Mechanism of MMP gene induction in osteoarthritis

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DESCRIPTION (provided by applicant): The goal proposed research is to elucidate the induction mechanism of matrix metalloproteinases (MMP) in chondrocyte cells of the osteoarthritis-affected joint tissue. Osteoarthritis (OA) is manifested by the degradation of cartilage leading to a total loss of the cushion between the bones of the joints causing stiffness, swelling and limitation of joint mobility. In normal cartilage, expression of each MMP is tightly regulated. During OA condition, however, MMPs are overexpressed resulting in the degradation of Collagen and other joint tissue-associated proteins necessary for maintaining normal environment of the cartilage. We hypothesize that a set of transcription factors, responsible for the increased expression of MMPs, is present at a higher active level in the chondrocyte cells of OA-cartilage. Consistent with this hypothesis, preliminary studies indicated that chondrocyte cells of the OA joint tissue contain a significantly higher level of several transcription factors, of which one is identified as SAF-1, an inflammation-responsive transcription factor. Over-expression of SAF-1 enhances MMP-1 expression in cultured chondrocyte cells. SAF-1 also interacts with the promoters of MMP-9 and -14 genes indicating its possible role in regulating expression of these MMP genes in OA condition. Identification of the involved transcription factors will provide a molecular basis for regulating their activity for future therapeutic efforts against OA. This research thus focuses on defining the role of SAF-1 in regulating expression of MMP-1, -9 and -14 genes. Another goal of this proposal is to identify other transcription factors involved in this process. Although pathology of OA most likely starts with biomechanical stress on the cartilage, cytokines appear at later stages of the disease. Therefore, an OA-like condition will be created by combining both biomechanical stress and cytokines and mechanisms of MMP gene induction will be studied in response to these signals. Towards this goal, the following specific aims are planned: 1) Characterize the role of SAF-1 in MMP-1 gene induction in chondrocytes of OA-cartilage. Define other responsive elements and factors involved in increasing MMP-1 expression in OA condition. 2) Investigate the role of SAF-1 in the induction of MMP-9 gene expression in OA-cartilage. Identify other regulatory elements and factors involved in this process. 3) Assess the role of SAF-1 in the induction of MMP-1 4 gene and identify other regulatory elements and factors involved in increasing MMP-1 4 expression in chondrocytes under OA-like condition. Completion of the above experimental objectives will form the basis for future investigation on: a) transmembrane signaling pathways in OA chondrocytes that enhance transcriptional activity, and b) evaluation of inhibitors of involved signaling pathway as potential therapeutic agents to control abnormal MMP expression.