The overall goal of these studies is to understand the role of matrix metalloproteinases (MMPs) in the severe and irreversible degradation of cartilage, bone and tendon that accompanies rheumatoid arthritis. The application proposes to continue examining molecular mechanisms controlling expression of the MMP-1 (collagenase-1) as well as MMP-13 (collagenase-3). Previous and preliminary studies have characterized the regulation of MMP-1 and MMP-13 by IL-1 and TNF-alpha in rabbit synovial fibroblasts and human chondrosarcoma cells. These studies and recent cloning of the rabbit MMP-13 gene in the applicant's laboratory indicate that the rabbit is an appropriate model for assessing the relative contributions of MMP-1 and MMP-13 in the invasion/degradation of collagen in RA. Preliminary studies also identified a single nucleotide polymorphism (SNP) within the human MMP-1 promoter, which creates a new PEA3 site that binds Ets transcription factors and enhances transcription of MMP-1 in human fibroblasts. These results suggest that RA patients with this allele may display heightened MMP-1 expression and particularly erosive synovitis. Thus, the specific aims are to (1) recapitulate the pathogenesis of RA in a rabbit model of polycation-induced arthritis and correlate the temporal expression of MMP-1 and MMP-13 gene with the erosive/invasive ability of synovial tissue through a matrix of type II collagen; (2) examine the mechanisms regulating expression of the endogenous MMP-13 gene in chondrocytes and fibroblasts treated with TNF and IL-1 and understand its regulation at the molecular level; and (3) determine the frequency and functional significance in patients with RA of a SNP in the human MMP-1 promoter that augments transcription. These studies are expected to increase our molecular understanding of the relative roles of the two interstitial collagenases that are central mediators of the connective tissue destruction accompanying RA.
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