The role of synovitis in osteoarthritis pathogenesis

Abstract

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".

Figure 1. Representative synovial histopathology observed in osteoarthritis

Paraffin-embedded, formalin fixed thin sections of synovial membrane from patients with OA undergoing total joint arthroplasty. Hematoxylin and Eosin (panels a and b, 2×) or immunohistochemical stains with specific monoclonal antibodies against a macrophage marker (panels c and d, anti-CD68,10× and 40×), a T-lymphocyte marker (panel e, anti-CD3, 40×), or a B-lymphocyte marker (panel f, anti-CD20, 40×). Panel a depicts normal appearing synovial membrane with a thin lining layer and loose connective tissue subintimal layer. The section in panel b demonstrates synovial lining hyperplasia (arrow), villous hyperplasia (arrowhead), fibrosis (star) and perivascular mononuclear cell infiltrates (double-headed arrow) which are histopathologic features often observed in OA. Panel c & d depict the two typical distributions of CD68+ cells in OA SM: (c) concentrated in the synovial lining layer and (d) scattered throughout the subintimal layer and the perivascular infiltrates. Panel e and f demonstrate that the majority of cells within the perivascular infiltrates express markers of (e) T and (f) B lymphocytes. (Immunostaining courtesy of Frank Pessler, MD PhD, Section of Rheumatology/Immunology, Klinik und Poliklinik für Kinder- und Jugendmedizin, Dresden, Germany. Photomicrographs generously provided by Edward DiCarlo, MD, Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York NY.)

Figure 2. The impact of synovitis on disease manifestations in OA

There is a substantial body of evidence from multiple sources demonstrating a relationship between the presence of synovitis and symptoms such as pain, swelling, and joint dysfunction in knee OA patients. Evidence from a smaller number of arthroscopic and imaging studies suggests that the presence of synovitis may be associated with faster rates of cartilage erosion in OA. Although not yet demonstrated in patients, additional studies of animal models suggest that synovial macrophages, increased in synovitis, may be involved in osteophyte formation in OA.

Figure 3. A model of Toll-like Receptor (a) and complement activation (b) in the joint leading to synovitis and potentiation of cartilage erosion in OA

Joint tissue injury, either acute traumatic injury to joint tissues, or chronic cartilage damage occurring throughout the course of OA, can lead to the elaboration of both matrix molecules and complement components that are released into the synovial fluid. Some matrix molecules may act as TLR agonists while others can activate the complement cascade. TLR activation is depicted on the left (a). Certain matrix components increased in OA and injury can interact with TLRs on resident and infiltrating cells of the synovium. In addition, TLR expression on chondrocytes is increased in lesional areas of cartilage. Binding of these ligands to TLRs leads to the generation of inflammatory cytokines and chemokines, which can promote cellular infiltration, the hallmark of synovitis. This molecular and cellular inflammation can then potentiate cartilage erosion via production of enzymatic mediators of matrix degradation. Complement activation in the joint is depicted on the right (b). Synovial inflammation can lead to leakage of plasma complement proteins into the joint, but chondrocytes and the SM itself also may be a source of complement components. Articular matrix components distinct from those activating TLRs have been demonstrated to bind complement components, leading to activation of the complement cascade and generation of active complement proteins. These proteins also can bind to receptors or deposit on cells of the synovium leading to increased cytokine production, and increased synoviial inflammation.