential utility of emerging techniques for imaging of early inflammation and molecular inflammatory markers of synovitis, including quantitative MRI, superb microvascular imaging, and PET. The development of therapeutic treatments targeting inflammatory features, particularly in early OA, would greatly increase the importance of these imaging methods for clinical decision-making and evaluation of therapeutic efficacy.

Introduction: Synovium has been documented as a primary site of inflammation and a major effector organ in a variety of joint diseases. Study of simple technique like synovial biopsy can help in early diagnosis and treatment of diseases significantly improving outcome of patient in cases of rheumatoid arthritis, osteoarthritis, etc., Only limited data exist on utility of synovial biopsies., Aim and Objectives: To analyze the pattern of synovial lesions to differentiate between different kinds of arthritis. Also, to identify early stages of arthritis so as to prevent unnecessary invasive surgical procedure., Materials and Methods: It's a retrospective study to analyze 103 cases of synovial lesions diagnosed in last five years at a tertiary care orthopedic center. All synovial biopsies obtained mainly by open method and few by arthroscopic method, that came to the Dept of Pathology were included. Lesions were classified into four categories that is, inflammatory joint diseases, degenerative joint diseases, tumor-like conditions and tumors., Results: Age group most affected was between 61 and 70 years, with male predominance. Osteoarthritis (OA) was the most common histopathological diagnosis. Early OA tissues showed greater lining layer thickness, vessel proliferation, and inflammation, while surface fibrin deposition along with fibrosis was noted in later stages., Conclusion: The histo-morphological observations made in this study may have important therapeutic implications for some patients during the early evolution of arthritis and could prevent unnecessary operative intervention of later stages.

Injury to the meniscus is common and frequently leads to the development of post-traumatic osteoarthritis (PTOA). Many times meniscus injuries occur coincident with anterior cruciate ligament (ACL) injuries and lead to a bloody joint effusion. Hemarthrosis, or bleeding into the joint, has been implicated in degeneration of joint tissues. The goal of this review paper is to understand the pathophysiology of blood-induced joint damage, the possible effects of blood on meniscus tissue, and the implications for current meniscus repair techniques that involve the introduction of blood-derived products into the joint. In this review, we illustrate the similarities in the pathophysiology of joint damage due to hemophilic arthropathy (HA) and osteoarthritis (OA). Although numerous studies have revealed the harmful effects of blood on cartilage and synovium, there is currently a gap in knowledge regarding the effects of hemarthrosis on meniscus tissue homeostasis, healing, and the development of PTOA following meniscus injury. Given that many meniscus repair techniques utilize blood-derived and marrow-derived products, it is essential to understand the effects of these factors on meniscus tissue and the whole joint organ to develop improved strategies to promote meniscus tissue repair and prevent PTOA development., (Copyright © 2020 Osteoarthritis Research Society International. All rights reserved.)

Purpose: To establish the characteristics of synovium-derived mesenchymal stem cells (MSCs) from the hip joints of patients with femoroacetabular impingement syndrome (FAIS) and osteoarthritis (OA), particularly their proliferation and differentiation potentials. We further investigated their functional differences., Methods: Synovium samples were harvested from 21 patients with FAIS who underwent hip arthroscopic surgery and from 14 patients with OA who underwent total hip arthroplasty. The MSC number, colony-forming units, cell viability, and differentiation potential were compared. Real-time polymerase chain reaction assessed the differentiation potential into adipose, bone, and cartilage tissues., Results: The number of colonies at a density of 10 4 at passage 0 from OA synovium was significantly greater than that from FAIS synovium (P < .01). However, their proliferation and viability were significantly lower than those of FAIS synovium cells (P = .0495). The expression of lipoprotein lipase mRNA in OA synovium cells was greater than that in FAIS synovium cells (P < .01). Meanwhile, the fraction of colonies positive for von Kossa and alkaline phosphatase staining, as well as the level of bone gamma-carboxyglutamate protein expression in OA synovium cells, were greater than those in FAIS synovium cells (P < .01). In chondrogenic pellet culture experiments, the expression of COL10A1 mRNA was lower in OA synovium than in FAIS synovium (P < .01)., Conclusions: Synovial MSCs from patients with OA had greater colony numbers but less viability and proliferative potential. They also showed greater osteogenic and adipogenic potentials, whereas those from patients with FAIS showed greater chondrogenic potential., Clinical Relevance: MSCs from patients with FAIS exhibited good potential as cell sources for stem cell therapy in case of cartilage damage in the hip joint., (Copyright © 2020 Author(s). Published by Elsevier Inc. All rights reserved.)

In the current experiment, the effects of transforming growth factor (TGF)-β1/Smad and ERK pathway crosstalk on synovial and pulmonary systems during rheumatoid arthritis have been investigated. For this purpose, rats were divided into normal control (NC) and model control (MC) groups. In the MC group, 0.1 ml Freund's complete adjuvant was injected intradermally into the right hind paw, and the resulting inflammation represented a rheumatoid arthritis model. Joint swelling and changes in lung functions were observed in arthritic rats. Synovial and lung were observed by light and electron microscopies. Enzyme-linked immunosorbent assays were used to detect TGF-β1, interleukin (IL)-1β, IL-4, IL-10, interferon-γ (IFN-γ), connective tissue growth factor (CTGF), and fibroblast growth factor (FGF). PCR, immunohistochemistry, and immunoblotting were used to detect changes in Smad and ERK pathways of synovial and lung tissues. Compared with the NC group, toe swelling was elevated in the MC group. Pulmonary functions FEV1, FEF50, FEF75, MMF, and PEF were decreased (P&lt; 0.01). Serum cytokines IL-1β, IL-4, TGF-β1, and CTGF were increased, while IFN-γ, IL-10, Th1/Th2 cell ratio, and FGF were decreased (P&lt; 0.01 or P&lt; 0.05). Expression of TGF-β1 and Smad2/3/4 mRNAs and TGF-β1, TβRI, TβRII, Smad2/3, p-Smad2/3, and Smad4 proteins in the synovial membrane and lung tissue were increased, and expression of Smad7 mRNA and protein was decreased (P&lt;0.01) or P&lt;0.05). Expression of ERK2 mRNA and p-ERK1/2 protein was increased in the synovial membrane and lung tissue, and expression of ERK1/2 mRNAs and ERK1/2 and p-ERK1/2 proteins was increased in lung tissue (P&lt; 0.01 or P&lt; 0.05). Correlation analysis showed that FEV1 was negatively correlated with TGF-β1 mRNA and protein in arthritic rats, FEF25 was negatively correlated with Smad4 protein, and FEF50 was negatively correlated with the TβRII protein, and FEF75, TGF-β1 and Smad3 mRNAs. There was a negative correlation between Smad2/3 protein and a negative correlation between PEF and TGF-β1 protein (P&lt; 0.05). FEF50 and MMF were positively correlated with Smad7 mRNA (P&lt; 0.05). FEV1 was negatively correlated with ERK2 mRNA, and FEF25 was negatively correlated with p-ERK1/2 protein. FEF75 and MMF were negatively correlated with ERK1/2 and p-ERK1/2, respectively (P&lt; 0.05). ERK1 mRNA was positively correlated with Smad3 mRNA and TβRII protein, ERK2 mRNA was positively correlated with p-Smad2/3, and ERK1/2 protein was positively correlated with Smad2 mRNA, Smad4 protein, p-ERK1/2 protein, Smad4 mRNA, and p-Smad2/3 protein (P&lt; 0.05). p-ERK1/2 protein was negatively correlated with Smad7 protein (P&lt; 0.05). It is concluded that arthritic rats have synovial and systemic pulmonary damage. Smad and ERK pathway crosstalk leads to systemic lesions. Smad and ERK pathways are gradually activated by phosphorylation under the induction of the TGF-β1 promoter, and then participate in transcriptional activities, leading to the increase in synovial inflammation of arthritis, pulmonary lesions, and decreases in lung functions.

