{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:13:33Z","timestamp":1790936013002,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2007,9,28]],"date-time":"2007-09-28T00:00:00Z","timestamp":1190937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2007,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To evaluate the role of the MEK\/ERK MAP kinase pathway in murine collagen\u2010induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine\u2010stimulated synovial fibroblasts and in cytokine\u2010induced arthritis in rabbits to investigate its antiinflammatory mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p\u2010ERK. Western blotting and immunohistochemistry techniques were used to assess p\u2010ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin\u20101\u03b1 (IL\u20101\u03b1)\u2013stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme\u2010linked immunosorbent assay. A rabbit IL\u20101\u03b1\u2013induced arthritis model was used to assess the effects of the inhibitor on IL\u20101\u03b1\u2013induced MEK activity, stromelysin production, and cartilage degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dose\u2010dependent manner. Disease\u2010induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease\u2010induced p\u2010ERK levels in the joints was seen with the inhibitor. Levels of p\u2010ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL\u20101\u03b1\u2013induced p\u2010ERK levels in human RA synovial fibroblasts. The production of p\u2010ERK and stromelysin was also inhibited in IL\u20101\u03b1\u2013stimulated rabbit synovial fibroblasts. We observed IL\u20101\u03b1\u2013induced p\u2010ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL\u20101\u03b1\u2013induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.22869","type":"journal-article","created":{"date-parts":[[2007,9,28]],"date-time":"2007-09-28T17:48:13Z","timestamp":1191001693000},"page":"3347-3357","source":"Crossref","is-referenced-by-count":89,"title":["Central role of the MEK\/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms"],"prefix":"10.1002","volume":"56","author":[{"given":"Melissa 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