Deficient Smad7 expression: A putative molecular defect in scleroderma

Chunming Dong, Shoukang Zhu, Tao Wang, Woohyun Yoon, Zhiru Li, Rene J. Alvarez, Peter Ten Dijke, Barbara White, Fredrick M. Wigley, Pascal J. Goldschmidt-Clermont

Research output: Contribution to journalArticle

Abstract

Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) β has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-β 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-β pathway and TGF-β activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-β-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-β 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-β 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-β hyperresponsiveness observed in scleroderma.

Original languageEnglish (US)
Pages (from-to)3908-3913
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number6
DOIs
StatePublished - Mar 19 2002

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Deficient Smad7 expression: A putative molecular defect in scleroderma'. Together they form a unique fingerprint.

  • Cite this

    Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R. J., Ten Dijke, P., White, B., Wigley, F. M., & Goldschmidt-Clermont, P. J. (2002). Deficient Smad7 expression: A putative molecular defect in scleroderma. Proceedings of the National Academy of Sciences of the United States of America, 99(6), 3908-3913. https://doi.org/10.1073/pnas.062010399