RETRACTED: Deficient Smad7 expression: A putative molecular defect in scleroderma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 6; pp. 3908 - 3913
• Main Authors: Dong, Chunming, Zhu, Shoukang, Wang, Tao, Yoon, Woohyun, Li, Zhiru, Alvarez, Rene J., ten Dijke, Peter, White, Barbara, Wigley, Fredrick M., Goldschmidt-Clermont, Pascal J.
• Format: Journal Article
• Language: English; Japanese
• Published: 19.03.2002
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.062010399

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.