Rheumatoid arthritis is an autoimmune disease characterized by inflammation in the synovial fluid within the synovial joint connecting two contiguous bony surfaces. The inflammation diffuses into the cartilage adjacent to each of the bony surfaces, resulting in their gradual destruction. The interface between the cartilage and the synovial fluid is an evolving free boundary. In this paper we consider a two-phase free boundary problem based on a simplified model of rheumatoid arthritis. We prove global existence and uniqueness of a solution, and derive properties of the free boundary. In particular it is proved that the free boundary increases in time, and the cartilage shrinks to zero as [Formula: see text], even under treatment by a drug. It is also shown in the reduced one-phased problem, with cartilage alone, that a larger prescribed inflammation function leads to a faster destruction of the cartilage.

The purposes were to calculate total voxel volume of the entire capsulo-synovial enhanced portion on contrast-enhanced (CE) MRI in adhesive capsulitis, and to investigate its association with glenohumeral joint volume and passive range of motions (ROMs), which are a well-known diagnostic reference standard and clinical hallmark of this condition. Medical records of 169 consecutive patients who underwent ultrasound-guided intraarticular injection with adhesive capsulitis and CE-MRI to exclude other mimicking shoulder diseases were retrospectively reviewed. To calculate total voxel volume of entire capsulo-synovial enhanced portion on CE-MRI, voxel-based 3-dimensional (3D) segmentation was obtained semi-automatically using Fiji, an open-source image processing software. Pearson's correlation coefficients were analyzed. Sixty patients who met eligibility criteria were included. Total voxel volume showed a significant inverse correlation with the glenohumeral joint volume (r = -0.528, P < 0.001), forward elevation, external rotation, and abduction (r = -0.407, P = 0.001; r = -0.342, P = 0.007; r = -0.275, P = 0.034, respectively). Intra-observer and inter-observer reliabilities, measured by intraclass correlation coefficients (ICC), were excellent (ICC = 0.87 and 0.77, respectively). This study's results indicate that voxel-based 3D segmentation of entire capsulo-synovial enhanced portion from CE-MRI can represent the severity of clinical impairments, such as obliterated joint volume and limited passive ROMs in adhesive capsulitis.

Background and Aim of the Work: Suprapatellar synovial plica is caused by a congenital thickening of the synovial membrane and is generally asymptomatic. In the literature, suprapatellar plicae are described as one of the causes of anterior knee pain however, their real role in determining symptoms is controversial. The aim of the current paper is to describe the anatomy, classifications, pathophysiology, symptoms and management of suprapatellar plica syndrome, as well as the differential diagnosis from other causes of anterior knee pain., Method: Via a search within the MEDLINE/PubMed database, a current review was conducted, and the results summarized., Results: Due to idiopathic, traumatic or inflammatory conditions, plicae can become pathological, causing anterior knee pain with possible knee clicking, swelling, giving way and locking after prolonged flexion of the knee. The diagnosis should be formulated based on an accurate medical history and clinical examination, followed by an appropriate imaging study. However, arthroscopy remains the "golden standard" for detecting all synovial plica., Conclusions: In patients with anterior knee pain, where doubt is present in the imaging investigation for intraarticular or periarticular lesions, pathological suprapatellar synovial plica must be suspected. The treatment should initially be conservative, but in cases where symptoms persist, patients should undergo arthroscopy to confirm diagnosis and to determine a suitable treatment. In the presence of pathological plica associated with cartilage damage of the femoral condyle or patella at the time of diagnostic arthroscopy, plicae excision leads to favourable results in a high number of cases.

Purpose: To shed light on the idea that mesenchymal stem/stromal cells (MSCs) recruited in synovium (SM) (i.e. Synovium-Derived Stromal Cells, SDSCs) could be involved in Osteoarthritis (OA) pathophysiology. Attention was also paid to a further stromal cell type with a peculiar ultrastructure called telocytes (TCs), whose role is far from clarified. Methods: In the present in vitro study, we compared SDSCs isolated from healthy and OA subjects in terms of phenotype, morphology and differentiation potential as well as in their capability to activate normal Peripheral Blood Mononuclear Cells (PBMCs). Histological, immunohistochemical and ultrastructural analyses were integrated by qRT-PCR and functional resorbing assays. Results: Our data demonstrated that both SDSC populations stimulated the formation of osteoclasts from PBMCs: the osteoclast-like cells generated by healthy-SDSCs via transwell co-cultures were inactive, while OA-derived SDSCs have a much greater effectiveness. Moreover, the presence of TCs was more evident in cultures obtained from OA subjects and suggests a possible involvement of these cells in OA. Conclusions: Osteoclastogenic differentiation capability of PBMCs from OA subjects, also induced by B synoviocytes has been already documented. Here we hypothesized that SDSCs, generally considered for their regenerative potential in cartilage lesions, have also a role in the onset/maintenance of OA. Clinical relevance: Our observations may represent an interesting opportunity for the development of a holistic approach for OA treatment, that considers the multifaceted capability of MSCs in relation to the environment., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objectives: To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally., Methods: 144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression., Results: Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) d iffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression., Conclusions: We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

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.

