title: Deficient Smad7 expression: a putative molecular defect in scleroderma.
abstract: Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) beta has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-beta 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-beta pathway and TGF-beta activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-beta 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-beta 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-beta hyperresponsiveness observed in scleroderma.
authors.affiliation: Division of Cardiology, Duke University Medical Center, 7504 Duke Hospital North, Box 3845, Durham, NC 27710, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
authors.forename: Shoukang
authors.initials: S
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Woohyun
authors.initials: W
authors.lastname: Yoon
authors.forename: Zhiru
authors.initials: Z
authors.lastname: Li
authors.forename: Rene J
authors.initials: RJ
authors.lastname: Alvarez
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Barbara
authors.initials: B
authors.lastname: White
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Wigley
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016038:Skin Transplantation; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta