Deficient Smad7 expression: a putative molecular defect in scleroderma

C Dong, S Zhu, T Wang, W Yoon, Z Li… - Proceedings of the …, 2002 - National Acad Sciences
C Dong, S Zhu, T Wang, W Yoon, Z Li, RJ Alvarez, P Ten Dijke, B White, FM Wigley…
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
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 …
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.
National Acad Sciences