Meniscal allograft transplantation yields good and excellent results but is limited by donor availability. The purpose of the study was to evaluate the effectiveness of radiated deep-frozen xenogenic meniscal tissue (RDF-X) as an alternative graft choice in meniscal transplantation. The xenogenic meniscal tissues were harvested from the inner 1/3 part of the porcine meniscus and then irradiated and deeply frozen. The medial menisci of rabbits were replaced by the RDF-X. Meniscal allograft transplantation, meniscectomy and sham operation served as controls. Only a particular kind of rabbit-anti-pig antibody (molecular ranging 60-80 kD) was detected in the blood serum at week 2. The menisci of the group RDF-X grossly resembled the native tissue and the allograft meniscus with fibrocartilage regeneration at postoperative 1 year. Cell incorporation and the extracellular matrix were mostly observed at the surface and the inner 1/3 part of the newly regenerated RDF-X, which was different from the allograft. The biomechanical properties of the group RDF-X were also approximate to those of the native meniscus except for the compressive creep. In addition, chondroprotection was achieved after the RDF-X transplantation although the joint degeneration was not completely prevented. To conclude, the RDF-X could be a promising alternative for meniscal transplantation with similar tissue regeneration capacity to allograft transplantation and superior chondroprotection. The potential minor immunological rejection should be further studied before its clinical application.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast-like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. How rheumatoid FLS acquire and sustain such a uniquely aggressive phenotype remains poorly understood. We describe the current state of knowledge of the molecular alterations in rheumatoid FLS at the genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels, which offers a means to reconstruct the pathways leading to rheumatoid pannus. Such data provide new pathologic insight and suggest means to more sensitively assess disease activity and response to therapy, as well as support new avenues for therapeutic development., (© 2018, American College of Rheumatology.)

Carpal Tunnel Syndrome (CTS) is the most common surgically treated problem in the hand. Aside from the neuropathy itself, the most common findings are fibrosis of the subsynovial connective tissue (SSCT) and increased intra carpal tunnel pressure. Normally, the SSCT is a multilayer tissue interspersed among the carpal tendons and nerve. As the tendons move, successive SSCT layers are recruited, forming a gliding unit and providing a limit to differential movement. Exceeding this limit, damages the SSCT as has been shown in both cadavers and animal models. This damage leads to a non-inflammatory response with progressive fibrosis and nerve ischemia leaving the SSCT more susceptible to injury. Although the direct consequences for patients are not fully understood, ultrasound research shows that this fibrosis restricts median nerve displacement during tendon loading. This article aims to provide insights into the mechanical properties of SSCT described so far and place it in the context of CTS pathophysiology. A theoretical damage model concerning the SSCT is proposed showing a chain of events and vicious cycles that could lead to the nerve compression as it is found in CTS. Although not complete, this model could explain the pathophysiological pathway of idiopathic CTS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There is an increasing biomechanical and anatomical understanding of the different types of meniscal lesions. Lesions of the posterior part of the medial meniscus in the meniscosynovial area have recently received increased attention. They generally occur in association with anterior cruciate ligament (ACL) injuries. They are often missed ("hidden lesions") due to the fact that they cannot be seen by routine anterior arthroscopic inspection. Furthermore, meniscosynovial lesions play a role in anteroposterior knee laxity and, as such, they may be a cause of failure of ACL reconstruction or of postoperative persistent laxity. Little information is available regarding their cause with respect to injury mechanism, natural history, biomechanical implications, healing potential and treatment options. This article presents an overview of the currently available knowledge of these ramp lesions, their possible pathomechanism, classification, biomechanical relevance as well as repair techniques.

Objectives: Epidemiological and experimental studies have established obesity to be an important risk factor for osteoarthritis (OA), however, the mechanisms underlying this link remains largely unknown. Here, we studied local inflammatory responses in metabolic-OA., Methods: Wistar rats were fed with control diet (CD) and high-carbohydrate, high-fat diet (HCHF) for period of 8 and 16 weeks. After euthanasia, the knees were examined to assess the articular cartilage changes and inflammation in synovial membrane. Further IHC was conducted to determine the macrophage-polarization status of the synovium. In addition, CD and HCHF synovial fluid was co-cultured with bone marrow-derived macrophages to assess the effect of synovial fluid inflammation on macrophage polarisation., Results: Our study showed that, obesity induced by a high-carbohydrate, high-fat (HCHF) diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before the cartilage degradation. This was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of pro-inflammatory M1 macrophages. In addition, bone marrow derived macrophages, cultured with synovial fluid collected from the knees of obese rats exhibited a pro-inflammatory M1 macrophage phenotype., Conclusion: Our study demonstrate a strong association between obesity and a dynamic immune response locally within synovial tissues. Furthermore, we have also identified synovial resident macrophages to play a vital role in the inflammation caused by the HCHF diet. Therefore, future therapeutic strategies targeted at the synovial macrophage phenotype may be the key to break the link between obesity and OA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Persistent inflammation of the synovial membrane is the main characteristic pathological symptom. Moxibustion for treating RA has achieved significant clinical effect in recent years. A large number of experimental studies have also shown that moxibustion promoted the repair of inflammatory damage induced by RA. Based on summarizing 10 years related literatures, the authors analyzed the repair mechanisms of moxibustion for inflammatory damage in RA from central mechanisms including glucocorticoid receptor, melatonine, hypothalamic-pituitary-adrenal axis, and cholinergic nerve to peripheral mechanisms including local inflammatory mediators, cytokine, and inflammatory cell signaling pathway, so as to provide evidences and reference for further research.

