Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that affects mostly women and is associated with significant morbidity and mortality. No effective therapies or cures for SSc are yet available. One of the hallmarks of SSc is overproduction of extracellular matrix components such as collagen and fibronectin by fibroblasts in the skin and internal organs. We have made the novel observation of a 20-fold increase in the expression of insulin-like growth factor binding protein 5 (IGFBP-5) in fibroblasts from the clinically affected skin of SSc patients. IGFBP-5, as well as IGFBP-3, are produced by fibroblasts and modulate the actions of IGF-I, including fibroblast activation and overproduction of collagen. We hypothesize that the IGFBP/IGF-I axis contributes to the development and perpetuation of skin and lung fibrosis in SSc. Our studies will use two unique sample sets available to us--fibroblasts and tissues from monozygotic (MZ) and dizygotic (DZ) twins discordant for SSc and from lungs of SSc patients undergoing lung transplant surgery and unused donor lungs-and target two organs affected by SSc--skin and lung. These samples constitute a unique and valuable resource.
Our aims are l) to determine the regulation of IGFBP-3 and IGFBP-5 in vitro and in vivo in skin an lung tissues of SSc patients and twin and non-twin controls; 2) to determine the function of IGFBPs on skin and lung fibroblasts and identify key molecules downstream of IGFBPs; 3) to determine the mechanism of IGFBP-mediated effects on fibroblasts, including whether the effect of IGFBPs is IGF-I-dependent or - independent, the identification of IGFBP binding partners, and the effect of suppressing IGFBP expression on the fibrotic phenotype. Our combined approach using lung and skin fibroblasts and tissues will allow us to identify the systemic mechanisms that underlie the skin and lung phenotype in SSc, while the use of samples from twins discordant for SSc will allow us to determine the importance of the inherited genetic background in the development of the 'scleroderma' phenotype. Our results will provide important insights into mechanisms of overproduction of extracellular matrix components by fibroblasts and thus the pathogenesis of fibrosis. Identifying key steps in the cascade of events culminating in fibrosis will facilitate the development of novel targeted therapies for scleroderma and for other fibrotic conditions.
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