Deficient Smad7 Expression: A Putative Molecular Defect in Scleroderma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-03, Vol.99 (6), p.3908-3913
• Main Authors: Dong, Chunming, Zhu, Shoukang, Wang, Tao, Yoon, Woohyun, Li, Zhiru, Alvarez, Rene J., Dijke, Peter ten, White, Barbara, Wigley, Fredrick M., Goldschmidt-Clermont, Pascal J.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological Sciences; Biopsies; Blotting, Western; Collagens; Disease; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - drug effects; Endothelial cells; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Immunohistochemistry; Immunology; Lesions; Male; Messenger RNA; Mice; Mice, SCID; Middle Aged; Phosphorylation; Phosphorylation - drug effects; Plasminogen Activator Inhibitor 1 - analysis; Plasminogen Activator Inhibitor 1 - genetics; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scleroderma, Systemic - genetics; Scleroderma, Systemic - metabolism; Signal Transduction - drug effects; Skin; Skin grafts; Skin Transplantation; Smad3 Protein; Smad7 Protein; Tissue grafting; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic - drug effects; Transforming Growth Factor beta - pharmacology; Up-Regulation - drug effects
• 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.