Articular ultrasound of 6500 joint recesses was performed for the purpose of identifying which joint had the highest measurements among small-sized (SSJ), medium-sized (MSJ) and large-sized (LSJ) joints. Quantitative measurements of synovial hypertrophy (QSR) and semiquantitative measurements of synovial hypertrophy (SSH), power Doppler (SPD) and bone erosion (SBE) (score: 0-3) were made. Higher measurements (p < 0.01) of QSR were obtained in the second metatarsophalangeal joint (MTP), talonavicular joint, and hip. The highest SSH scores (2/3) were obtained in the second MTP, talonavicular joint, hip and knee; the highest SPD scores (1/2/3) in the first MTP, second MTP, dorsal second metacarpophalangeal (MCP) and radiocarpal recesses; and the highest SBE scores (2/3) in the radiocarpal, ulnocarpal and posterior recesses of the glenohumeral joint. In conclusion, higher measurements of synovial hypertrophy were found in the first and second MTPs (SSJ), talonavicular recess (MSJ) and hip (LSJ). Synovial blood flow was frequent in the first MTP and radiocarpal recess. Bone erosion stood out only in the glenohumeral joint., (Copyright © 2017. Published by Elsevier Inc.)

Aim and Objective: To evaluate the association between ultrasonographic findings of inflammation (effusion, synovitis) and clinical findings in patients with primary painful knee osteoarthritis., Method: This cross-sectional study was performed on 142 patients with primary painful knee osteoarthritis (American College of Rheumatology criteria) in whom the visual analogue scale of pain was 30 or more. Clinical parameters were evaluated by a rheumatologist using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score while the ultrasonographic examination was performed by a musculoskeletal radiologist in our center. Knee joint synovitis and effusion were defined as synovial thickness ≥ 4 mm and depth of fluid in the suprapatellar recess ≥ 4 mm, respectively., Results: Sixty-eight (47.9%) patients demonstrated neither synovitis nor effusion, 37 (26.1%) had only effusion, 11 (7.7%) had only synovitis and 26 (18.3%) had both effusion and synovitis in the ultrasonographic examination. There was significant association between ultrasonographic knee arthritis (defined as presence of synovitis or effusion) and WOMAC pain sub-score, WOMAC physical function sub-score and WOMAC total score. No significant association was noted between sonographic signs of arthritis and WOMAC joint stiffness sub-score. We also found significant correlation between ultrasonographic synovitis and WOMAC pain sub-score (P < 0.001), WOMAC physical function sub-score (P < 0.001) and total WOMAC score (P < 0.001)., Conclusion: This study revealed a positive correlation between ultrasonographic synovitis and total WOMAC score, WOMAC pain and physical function sub-score. There was no association between sonographic signs of arthritis and WOMAC joint stiffness sub-score., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4-selective inhibitor, GSK199, in the murine collagen-induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end-points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non-citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan-PAD inhibitor Cl-amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end-points., (© 2017 British Society for Immunology.)

Purpose: Cervical spine meniscoids are intra-articular folds of synovial membrane that have been theorised to have potential clinical significance in neck pain. Recent anatomical and clinical research has re-visited the pathoanatomical capacity of these structures. The purpose of this review is to discuss cervical spine meniscoid morphology in light of recently published work, to provide an update on the plausible relevance of these structures to clinical practice., Methods: Narrative review critically discussing basic science and clinical research regarding cervical spine meniscoids, with focus upon implications for clinical practice., Results: Basic science research indicates that cervical spine meniscoids can be innervated and appear to vary in morphology in the presence of articular degeneration. In a clinical population, associations have been observed between cervical spine meniscoid morphology and presence of cervical spine symptoms., Conclusions: Recent studies regarding cervical spine meniscoid morphology provide further evidence of pathoanatomical capacity of these structures. Further research is required, however, in clinical populations to empirically investigate specific theorised mechanisms of cervical spine meniscoid involvement in neck pain.

Background: Diagnosis of a low-grade periprosthetic joint infection (PJI) prior to revision surgery can be challenging, despite paramount importance for further treatment. Arthroscopic biopsy of synovial and periprosthetic tissue with subsequent microbiological and histological examination can be beneficial but its specific diagnostic value has not been clearly defined., Methods: 20 consecutive patients who underwent percutaneous synovial fluid aspiration as well as arthroscopic biopsy due to suspected PJI of the hip and subsequent one- or two-stage revision surgery at our institution between January 2012 and May 2015 were enrolled. Indication was based on the criteria (1) history of PJI and increased levels of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), (2) suspicious cell count and differential but negative bacterial culture in synovial aspirate, (3) early loosening (

Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically.

Pigmented villonodular synovitis (PVNS) as well as tenosynovial giant cell tumor (TGCT) are both diagnosed and described in two forms, namely a localized and diffuse type. They form a diverse group of proliferative lesions in articular synovium and tendon sheaths. The inconsistent terminology impedes communication between patients, orthopedic surgeons, radiologists and pathologists, leading to misunderstandings and delaying treatment. In this paper, we present three cases of PVNS/TGCT (involving the fourth toe extensor tendon sheath, hip joint after resurfacing and flexor hallucis longus tendon sheath) together with suggestions regarding the unification of the terminology as well as diagnosis and treatment.

Rheumatoid arthritis (RA) is a destructive chronic autoimmune disease characterized by synovium inflammation, cartilage destruction, bone erosion and the presence of autoantibodies. Hypoxia is a prominent micro-environmental feature in a range of disorders including RA. A combination of increased oxygen consumptionby inflamed resident cells and infiltrating immune cells along with a disrupted blood supply due to vascular dysfunction contribute to tissue hypoxia in RA. Hypoxia in turn regulates a number of key signaling pathways that help adaptation. The primary signaling pathway activated by hypoxia is the hypoxia-inducible factor (HIF) pathway. It has been shown that HIFs are highly expressed in the synovium of RA. HIFs mediate the pathogenesis of RA through inducing inflammation, angiogenesis, cell migration, and cartilage destruction, and inhibiting the apoptosis of synovial cells and inflammatory cells. HIF expressed in RA can be regulated in both oxygen-dependent and independent fashions, like inflammatory cytokines, leading to the aggravation of this disease. Considering the vital role of HIF in the pathogenesis of RA, we reviewed the new advances about hypoxia and RA. In this review, we firstly discussed the hypoxia-inducible factor and its regulation, and then, the pathologic role of hypoxia in RA, mainly elucidating the role of hypoxia in synovitis and cartilage destruction and immune cells. Finally, we provided evidence about the potential therapeutic target for treating RA.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 - the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model., Competing Interests: The authors declare no competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)

Chamaecyparis obtusa essential oil (COE) has been widely used to treat allergic diseases and was suggested to exert anti-inflammatory, antioxidant, and antimicrobial effects. This study evaluated the effects of COE on pain-related behavior and pro-inflammatory cytokines in rats with carrageenan (CGN)-induced arthritis. Reduced dynamic weight load on inflamed joint in voluntarily walking rats was used as the behavior test for arthritic pain; 10% COE-treated group was significantly attenuated pain (6-8 h post-CGN injection) compared to VEH (mineral oil)-treated group. In addition, the protein levels of interleukin (IL)-1β, tumor necrosis factor-α, IL-6 (6-8 h), and cyclooxygenase (COX)-2 (8 h) within the synovial membrane, as well as IL-1β, COX-2 (6-8 h), and IL-6 (5-7 h) within the meniscus, of 10% COE-treated group were significantly reduced. The current results implicate that COE has anti-inflammatory and anti-nociceptive effects on arthritis in rats.

Despite being a frequent cause of arthritis and bone erosions, the underlying cellular and subcellular reaction in gout is insufficiently understood. The inflammasome as intracellular sensor for crystals plays an important role, notably resulting in interleukin (IL)-1 production. Morphologically, hyperplasia of the synovial membrane with joint effusion, along with fibrinogen deposition and influx of neutrophils and lymphocytes are observed. Extracellular NET formation by neutrophils is involved in the regulation of inflammatory tissue reaction. Furthermore, the release of IL-10 and tumor necrosis factor (TNF)-receptors along with lymphocyte proliferation induce the natural resolution of acute gouty arthritis which typically occurs after several days. In contrast to acute gout, tophi consisting of urate crystals are surrounded by histiocytes and multinucleated cells, resembling a foreign body reaction. The deposition of extracellular matrix by fibrocytes is usually observed around tophi. This fibrotic reaction is likely enhanced by Th2-lymphocytes. Bone erosions in gout occur around tophi and are triggered by osteoclast activation through RANK-ligand expression by lymphocytes. In conclusion, understanding the orchestration of inflammation in gout might help to identify new therapeutic targets.

Synovial fibrosis is often found in OA, contributing heavily to joint pain and joint stiffness, the main symptoms of OA. At this moment the underlying mechanism of OA-related synovial fibrosis is not known and there is no cure available. In this review we discuss factors that have been reported to be involved in synovial fibrosis. The aim of the study was to gain insight into how these factors contribute to the fibrotic process and to determine the best targets for therapy in synovial fibrosis. In this regard, the following factors are discussed: TGF-β, connective tissue growth factor, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2, tissue inhibitor of metalloproteinase 1, A disintegrin and metalloproteinase domain 12, urotensin-II, prostaglandin F2α and hyaluronan., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To determine whether clinical, laboratory or Magnetic Resonance Imaging (MRI) measures differentiate Juvenile Idiopathic Arthritis (JIA) from other forms of active childhood arthritis., Materials and Methods: We prospectively collected data of 80 treatment-naïve patients clinically suspected of JIA with active non-infectious arthritis of (at least) one knee for <12 months duration. Upon presentation patients underwent clinical and laboratory assessments and contrast-enhanced MRI. MRI was not used as a diagnostic criterion., Results: Forty-four (55%) patients were clinically diagnosed with JIA, whereas in 36 (45%) patients the diagnosis of JIA was discarded on clinical or laboratory findings. MRI-based synovitis was present in 27 (61.4%) JIA patients and in 7 (19.4%) non-JIA patients (P < 0.001). Five factors (male gender, physician's global assessment of overall disease activity, joints with limited range of motion, HLA-B27, MRI-based synovitis) were associated with the onset of JIA. In multivariate analysis MRI-based synovitis proved to be independently associated with JIA (OR 6.58, 95% CI 2.36-18.33). In patients with MRI-based synovitis, the RR of having JIA was 3.16 (95% CI 1.6-6.4)., Conclusions: The presence of MRI-based synovitis is associated with the clinical onset of JIA. Physical examination could be supported by MRI, particularly to contribute in the early differentiation of different forms of non-infectious childhood arthritis., Key Points: • Juvenile Idiopathic Arthritis (JIA) is a diagnosis of exclusion. • Differentiating JIA and other forms of childhood arthritis can be difficult. • MRI-techniques have substantially improved evaluation of joint abnormalities in JIA patients. • MRI-based synovitis is significantly associated with the clinical onset of JIA. • MRI could support physical examination in the early differentiation of childhood arthritis.

Osteoarthritis of the knee affects a large population worldwide and is associated with an extremely high economic burden largely attributable to the effects of disability, comorbid disease, and the expense of treatment. Since the initiating events that result in the cartilage degradation are poorly understood, there has been very limited success in demonstrating disease modification in clinical trials of potential therapies. Medial plica related medial abrasion phenomenon has recently been identified to have close relationship with medial compartment osteoarthritis. We hypothesized that this abrasion phenomenon will elicit lifelong interplay between pathologic medial plica and the facing medial femoral condyle and might play a role in the pathogenesis of knee osteoarthritis by both physical and chemical effects. After evaluating current evidence, we designed a study to prove that the concentrations of total protein, cartilage degrading related cytokines (tumor necrosis factor-α and interleukin-1β) and enzyme (matrix metalloproteinase-3) are higher in the medial compartment of the knee having the phenomenon of medial abrasion. The accumulating data and findings about medial abrasion phenomenon might be important for the understanding of the pathogenesis or progression of this common disease. We hope that our hypothesis will stimulate further studies verifying if medial abrasion phenomenon plays more roles in the pathogenesis of knee osteoarthritis. Further clinical observations for its appropriate treatment based on this hypothesis are also mandatory for the benefits of patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Cadherin-11 (CDH11) is an adhesion molecule that anchors β-catenin and is involved with various functions of synovial fibroblast cells (SFCs) during the development of rheumatoid arthritis (RA). However, the mechanism of CDH11 during RA-SFC proliferation is unclear. The aim of our study was to clarify the involvement of CDH11 and β-catenin signalling during proliferation., Methods: IL-1β-induced and tumour necrosis factor-α (TNF-α)-induced cell proliferation, with CDH11 siRNAs, β-catenin-specific siRNAs and a CDH11-neutralizing antibody, were assessed by 5-Bromo-2'-deoxy-uridine ELISA., Key Findings: Using CDH11 siRNAs, there were a 42% reduction in IL-1β-induced proliferation and a 64% reduction in β-catenin protein. When β-catenin siRNAs were applied, there was a 63% reduction in IL-1β-induced proliferation. The median effective concentration (EC50 ) values for IL-1β-induced proliferation via CDH11-mediated β-catenin-dependent, total β-catenin-dependent and β-catenin-independent signalling were 0.0015, 0.016 and 0.18 ng/ml, respectively. Blocking CDH11 ligation with a CDH11-neutralizing antibody did not decrease IL-1β-induced proliferation., Conclusions: CDH11-mediated β-catenin signalling was 42% involved in IL-1β-induced proliferation and had the highest susceptibility to IL-1β among the proliferative signallings analysed in this study. The mode of action for CDH11 during the cell proliferation was likely associated with a pool of β-catenin protein. In contrast, CDH11 and β-catenin were not involved in TNF-α-induced RA-SFC proliferation., (© 2015 Royal Pharmaceutical Society.)

