Type III Collagen Gene Expression in Cartilage

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DESCRIPTION (provided by applicant): The chick type III collagen gene produces two unrelated proteins, type III collagen and a small non-collagenous protein, Col3alt. The upstream promoter of this gene directs production of type III collagen mRNA and protein, while an internal promoter directs production of an alternative transcript that produces Col3alt. This gene displays a complex pattern of regulation during chondrogenesis and in cartilage pathology. Type Ill collagen is produced in prechondrogenic mesenchymal cells, but is not present in embryonic cartilages. However, type III collagen is found in adult articular cartilages and in the cartilage-like structures of the intervertebral disk. The amount of type III collagen is increased significantly in osteoarthritis and degenerative disk disease, and is induced in cultured chondrocytes by treatment with interleukin 1, a pro-inflammatory cytokine that plays an important role in osteoarthritis. Col3alt, the product of the alternative transcript of the type III collagen gene, is produced in prechondrogenic mesenchyme along with type III collagen; however, production of Col3alt continues in embryonic cartilages and in juvenile growth plates, where it is secreted into the matrix. The regulation of this gene and the functions of its two products will be investigated in the following specific aims: 1) Characterize the transcriptional mechanisms regulating cessation of type III collagen production during chondrogenesis; 2) Determine whether type III collagen gene expression is reactivated in chondrocytes in response to hydrostatic pressure and proinflammatory cytokines and identify the mechanisms responsible for reactivation; 3) Determine the role of type III collagen in the cartilage matrix and its function in the intervertebral disc; and 4) Examine the hypothesis that Col3alt is required for chondrogenesis, by modulating its production during in vitro and in vivo limb development. The proposed experiments will strengthen our understanding of the regulation and function of the type III collagen gene during chondrogenesis and in response to stress and proinflammatory cytokines, and will define the roles of type III collagen in cartilage and intervertebral disc and the function of Col3alt in chondrogenesis. Finally, these studies will provide unique insights into the regulation of a complex locus which is, in essence, a gene within a gene.