期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：6
页码：3908-3913
DOI：10.1073/pnas.062010399
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) {beta} has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-{beta} receptors. Three families of Smads have been identified: (i) receptor-regulated Smad2 and -3 (R-Smads); (ii) common partner Smad4 (Co-Smad); and (iii) inhibitory Smad6 and -7 (I-Smads, part of a negative feedback loop). We have investigated the signaling components for the TGF-{beta} pathway and TGF-{beta} activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-{beta}-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-{beta} signaling events, including phosphorylation of Smad2 and -3, and transcription of the PAI-1 gene are increased in scleroderma fibroblasts, relative to normal fibroblasts. In vitro adenoviral gene transfer with Smad7 restores normal TGF-{beta} signaling in scleroderma fibroblasts. These results suggest that alterations in the Smad pathway, including marked Smad7 deficiency and Smad3 up-regulation, may be responsible for TGF-{beta} hyperresponsiveness observed in scleroderma.