We previously reported adiponectin (AD) is highly expressed in the inflamed synovial joint tissue and correlates closely with progressive bone erosion in Rheumatoid arthritis (RA) patients. Here, we investigate the role of adiponectin in regulating Th17 response and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in mice with CIA mice by intraarticularly injection of adiponectin into knee joints on day 17, day 20 and day 23 post first collagen immunization. The increased adiponectin expression was found in inflamed joint tissue of collagen-induced arthritis (CIA) mice. Adiponectin injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia, bone erosion and osteoporosis in CIA mice. CD4(+)IL-17(+) Th17 cells, IL-17 mRNA and RANKL mRNA expression were markedly increased in the joint tissue of adiponectin treated CIA mice. Moreover, adiponectin treatment markedly enhanced Th17 cell generation from naive CD4(+) T cells in vitro, which accompanied by the high expression of Th17 transcription factor ROR-γt, and Th17 cytokine genes included IL-22 and IL-23. This study reveals a novel effect of adiponectin in exacerbating CIA progression by enhancing Th17 cell response and RANKL expression.

Background: Radioactive synoviorthesis was carried out by an injection of radioactive materials into the joint that has been known as a successful alternative treatment to invasive surgical synovectomy. This study was designed to evaluate short-term and long-term results and complications of radioactive synovectomy of hemophilic arthropathy using radioactive phosphorus., Materials and Methods: This study was conducted on 40 patients with hemophilic arthropathy. After obtaining clotting factors, the intra-articular injections of radioactive phosphorus were done. Thirteen patients were evaluated during 36 months (short-term follow-up) and 27 patients were followed up for more than 36 months (long-term follow-up). Patients were evaluated for hemarthrosis, factor consumption per month, joint range of motion (ROM) and clinical and radiological involvement grade., Results: The patients mean age was 22.9 ± 6.6 and there were 38 men and 2 women. Consumption of clotting factors was significantly reduced in the short-term follow-up of patients (p < 0.05), but there was no significant difference in the long-term follow-up (p > 0.05). ROM decreased significantly in the long-term follow-up (p < 0.05). Radiologic evaluation showed significantly increased involvement in their joints (p < 0.05)., Conclusion: Using radioactive synoviorthesis led in decreased consumption of clotting factors and the hemarthrosis incidence in short term but it did not have significant impact on clinical situation (ROM) and radiological findings of hemophilic patients in long-term follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Fibroblast-like synoviocytes (FLS) participate in joint inflammation and damage in rheumatoid arthritis (RA) and its animal models. The purpose of this study was to define the importance of KCa1.1 (BK, Maxi-K, Slo1, KCNMA1) channel expression and function in FLS and to establish these channels as potential new targets for RA therapy., Methods: We compared KCa1.1 expression levels in FLS from rats with pristane-induced arthritis (PIA) and in FLS from healthy rats. We then used ex vivo functional assays combined with small interfering RNA-induced knockdown, overexpression, and functional modulation of KCa1.1 in PIA FLS. Finally, we determined the effectiveness of modulating KCa1.1 in 2 rat models of RA, moderate PIA and severe collagen-induced arthritis (CIA)., Results: We found that PIA FLS expressed the KCa1.1 channel as their major potassium channel, as has been found in FLS from patients with RA. In contrast, FLS from healthy rats expressed fewer of these channels. Inhibiting the function or expression of KCa1.1 ex vivo reduced proliferation and invasive properties of, as well as protease production by, PIA FLS, whereas opening native KCa1.1 or overexpressing the channel enhanced the invasiveness of both FLS from rats with PIA and FLS from healthy rats. Treatment with a KCa1.1 channel blocker at the onset of clinical signs stopped disease progression in the PIA and CIA models, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation., Conclusion: Our results demonstrate a critical role of KCa1.1 channels in the regulation of FLS invasiveness and suggest that KCa1.1 channels represent potential therapeutic targets in RA., (Copyright © 2015 by the American College of Rheumatology.)

Objective: The transcription factor Snail is involved in various biologic functions. We hypothesized that this molecule regulates tumor necrosis factor α (TNFα)-mediated synovial fibroblast activation in the rheumatoid joint. The aim of this study was to examine the role of Snail in the expression of cadherin-11 (Cad-11) and myofibroblast markers, interleukin-6 (IL-6) production, and the invasive ability of cells., Methods: Synovium samples were obtained from patients with rheumatoid arthritis (RA) and from rats with collagen-induced arthritis (CIA). Synovial fibroblasts were treated with TNFα or a Wnt signaling inducer, and the joints of rats with CIA were injected with a TNFα antagonist. Modulation of Snail expression in the synovial fibroblasts and joints was performed by lentiviral vector-mediated transfer of complementary DNA or short hairpin RNA., Results: The expression of Snail and Cad-11 was higher in synovium and synovial fibroblasts from patients with RA compared with patients with osteoarthritis and was increased in rats with CIA. TNFα stimulation or activation of Wnt signaling up-regulated the expression of Snail, Cad-11, and α-smooth muscle actin (α-SMA) in synovial fibroblasts, and anti-TNFα therapy down-regulated the expression of Snail, Cad-11, and α-SMA in the joints of rats with CIA. Although synovial fibroblast transfectants in which Snail was overexpressed showed increased expression of Cad-11 and α-SMA and enhanced TNFα-mediated invasive capacity and IL-6 production, synovial fibroblast transfectants from rats with CIA in which Snail was silenced showed decreased expression and had the opposite effect on these functions. Normal joints in which Snail was overexpressed had hyperplastic synovium, with increased expression of Cad-11, α-SMA, and IL-6. Silencing Snail expression ameliorated arthritis, with reduced Cad-11 expression and reduced levels of extracellular matrix deposition in the joints of rats with CIA, whereas overexpression of Snail exacerbated arthritis, with increased Cad-11 expression and increased levels of extracellular matrix deposition., Conclusion: Our results demonstrate that Snail regulates TNFα-mediated activation of synovial fibroblasts in the rheumatoid joint. These findings may contribute to the pharmacologic development of therapeutics targeting synovial fibroblasts in patients with RA., (Copyright © 2015 by the American College of Rheumatology.)

