Among the significant structural changes that take place during the development of OA is the presence of synovial inflammation. The synthesis and release of a number of mediators by the inflamed tissue is an important factor in the development and/or progression of OA changes. As previously mentioned, among the inflammatory factors the proinflammatory cytokine IL-1β plays a central role in OA pathophysiology. Factors that regulate its synthesis and/or activity are therefore favoured targets. Other approaches are broader and include activating or increasing the level of factors able to inhibit proinflammatory cytokines or other catabolic factors.
For specific inhibition of the production/activity of IL-1β, basic research has demonstrated that various strategies can be used. These include receptor blockade, neutralization of the cytokine by soluble receptors or monoclonal antibody, blocking the formation of active IL-1β, or inhibiting the IL-1β cellular signalling pathways. One strategy (as mentioned above under Cytokine inhibition and below under Gene therapy) is the use of recombinant human IL-1Ra. This factor is a competitive antagonist of IL-1 that blocks the actions of IL-1 without any detectable agonist activity. Reports indicate that Anakinra (a recombinant methionyl human IL-1Ra; Amgen, Thousand Oaks, CA, USA), when injected subcutaneously, is safe and well tolerated in a diverse population of patients with RA, and slows radiographically observed progression of the disease [45
]. However, its rapid clearance as well as the difficulty of knowing how much of the injected material accumulates in the OA joints has thus far promoted the strategy of delivering IL-1Ra intra-articularly (see Pharmacological therapies, above).
Soluble receptors play an important physiological role in neutralizing cytokines. The transmembrane domain of both IL-1 receptors (IL-1 receptor I and IL-1 receptor II) is susceptible to lysis by proteases, leading to the release of a soluble form of the receptor (sIL-1R). Free IL-1 binds to its specific sIL-1R, resulting in less IL-1 being available to bind to the membrane-specific receptor. However, IL-1Ra also binds the sIL-1R, and the binding affinity of sIL1R to both IL-1 isoforms and IL-1Ra differs. Type II sIL-1R binds IL-1β more readily than IL-1Ra; in contrast, type I sIL-1R binds IL-1Ra with high affinity [46
]. Therefore, the strategy using type II sIL-1R alone or in combination with IL-1Ra would seem more promising. However, soluble receptors have short plasma half-lives, and repeated doses would be required to neutralize the effects of the cytokine. This limitation can be circumvented by conjugating soluble receptors with a human proteolytic fragment of IgG, which can extend the half-lives of these molecules. Another alternative that has been used for the tumour necrosis factor-α is to polymerize the soluble receptor; this can reduce antigenicity and prolong the half-life.
Data on IL-1 signalling show that after IL-1 binding to the cell membrane IL-1 receptor I, the IL-1 receptor accessory protein (IL-1RAcP) is recruited to form a high-affinity receptor complex, which initiates the intracellular signalling cascade [49
]. In collagen-induced arthritis, treatment with sIL-1RAcP had a marked effect when given prophylactically [51
]. The characteristics of this molecule make it an interesting inhibitor of IL-1 activity because it competes with membrane-bound IL-1RAcP for receptor complex formation with IL-1 receptor I. Moreover, sIL-1RAcP is an IL-1-specific target cell discriminating inhibitor, because it can only induce functional inhibition in the presence of IL-1 bound to IL-1 receptor I. sIL-1RAcP can also interact with the type II sIL-1R or shed type II IL-1R, resulting in the formation of soluble IL-1 scavenger receptor. A report indicates that sIL-1RAcP associates as ligand-bound to type II sIL-1R, increasing the binding affinity of IL-1α and IL-1β to type II sIL-1R by approximately 100-fold, while leaving unaltered the low binding affinity of IL-1Ra to type II sIL-1R, thus enhancing inhibition of IL-1 when both IL-1Ra and sIL-1RAcP are present [52
Relevant to the IL-1 neutralization strategy, Economides and colleagues [53
] engineered a high-affinity 'trap' by combining the extracellular domains of both the IL-1 receptor I and IL-1RAcP. This IL-1Trap preferentially binds IL-1β. A phase II clinical trial for the treatment of RA has been initiated [54
The use of antibodies against IL-1 or against IL-1 receptor I is another approach to neutralizing this cytokine. The type of antibody appears to be critical to its clinical efficacy. The concept is to use chimaeric and humanized monoclonal antibodies, which should be less immunogenic than murine monoclonal antibodies (first utilized for RA). No study has yet been conducted in patients with OA.
IL-1β is primarily synthesized as a precursor (pro-IL-1β), and must be cleaved by a cysteine-dependent protease, named IL-1β converting enzyme (or caspase-1), to generate the mature cytokine. In OA tissues, this enzyme was also found to be intimately involved in the maturation of IL-1β [55
]. It is also responsible for the cleavage and release of mature IL-18. Thus, an inhibitor against this enzyme will block activation of two very potent proinflammatory cytokines. IL-1β converting enzyme inhibitor was found to reduce the progression of joint damage in two experimental mouse models of OA [56
]. A recent clinical trial conducted in RA patients was terminated because of what is believed to be toxicity.
IL-1 activity is mediated by its binding only to type I receptor; type II receptor did not mediate IL-1 activity. After IL-1 binding to its type I receptor, there is induction of multiple phosphorylation-dependent signalling pathways that regulate gene expression. These pathways include the serine-threonine kinases of the mitogen-activated protein kinase family and nuclear factor-κB cascades. It is now recognized that the mitogen-activated protein kinase superfamily is composed of at least three main and distinct signalling pathways: the extracellular signal-regulated protein kinases, the c-Jun amino-terminal kinases or stress-activated protein kinases, and the p38 family of kinases.
To date, at least one experimental in vivo
study has reported a therapeutic effect of a specific extracellular signal-regulated protein kinase inhibitor, namely PD198306, in experimental rabbit OA [57
]. It was associated with significant reductions in structural changes (cartilage destruction and osteophyte width) and in the severity of synovial inflammation.
c-Jun amino-terminal kinase inhibitors also have demonstrated preventative effects on the destruction of bone and cartilage in RA [58
]. However, little is known about the effect of these compounds in OA models. It was recently reported that phenyl N-tert-butylnitrone, a spin-trap agent, downregulates IL-1-induced MMP-13 expression via the inhibition of the c-Jun amino-terminal kinase pathway in OA chondrocytes [61
The p38 inhibitor SB203580 had anti-inflammatory effects in cartilage explants and in animal models. In bovine cartilage explants, it blocked IL-1-mediated collagen breakdown, whereas proteoglycan degradation was unaffected [62
]. However, p38 mitogen-activated protein kinase inhibitors were shown to blunt chondrocyte and cartilage proteoglycan synthesis in response to transforming growth factor-β, but the response to insulin-like growth factor-I was unaffected. In the collagen-induced arthritis model of RA, SB203580 inhibited tumour necrosis factor-α and IL-6 production, reduced paw inflammation, and inhibited the formation of joint lesions [63
]. The p38 inhibitors also decreased levels of nitric oxide (NO).