PATHOLOGIC STUDIES IN A HUMAN MODEL OF OSTEOARTHROSIS

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Osteoarthrosis (OA) is an extremely common disorder. Although its pathogenesis is poorly understood, the concept has emerged that it reflects an imbalance between the processes of articular cartilage destruction and repair favoring the former. This study will address this imbalance and focus on why cartilage repair progressively fails. The results from the current grant indicate that many of the chondrocytes involved in cartilage repair go through a differentiation process that closely resembles that which occurs in differentiating growth plate chondrocytes. The biosynthetic changes associated with this process may account for many of the observed biochemical alterations in OA cartilage and may contribute to accelerated cartilage degradation. The goal of this study is to define the biosynthetic events associated with this dynamic process, characterize the matrix produced by the cells as they proceed through differentiation, and examine the in vitro effect of selected agents on these parameters. Because of the focal nature of articular cartilage repair and the difficulties encountered in assessing the process over time, the normal skeletal growth plate which exhibits a highly organized spacial representation of the temporal events that constitute chondrocyte differentiation will be employed to define the above parameters and guide studies of the OA articular cartilage. Growth plate and OA articular cartilage will be studied by light and electron microscopic immune and lectin histochemistry, autoradiography, and in situ hybridization. Monoclonal antibodies to matrix components: types I-VI, IX (G), X (M), and 1alpha, 2alpha, 3alpha collagens; chondroitin-4-and -6- sulfate, keratan sulfate and hyaluronic acid binding region, substructures of cartilage proteoglycan; link protein; fibronectin; and cDNA probes to specific skeletal procollagen mRNAs will be employed. To biochemically confirm the microscopic observations, microsamples of the cartilages corresponding to different stages of chondrocyte differentiation and degrees of cartilage repair will be studied in organ culture by HPLC and SDS-PAGE methods to determine the presence of and relative proportions of isotopically labelled major and minor collagens and glycosaminoglycans in newly synthesized matrix and the effects of potential therapeutic agents on these parameters. These studies should provide a comprehensive view of chondrocyte differentiation in the two tissues, insights into why cartilage repair is fails in OA, and new ideas for therapy.