Targeted disruption of TGF-β/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma

Gabriella Lakos, Shinsuke Takagawa, Shu Jen Chen, Ahalia M. Ferreira, Gangwen Han, Koichi Masuda, Xiao Jing Wang, Luisa A. DiPietro, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is a potent stimulus of connective tissue accumulation, and is implicated in the pathogenesis of scleroderma and other fibrotic disorders. Smad3 functions as a key intracellular signal transducer for profibrotic TGF-β responses in normal skin fibroblasts. The potential role of Smad3 in the pathogenesis of scleroderma was investigated in Smad3-null (Smad3-/-) mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. At early time points, bleomycin-induced macrophage infiltration in the dermis and local TGF-β production were similar in Smad3-/- and wild-type mice. In contrast, at day 28, lesional skin from Smad3-/- mice showed attenuated fibrosis, lower synthesis and accumulation of collagen, and reduced collagen gene transcription in situ, compared to wild-type mice. Connective tissue growth factor and α-smooth muscle actin expression in lesional skin were also significantly attenuated. Electron microscopy revealed an absence of small diameter collagen fibrils in the dermis from bleomycin-treated Smad3 -/- mice. Compared to fibroblasts derived from wild-type mice, Smad3-/- fibroblasts showed reduced in vitro proliferative and profibrotic responses elicited by TGF-β. Together, these results indicate that ablation of Smad3 is associated with markedly altered fibroblast regulation in vivo and in vitro, and confers partial protection from bleomycin-induced scleroderma in mice. Reduced fibrosis is due to deregulated fibroblast function, as the inflammatory response induced by bleomycin was similar in wild-type and Smad3-/- mice.

Original languageEnglish (US)
Pages (from-to)203-217
Number of pages15
JournalAmerican Journal of Pathology
Volume165
Issue number1
DOIs
StatePublished - Jul 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Lakos, G., Takagawa, S., Chen, S. J., Ferreira, A. M., Han, G., Masuda, K., Wang, X. J., DiPietro, L. A., & Varga, J. (2004). Targeted disruption of TGF-β/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. American Journal of Pathology, 165(1), 203-217. https://doi.org/10.1016/S0002-9440(10)63289-0