Fibrotic disorders represent the largest segment of human disease for the populations of North America, Europe and Japan. These disorders are characterized by an overproduction of connective tissue (primarily collagen) and are widely recognized to be initiated in response to some type of injury which leads to the chronic inflammation and subsequent overproduction of growth factors that encourage the formation of connective tissue. There are no current therapies short of transplant or grafts which are effective to control the progression of any fibrotic disorder. Intensive studies over the last 25 years now suggest that a common mechanism may underlie many of these disorders. Thus, an advancement in our understanding of the cellular and molecular control mechanisms which regulate this process could have a significant impact on a wide range of human diseases, including atherosclerosis, pulmonary fibrosis, glomerulosclerosis, arthritis, glaucoma, diabetic retinopathy and others. One common growth factor which has been demonstrated to be overproduced in all fibrotic disorders examined to date is TGFb, which is believed to be an initiator of the connective tissue formation in these disorders. During the course of our studies on mechanisms whereby TGFb stimulates connective tissue formation, we discovered another growth factor, Connective Tissue Growth Factor (CTG F). CTGF synthesis selectively induced in mesenchymal cells by TGFb. We have found that agents which block CTGF synthesis or action are effective inhibitors of TGFb induced fibroblastic cell proliferation and collagen synthesis. This suggests that CTGF may be an important therapeutic target for the control of connective tissue formation in fibrotic disorders. Recently, we have determined that the individual domains of CTGF are responsible for signaling either the mitogenic activity (C-terminal domain of CTGF) or matrigenic activity (N-terminal domain). Our data also indicate that CTGF has an absolute requirement for the presence of EGF for mitogenic and IGF-2 for matrigenic activity. The current project will determine in a more detailed manner the role of the CTGF, CTG F, lGF and EGF receptors and the roles of EGF and IGF factor for signaling the mitogenic and matrigenic actions induced by TGFb in fibroblastic cells.
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