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 Goldschmidt-Clermont

Research output: Contribution to journalArticle

222 Citations (Scopus)

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
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
Externally publishedYes

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Transforming Growth Factors
Fibroblasts
Smad Proteins
Growth Factor Receptors
Plasminogen Activator Inhibitor 1
Transducers
Genes
Fibrosis
Chronic Disease
Up-Regulation
Phosphorylation
Skin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Deficient Smad7 expression : A putative molecular defect in scleroderma. / Dong, Chunming; Zhu, Shoukang; Wang, Tao; Yoon, Woohyun; Li, Zhiru; Alvarez, Rene J.; Ten Dijke, Peter; White, Barbara; Wigley, Fredrick M.; Goldschmidt-Clermont, Pascal.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 6, 19.03.2002, p. 3908-3913.

Research output: Contribution to journalArticle

Dong, C, Zhu, S, Wang, T, Yoon, W, Li, Z, Alvarez, RJ, Ten Dijke, P, White, B, Wigley, FM & Goldschmidt-Clermont, P 2002, 'Deficient Smad7 expression: A putative molecular defect in scleroderma', Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 6, pp. 3908-3913. https://doi.org/10.1073/pnas.062010399
Dong, Chunming ; Zhu, Shoukang ; Wang, Tao ; Yoon, Woohyun ; Li, Zhiru ; Alvarez, Rene J. ; Ten Dijke, Peter ; White, Barbara ; Wigley, Fredrick M. ; Goldschmidt-Clermont, Pascal. / Deficient Smad7 expression : A putative molecular defect in scleroderma. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 6. pp. 3908-3913.
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