Rheumatoid arthritis (RA) and osteoarthritis (OA) are debilitating disorders that are characterized by progressive degradation of articular cartilage and bone. While the etiologies of these two diseases are quite different, the degradative components are similar in that the interstitial collagens of cartilage and bone are digested by a group of proteolytic enzymes that are collectively known as the matrix metalloproteinases (MMP). One MMP that has been recently implicated in the progression of RA and OA is collagenase-3, or MMP-13. Of the MMPs, MMP-13 is the most efficiently degrades type II collagen, the primary collagen present in articular cartilage. MMP- 13 is expressed in osteoarthritic cartilage and rheumatoid synovium, and is induced in chondrocytes that have been stimulated with the inflammatory cytokines interleukin-l (IL-I) and tumor necrosis factor-alpha (TNF). Thus, inhibition of MMP-13 in OA and RA is an important goal for therapies of chondroprotection. We have found that a novel retinoid, BMS-189453, inhibits MMP-13 synthesis in a mouse collagen-induced arthritis model. We have also demonstrated that a novel steroid, 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO), also inhibits MMP-13 synthesis in chondrocytes and has potent anti-inflammatory properties. In this application, we propose studies that will define, on the cellular level, the mechanisms of MMP-13 gene repression in chondrocytes by BMS-189453 and CDDO. Specifically, these studies will define transcription factors and signal transduction intermediates that are targets of these compounds. Since steroids and retinoids inhibit collagen degradation more effectively together, we will test the combination of BMS- 189453 and CDDO, to see if lower doses of each can be used. We will extend this work to establish the chondroprotective efficacy of BMS-189453 and CDDO, alone and in combination, in the STR/ORT spontaneous mouse model of OA, and in the mouse collagen-induced arthritis (CIA) model of RA. Our goals are to establish the potency of each compound in an inflammatory (CIA) and non-inflammatory (STR/ORT) model of arthritis, and assess the potential of combinatorial treatment, which may lead to therapies with fewer side effects. This work will examine cellular/molecular events and whole animal models to characterize the chondroprotective potential of a novel steroid and a novel retinoid for the treatment of arthritis.
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