Signal transduction in rheumatoid arthritis.

PURPOSE: Signal transduction pathways are the intracellular mechanism by which cells respond and adapt to environmental stress. Understanding the critical networks in diseases like rheumatoid arthritis can potentially identify novel therapeutic targets. RECENT
FINDINGS: Dissecting the complex pathways involved in rheumatoid synovitis, including mitogen-activated protein kinases, NF-kB, tumor suppressors, Janus kinases, the signal transducer and activator of transcription, suppressors of cytokine stimulation, and toll-like receptors may lead to new approaches to inflammatory arthritis. For instance, targeting NF-kB via IkB kinase 2 with specific inhibitors may block an array of proinflammatory cytokines that contribute to synovitis. Inhibition of Janus kinases and p38 could block metalloproteinase expression and protect the extracellular matrix. Overexpression of suppressors of cytokine stimulation and inhibition of signal transducer and activator of transcription are additional approaches that have demonstrated efficacy in animal models of arthritis. Tumor suppressor proteins and cell cycle inhibitors represent additional targets with unexpected anti-inflammatory activities. Recent evidence also suggests that targeting toll-like receptors may regulate cytokine expression in rheumatoid arthritis.
SUMMARY: Multiple signal transduction pathways have been implicated in rheumatoid arthritis, and preclinical models have confirmed the therapeutic potential of small molecule inhibitors. Orally bioavailable inhibitors of the mitogen-activated protein kinase and NF-kB pathways have been designed and are currently being evaluated. Many other pathways could be targeted and offer new therapeutic options for rheumatoid arthritis.