Sustained activation of fibroblast transforming growth factor-β/Smad signaling in a murine model of scleroderma

Shinsuke Takagawa, Gabriella Lakos, Yasuji Mori, Toshiyuki Yamamoto, Kiyoshi Nishioka, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Transforming growth factor-β is responsible for triggering a cascade of events leading to fibrosis in scleroderma. The Smads are intracellular signal transducers recently shown to mediate fibroblast activation and other profibrotic responses elicited by transforming growth factor-β in vitro. To understand better the involvement of Smads in the pathogenesis of fibrosis, we examined Smad expression and activation in situ in a murine model of scleroderma. Bleomycin injections induced striking dermal infiltration with macrophages by 3 d, and progressive fibrosis by 2 wk. Infiltrating macrophages and resident fibroblasts expressed Smad3, the positive mediator for transforming growth factor-β responses. Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3. Furthermore, phosphorylated Smad2/3 in fibroblasts was detected even after the resolution of inflammation. Expression of Smad7, the endogenous inhibitor of transforming growth factor-β/Smad signaling, was strongly induced in dermal cells by transforming growth factor-β, but not by bleomycin injections. Collectively, these results indicate that bleomycin-induced murine scleroderma is associated with rapid and sustained induction of transforming growth factor-β/Smad signaling in resident dermal fibroblasts. Despite apparent activation of the intracellular transforming growth factor-β signaling pathway in the lesional dermis, the expression of transforming growth factor-β-inducible Smad7 was not upregulated. In light of the critical function of Smad7 as an endogenous inhibitor of Smad signaling that restricts the duration and magnitude of transforming growth factor-β responses, and as a mediator of apoptosis, relative Smad7 deficiency observed in the present studies may account for sustained activation of transforming growth factor-β/Smad signaling in lesional tissues. These findings raise the possibility that Smads plays an important part in the pathogenesis of fibrosis, and may therefore represent targets for selective anti-fibrotic interventions.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalJournal of Investigative Dermatology
Volume121
Issue number1
DOIs
StatePublished - Jul 1 2003

Keywords

  • Bleomycin
  • Murine scleroderma
  • Smad
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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