IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

摘要: During the pathogenesis of rheumatoid arthritis (RA), synovial fibroblasts increase in number and produce proinflammatory cytokines matrix metalloproteinases (MMPs) that function to promote inflammation joint destruction. Recent investigations have suggested cell cycle activity may be linked. However, little is known about mechanisms responsible for coordinate regulation proliferation expression molecules RA fibroblasts. Here, we demonstrate a 50 +/- 10% decrease p21, inhibitor, fibroblast population from compared with osteoarthritis (OA) tissue. Moreover, p21 positivity inversely correlates medium lining thickness (r = -0.76; p < 0.02). The also reduced isolated OA Adenovirus-mediated delivery (Ad-p21) arrests both G(0)/G(1) phase without inducing cytotoxicity. spontaneous production IL-6 MMP-1 suppressed only Ad-p21-infected fibroblasts, indicating novel role RA. Analyses p21-deficient mouse reveal 100-fold protein enhance MMP-3 mRNA. Restoration but not overexpression Rb, which induces arrest, decreases synthesis p21-null Furthermore, ectopic reduces activation AP-1 transcription factor. Additionally, display enhanced wild-type These data suggest alterations activate leading cytokine MMP development autoimmune disease.