Metalloproteinases are enzymes that are active at neutral pH, that contain Zn++, and that are generally not stored within the cells. The enzymes are secreted in latent form and upon activation, are capable of degrading the extracellular matrix. Metalloproteinases comprise a multi- gene family and two members are collagenase and stromelysin. Collagenase has the singular ability to initiate the degradation of collagen, the body's most abundant structural protein while stromelysin degrades non- collagenous matrix, such as proteoglycans, laminin and fibronectin. Of interest is the fact that stromelysin shares considerable homology with transin, a rat oncogene-induced proteinase, thus supporting the hypothesis that metalloproteinases may play a role in tumor/tissue invasion. Indeed, the combination of collagenase and stromelysin permits a concerted attack on most matrix components. No where is this degradative/invasive ability more apparent than in rheumatoid arthritis. In this disease, excessive production of collagenase and stromelysin by the fibroblasts that line the joint mediates the degradation of articular cartilage and subchondral bone, resulting in severe crippling and deformity. Previously, these studies have used monolayer cultures of rabbit synovial fibroblasts as a model system to study mechanisms controlling metalloproteinase gene expression as they pertained to joint disease. Most recently, however, they have been extended to human fibroblasts and results indicate that common mechanisms controlling the expression of these enzymes may be operative throughout the body. Plans for the next grant period will extend our knowledge of collagenase and stromelysin to include a more detailed understanding of the relationship between them. Thus, the specific aims of the proposal are (1) to study mechanisms regulating transcription of the rabbit collagenase gene by characterizing the sequences responsible for the induction (by agents such as Interleukin-1, phorbol esters, heat shock) and suppression (by glucocorticoids and retinoids) of collagenase synthesis; (2) to understand the comparative roles of rabbit and human stromelysin I and II in connective tissue degradation and the mechanisms regulating their expression; (3) to understand the relationship of rat collagenase to rabbit and human collagenase; and, (4) to investigate the importance of metalloproteinase expression in normal development and in tumor invasion by developing transgenic mice which carry the rabbit collagenase gene. These studies should increase our understanding of he role of metalloproteinases in the connective tissue modeling and remodeling that occurs in both normal and disease states.
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