Human development, growth and health critically depends on tissue remodeling and the exquisite balance between the synthesis and degradation of connective tissues. At times, inconsistencies in tissue remodeling result in developmental anomalies and devastating connective tissue diseases that can affect the skin, blood vessels, bone and cartilage of the joints. A number of these diseases are known to be genetic and inherited and are the result of structural mutations in the genes that encode collagen, the most abundant proteins of the body. In many acquired type of connective tissue diseases such as osteoarthritis and rheumatoid arthritis, the underlying causes have not been identified. However, increasing evidence suggests a critical role for the connective tissued degrading enzymes or matrix metalloproteinases, growth factors and inflammatory cytokines in the pathogenesis of arthritic joint destruction. We hypothesize that tissue remodeling is largely controlled by the expression of matrix metalloproteinases. Accordingly, in this proposal, we will study the regulation of expression of matrix metalloproteinases at a genetic level, using mutational analysis and transient gene transfection of cultured cells. In particular, we plan to study the activation and inhibition of tissue collagenase and stromelysin genes by cytokines and growth factors including IL-1beta, TNFalpha and FGF, and hormones such as glucocorticoids and retinoic acid. Recently, we and others have shown that several proto-oncogenes are involved in the expression and regulation of matrix metalloproteinase genes. We therefore also propose to systematically study a wide variety of different oncoprotein and transcription factors for their effects on collagenase ad stromelysin gene expression and for their role in the regulation induced by cytokines, growth factors and glucocorticoid and retinoid hormones. As long term goals, research applications of these studies are targeted for the regulation of matrix metalloproteinase genes in vivo, and the treatment and prevention of major connective tissue disorders and diseases such as arthritis.
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