Objective: To investigate the role of CXCL13 in the onset and development of knee osteoarthritis by observing and comparing the expression of CXCL13 between osteoarthritis and normal synovium., Methods: The synovium samples were collected from 30 patients with osteoarthritis who received total knee replacement (osteoarthritis group), including 11 males and 19 females with an average age of 66.7 years (range, 62-76 years). The synovium samples were collected from 22 patients without osteoarthritis who underwent traumatic amputation (control group), including 15 males and 7 females with an average age of 51.3 years (range, 48-56 years). The NimbleGen microarray detection was used to defect differentially expressed genes; the immunohistochemistry staining, Western blot, and real-time quantitative PCR (qRT-PCR) were used to detect the expressions of CXCL13 mRNA and protein., Results: There were 451 up-regulated genes and 810 down-regulated genes in the 22 885 genes which contained by mRNA gene chip, and CXCL13 gene expression was down-regulated. Immunohistochemistry staining and Western blot assay showed that the expression of CXCL13 protein was significantly lower in osteoarthritis group (0.408 0 ± 0.101 8) than in control group (0.785 9 ± 0.057 9) (t = 15.630, P = 0.000). qRT-PCR results showed that the expression of CXCL13 mRNA was significantly lower in osteoarthritis group (0.011 7 ± 0.003 2) than in control group (1.041 4 ± 0.129 7) (t = 43.634, P = 0.000)., Conclusion: Low expression of CXCL13 in the knee osteoarthritis synovium tissue may be associated with the onset and development of knee osteoarthritis.

Finger flexor tendinopathies and carpal tunnel syndrome are histologically characterised by non-inflammatory fibrosis of the subsynovial connective tissue (SSCT) in the carpal tunnel, which is indicative of excessive and repetitive shear forces between the finger flexor tendons and SSCT. We assessed flexor digitorum superficialis (FDS) tendon and adjacent SSCT displacements with colour Doppler ultrasound as 16 healthy participants completed long finger flexion/extension movements captured by a motion capture system. FDS tendon displacements fit a second-order regression model based on metacarpophalangeal and proximal interphalangeal joint flexion angles (R(2) = 0.92 ± 0.01). SSCT displacements were 33.6 ± 1.7% smaller than FDS tendon displacements and also fit a second-order regression model (R(2) = 0.89 ± 0.01). FDS tendon and SSCT displacement both correlated with finger joint thickness, enabling participant-specific anthropometric scaling. We propose the current regression models as an ergonomic method to determine relative displacements between the finger flexor tendons and SSCT., Practitioner Summary: Relative displacements between the finger flexor tendons and SSCT provide insight into gliding and friction in the carpal tunnel. Our regression models represent a move towards mechanistic-based ergonomic risk assessment of the wrist/hand. This is a natural evolution of ergonomic methods based on tendon-joint interaction.

Vitamin D deficiency is associated with increased susceptibility to inflammatory arthritis. Sensory and sympathetic synovial nerves are critical to the development of inflammatory arthritis and spontaneously degenerate in the early phases of disease. These nerves contain vitamin D receptors and vitamin D influences nerve growth and neurotrophin expression. We therefore examined the density of synovial nerves and neurotrophin-containing cells in vitamin D-deficient rats. Seven-week-old Sprague-Dawley rats were fed either control or vitamin D-deficient diets for 4weeks. Knee synovium sections extending from the patella to the meniscus were immunostained for total nerves, myelinated and unmyelinated nerves, sympathetic nerves, peptidergic and non-peptidergic sensory nerves, and neurotrophins and immune cell markers. In control rats, intimal innervation by unmyelinated sensory fibers was denser than subintimal innervation. In contrast, sympathetic innervation was confined to the subintima. Many sensory axons contained markers for both peptidergic and non-peptidergic nerves. Nerve growth factor (NGF) was primarily expressed by intimal CD163-negative type B synoviocytes, while neurturin, a ligand selective for non-peptidergic sensory neurons, was expressed by synovial mast cells. In vitamin D-deficient rats, there were significant reductions in sensory nerves in the intima and sympathetic nerves in the subintima. While there was no significant change in NGF-immunoreactivity, the number of neurturin-expressing mast cells was significantly reduced in the intima, suggesting that intimal reductions in sensory nerves may be related to reductions in neurturin. Vitamin D deficiency therefore may increase susceptibility to inflammatory arthritis by depleting sensory and sympathetic synovial nerves as a result of reduced synovial neurotrophin content., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Rheumatoid Arthritis is characterized by autoimmune-mediated attack of the joint synovial lining resulting in destruction of bone and cartilage, and is a clinically and biologically heterogenous disease with respect to both course of disease and outcome to therapy. The current armamentarium of approved therapies does not result in complete clinical response in all patients. Improved techniques for imaging and performing biopsies on the rheumatoid synovium have facilitated multiple studies of the dysregulated cellular and molecular pathways in disease, and have provided evidence for a spectrum of pathogenic phenotypes across RA patients. These phenotypes are differentially affected by targeted therapies such as anti-TNFα and anti-CD20, and their presence prior to treatment impacts upon subsequent clinical outcomes. Ongoing histologic and molecular assessment of these synovial phenotypes through the implementation of routine synovial biopsy or using systemic biomarkers will improve targeting of therapies to specific patient subsets in both clinical trials and practice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. Here we investigated whether mitochondrial dysfunction induces inflammatory responses in cultured normal human synoviocytes, a hallmark of RA., Methods: Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-κB (NF-κB) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-κB inhibitor (BAY-117085) were used to investigate the pathways involved. The natural anti-inflammatory antioxidant resveratrol was also tested., Results: Mitochondrial dysfunction per se significantly stimulated mitochondrial ROS production as well as low-grade expressions of COX-2, PGE2 and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1β to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-κB activation since the inflammatory response was counteracted by both N-acetylcysteine and mitoTEMPO and it was also reduced by BAY-117085. Antimycin A and paraquat (inhibitors of mitochondrial function) also induced inflammatory responses. Furthermore, resveratrol significantly reduced the inflammatory response by decreasing ROS production and NF-κB activation., Conclusion: These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1β. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Traumatic injury as a trigger for the subsequent development of psoriatic arthritis (PsA) has been implicated by several case reports and case series. However, it is still unclear whether trauma is the inciting event or just an incidental finding. It is thought that the interplay of genetic, immunologic, and environmental factors, such as trauma, may trigger the development of PsA. At least two hypotheses of how trauma may be linked to the development of PsA have surfaced and involve a "deep Koebner effect," the concept of a synovio-entheseal complex and activation of the innate immune system by biomechanical factors. The role of neuropeptides such as substance P and vasoactive intestinal peptide has been highlighted in the synovium after trauma. Better understanding of this phenomenon would shed light into the pathophysiology of Psa and help the development of preventive and therapeutic strategies.

