Many putative TLR ligands are modified in form or distribution, or increased in concentration in joint fluids or tissues in the setting of joint injury and OA. These include matrix components such as tenascin C [72] and [19], fibronectin isoforms [17] and [59],

small molecular weight species of hyaluronic acid [6], [91], [105] and [106] and biglycan [9], [23], [80] and [90]. Recently, certain plasma proteins increased in OA SF were demonstrated to activate macrophages in vitro via TLR-4 [98]. In a murine model of autoimmune arthritis [1], TLR-4 deficiency resulted in reduced disease severity reflected by less synovial cellular influx, Mitomycin C solubility dmso cartilage damage and bone erosion. On the other hand, TLR-2 knock-out mice developed more severe disease, suggesting a protective role in this particular model. The regulatory processes involved in TLR activation are complex, and their role in promoting synovitis in OA is not fully established. However, targeting TLRs and the ligands and pathways that trigger their activation need to be explored as potential therapeutic approaches in OA. In addition to the development of synovitis, AZD2281 mw TLR activation has implications for cartilage degeneration in OA. Enzymes involved in articular matrix turnover and degradation

include matrix metalloproteinases (MMPs) and aggrecanases, which may be produced by both chondrocytes and synovial cell populations. In cartilage, TLR-2 and -4 are up-regulated specifically in lesional areas in patients with OA [52]. A more recent study demonstrated that TLR2 and TLR4 signals are important in mediating catabolic responses and in increasing MMP-3 and MMP-13 production in murine Interleukin-3 receptor cartilage explants [63]. A recent genetic study in a Chinese population identified a TLR-9 polymorphism that is associated with the presence of radiographic knee OA [102]. This report did

not reveal an association with common TLR-2 or -4 polymorphisms, and how TLR-9 is linked to increased risk of OA is not yet clear. Taken together, though, these results implicate numerous members of the TLR family of pattern recognition receptors in inflammation, cartilage responses, and disease susceptibility in OA. A potential mechanism for activation of TLRs is depicted in Fig. 3. The complement cascade is one of the major effector mechanisms of immune system activation. The three main pathways of complement activation (the classical, alternative and lectin pathways) are important in both innate (alternative and lectin pathways) as well as adaptive immune responses (the classical pathway, triggered by antibody/immune complexes), and have been extensively reviewed elsewhere [27]. Soluble complement mediators such as C3a, C3b and C5a are produced by serial proteolytic activation of this cascade, and these mediators promote inflammation and phagocytosis.