(Taken from the application): During the process of endochondral bone development, most of the cartilage model will be replaced with bone, however, there are several sites where mature cartilage persists, including the joint surfaces. The persistence of articular cartilage as a mature, resting cartilage is required for proper joint function. Degeneration of articular, cartilage results in osteoarthritis, the leading cause of musculoskeletal disability in the industrialized world. Almost nothing is known about the growth factors that are involved in regulating the formation and persistence of articular cartilage. The long term objective of this study is to understand these signals and how they can prevent cartilage destruction or facilitate cartilage repair. Transforming Growth Factor -beta (TGF-B) is a potentially important factor in the formation, maintenance, and repair of articular cartilage. TGF-B has been shown to regulate both chondrocyte differentiation and expression of specific cartilage matrix genes. We have generated transgenic mice that express a dominant-negative mutation of the TGF-B type II receptor (MT-DNIIR) in articular cartilage. The transgenic mice develop a progressive skeletal disease that resembles osteoarthritis in humans and is preceded by loss of proteoglycan staining and hypertrophic differentiation in articular cartilage. The phenotype suggest TGF- normally acts as a chondroprotective agent, preventing destruction of articular cartilage. Based on the potential clinical significance, studies to determine the mechanism of the chondroprotective effect of TGF- will be undertaken through the following specific aims: 1 ) To test the hypothesis that dominant-negative interference of TGF-B signaling alters the expression of proteoglycans and collagens which are required for the structural integrity of articular cartilage. 2) To test the hypothesis that TGF-B is one of the factors that prevents the process of endochondral bone formation in articular cartilage. 3) To identify gene targets of TGF- in articular cartilage. Data from the proposed experiments will provide insight into the mechanism of chondroprotection by TGF-B and potential strategies for preventing and treating damaged or arthritic cartilage.