The aim of the article is an evaluation of effectiveness of the complex outpatient care to patients with osteoarthrosis and degenerative-dystrophic diseases ofjuxtaarticular soft tissues. Recent researches showed that the key factors of the pathogenesis of diseases were degenerative-dystrophic and inflammatory changes in the synovio-entheseal complex ofparaarticular muscles' tendon. 411 patients with osteoarthrosis of 531 synovial joints and degenerative-dystrophic diseases of periarticular soft tissues underwent sequential corticosteroid therapy combined with hyaluronic acid injections. In 84% of cases positive results were observed.

Osteoarthritis is the most common joint disorder and a major cause of disability with a major socio-economic impact. In these circumstances is very important to understand its pathogenesis. Although previous research focused primarily on changes in the articular cartilage, more recent studies have highlighted the importance of the subchondral bone, synovium, menisci, ligaments, periarticular muscles and nerves. Now osteoarthritis is viewed as a multifactorial disease affecting the whole joint.

Purpose: To comprise current knowledge on morphology, embryology and pathophysiology of synovial plicae as well as on clinical and therapeutic aspects of the plica syndrome., Methods: Review of the literature combined with a meta-analysis of studies assessing the outcome of open or arthroscopic plica excision including the author's own series., Results: The term synovial plica has been devised to describe a number of intra-capsular folds thought to represent remnants of a membranous knee joint partition present during foetal development. Although four such folds have been defined, it is mainly the medial patellar plica which is implicated in carrying clinical significance as a potential cause of anteromedial knee pain particularly in adolescents. Blunt trauma, a sudden increase in athletic activity or any form of transient synovitis are associated with plica inflammation leading to tissue fibrosis and subsequent loss of elasticity. A plica affected in this way may impinge against intra-articular structures in its proximity, often creating localised chondromalacia particularly of the patello-femoral joint. The diagnosis is based on history and clinical examination although MRI can be of value. Twenty-three studies assessing the clinical out-come of 969 patients following open or arthroscopic plica excision were identified. The average age was 25 years with equal male-to-female ratio. Trauma was considered the cause in 57 %. At a mean follow-up of 27.5 months, 64 % of patients were symptom free, 26 % improved and 10 % considered failures., Conclusion: Symptomatic plicae may initially be treated with physiotherapeutic measures and structured exercise regimes but success rates are generally low. Intra-plical or intra-articular corticosteroid injections may be beneficial if administered early in the disease process. Arthroscopic excision of the entire plical fold becomes indicated in recalcitrant cases and once a plica has undergone irrevocable morphological changes. The procedure carries low morbidity, and results are universally good especially if the plica is the sole pathology. Factors associated with a favourable outcome are young patient age, localised symptoms of short duration and absence of plica induced chondromalacia.

Background: Rheumatoid arthritis (RA) is characterized by chronic synovitis and articular cartilage destruction. Increased activities of cathepsin S and cathepsin L, two potent cysteine proteases, are thought to play a role in the pathogenesis of the irreversible articular cartilage destruction. Nevertheless, data regarding the potential importance of the cathepsins as circulating biomarkers in RA patients are limited., Method: Subjects enrolled in this study are part of a larger study where patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study. In total, 71 patients were included, along with 44 age- and sex-matched control subjects. Plasma levels of cathepsin S and L were analysed. Disease severity was assessed using the 28-joint count Disease Activity Score (DAS28)., Results: Plasma levels of cathepsin S and L were significantly increased in patients with RA compared to healthy controls (p < 0.05 for both). However, in the patients with RA, no association between the cathepsins and the severity of the disease, as characterized by DAS28, was observed (p > 0.51)., Conclusions: Although circulating levels of cathepsin S and L were significantly increased in patients with recently diagnosed RA, our data do not support the notion that circulating levels of cathepsins are relevant biomarkers for disease severity.

The purpose of this study was to investigate the role of lubricin on the gliding resistance of intrasynovial tendons by comparing lubricin knockout, heterozygous, and wild type mice. A total of thirty-six deep digital flexor (DDF) tendons in the third digits of each hind paw from eighteen adult mice were used, including six lubricin knockout mice (Prg4 -/-), six heterozygous mice (Prg4 +/-), and six wild type mice (Prg4 +/+). The tendon gliding resistance was measured using a custom-made device. Tendon structural changes were evaluated by scanning electron and light microscopy. The gliding resistance of intrasynovial tendons from lubricin knockout mice was significantly higher than the gliding resistance of either wild type or heterozygous mice. The surface of the lubricin knockout tendons appeared to be rougher, compared to the wild type and heterozygous tendons. Synovial hyperplasia was found in the lubricin knockout mice. Cartilage-like tissue was found in the tendon and pulley of the lubricin knockout mice. Our findings confirm the importance of lubricin in intrasynovial tendon lubrication. This knockout model may be useful in determining the effect of lubricin on tendon healing and the response to injury.