Osteoarthritis (OA) is the most common type of arthritis. The prevalence of symptomatic OA is at least 12.1% in both sexes, whereas the prevalence of radiographically defined OA is much higher and increases with age (1). OA is a heterogeneous disease, and its classification leaves much to be desired (2–4). Primary OA, which has no apparent predisposing factor, and secondary OA, in which the patient has a prior trauma or condition related to OA, are the 2 most common subsets. Primary OA is called generalized OA when it affects many joints, nodal OA when it exhibits as nodes over interphalangeal joints, and erosive inflammatory OA when it exhibits as erosions in distal interphalangeal joints. Erosive inflammatory arthritis, which is characterized by flares of inflammation in joints and the presence of inflammation markers in peripheral blood, may represent the far end of the spectrum of generalized OA. Current treatments for OA are purely palliative, and the need for novel therapies is obvious. The etiology of primary OA is not known. Unidentified genetic factors have been implicated in the development of OA (5, 6), and a genetic component is supported by studies of families and twins (7). Clonal chromosome aberrations, such as the gain of chromosomes 5 and 7, were observed in the synovial membrane of certain patients with OA (8). Alpha1-antitrypsin (9), 1-antichymotrypsin (10), gene polymorphisms, and HLA alleles (9, 11) have been associated with generalized OA, whereas type II procollagen gene polymorphisms have been associated with precocious OA with mild chondrodysplasia (12).

Although the pathophysiology of OA is poorly understood, it is widely believed that primary OA is predominantly a disease of articular cartilage that may be caused by a biomechanical alteration, ie, abnormal forces acting on normal cartilage or normal forces acting on abnormal cartilage (13). Articular cartilage consists of chondrocytes and extracellular matrix (ECM). ECM contains water and certain macromolecules, including collagen, proteoglycans, and hyaluronic acid. Microscopic examination has revealed a loss of proteoglycans and proliferation of chondrocytes in the cartilage of patients with early OA (14). As the disease progresses, loss of chondrocytes and calcification occurs (14). The pathogenic mechanisms that lead to cartilage destruction and bone proliferation are not known. Point mutations of ECM macromolecules in articular cartilage have been reported (12). The structure of ECM molecules can also be altered by mutations in enzymes that cause posttranslational modification of collagen and the side chains of proteoglycan (5). Mutations in collagen or its modifying enzymes may cause subtle defects in cartilage. In that event, environmental factors, such as repetitive joint stress, may be responsible, at least in part, for the manifestation of OA. Proteolytic enzymes such as matrix metalloproteinases (MMPs) and their inhibitors appear to play a significant role in cartilage matrix degradation (15). However, changes in OA are not restricted to cartilage. In subchondral bone, there are early changes such as increased trabecular bone and stiffness (16), as well as late changes such as the presence of cysts and osteophytes, which are the hallmarks of OA. Furthermore, considerable inflammation occurs in the synovial membrane.