Interleukin-1 and TNF-a share common signal transduction pathways, and the key signaling molecules involved are targets for therapy [21,132]. The major pathways induced by catabolic cytokines involve signal transduction by the stress-activated protein kinases c-Jun N-terminal kinases (JNKs) and p38 kinases and the nuclear factor (NF)-kB/IkB pathway. In vitro studies in chondrocytes have shown that the p38 and JNK cascades mediate the induction of proteinases and proinflammatory genes by IL-1 and TNF-a. These pathways may also be activated by mechanical stress and cartilage matrix products via integrins and other receptor-mediated events [1,47,54,60]. Induction of IL-1 and TNFa gene expression by stress-induced pathways suggests a mechanism by which these cytokines may serve as secondary mediators .
Small-molecule inhibitors that specifically target cytokine-induced signaling molecules have been explored as potential therapies in models in vitro and in vivo. At least four isoforms of p38 mitogen-activated protein kinase (MAPK) exist , with different substrate specificities and differential effects on essential chondrocyte functions [17,174]. The development of specific p38 MAPK inhibitors that target adverse responses to inflammatory mediators has been the subject of intense investigation [48,138,235]. Several p38 MAPK inhibitors have antidestructive effects in animal models of inflammation [161,247]. The JNKs exist in humans as three isoforms, JNK-1, -2, and -3, which have been targeted for the development of small molecule inhibitors . A potent JNK1/2 inhibitor, SP600125, blocks inflammation and joint damage in a model of rheumatoid arthritis . Activated JNK is detected in OA, but not in normal cartilage , and JNK inhibition attenuates cytokine-induced chondrocyte responses [2,124,143]. However, the effects of JNK inhibitors in OA animal models have not yet been studied.
While small molecule inhibitors of the NF-kB pathway have efficacy in animal models of rheumatoid arthritis (RA) , less information directly relevant to OA is available. Nevertheless, many of the agents developed for treating OA, including diac-erhein, N-acetylglucosamine, and green tea polyophenols can, to some extent, inhibit IL-1-induced NF-kB activation . Two IkB kinases, IKK-1 and IKK-2, phosphorylate IkB. Inhibitors have been developed that dissociate IkB from NF-kB, thereby permitting translocation of active NF-kB to the nucleus [141,166]. NF-kB mediates the expression of cytokines and chemokines induced by fibronectin fragments . Inhibition of DNA-binding activity of NF-kB agents that deplete polyamine prevents the induction of IL-8 by TNF-a without promoting chondrocyte apoptosis . A reduction in synovial inflammation often accompanies the reduction of joint damage by the inhibitors of any of the cytokine-induced pathways. When inflammation exists in the OA joint, it therefore becomes a primary therapeutic target .
Was this article helpful?
This report may be oh so welcome especially if theres no doctor in the house Take Charge of Your Arthritis Now in less than 5-Minutes the time it takes to make an appointment with your healthcare provider Could you use some help understanding arthritis Maybe a little gentle, bedside manner in your battle for joint pain relief would be great Well, even if you are not sure if arthritis is the issue with you or your friend or loved one.