Articular cartilage damage remains an unsolved problem in orthopaedics. The purpose of the proposed studies is to elucidate the potential role of autocrine/paracrine mechanisms in growth factor-mediated articular cartilage repair. The studies will employ in vitro recombinant adeno-associated virus (rAAV) mediated gene transfer methods to test the following hypotheses: (1) local growth factor production can be achieved by rAAV vector-mediated gene transfer to bovine articular chondrocytes and will augment cartilage repair in acute cartilage trauma; (2) local growth factor production can be achieved by rAAV vector-mediated gene transfer of human articular chondrocytes and will augment repair of osteoarthritic cartilage; (3) local production of more than one growth factor can be achieved by rAAV vector-mediated gene transfer and expressed growth factors will interact in the regulation of repair in traumatic and osteoarthritic cartilage damage; and (4) local growth factor production, coupled with expression of growth factor receptors can be achieved by rAAV-mediated gene transfer to chondrocytes and will augment repair in traumatic and OA cartilage damage. These hypotheses will be tested using insulin-like growth factor I (IGF-I) and fibroblast growth factor-2, (FGF-2) and, in Aim 4, the type I IGF receptor (IGF-IR). Repair will be assessed using biosynthetic, histological, biochemical and biomechanical parameters. The demonstration by these studies that growth factor-mediated cartilage repair can be achieved through autocrine/paracrine mechanisms would not only lend insight into the role of these factors in cartilage regulation, but may serve to facilitate the development of future potential gene transfer-based therapies.
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