Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-β

Minghua Wu, Denisa S. Melichian, Eric Chang, Matthew Warner-Blankenship, Asish K. Ghosh, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

161 Scopus citations

Abstract

The nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-γ, originally identified as a key mediator of adipogenesis, is expressed widely and implicated in diverse biological responses. Both natural and synthetic agonists of PPAR-γ abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-β in vitro. To characterize the role of PPAR-γ in the fibrotic process in vivo, the synthetic agonist rosiglitazone was used in a mouse model of scleroderma. Rosiglitazone attenuated bleomycin-induced skin inflammation and dermal fibrosis as well as subcutaneous lipoatrophy and counteracted the up-regulation of collagen gene expression and myofibroblast accumulation in the lesioned skin. Rosiglitazone treatment reduced the induction of the early-immediate transcription factor Egr-1 in situ without also blocking the activation of Smad2/3. In both explanted fibroblasts and skin organ cultures, rosiglitazone prevented the stimulation of collagen gene transcription and cell migration elicited by TGF-β. Rosiglitazone-driven adipogenic differentiation of both fibroblasts and preadipocytes was abrogated in the presence of TGF-β; this effect was accompanied by the concomitant down-regulation of cellular PPAR-γ mRNA expression. Collectively, these results indicate that rosiglitazone treatment attenuates inflammation, dermal fibrosis, and subcutaneous lipoatrophy via PPAR-γ in a mouse model of scleroderma and suggest that pharmacological PPAR-γ ligands, widely used as insulin sensitizers in the treatment of type-2 diabetes mellitus, may be potential therapies for scleroderma.

Original languageEnglish (US)
Pages (from-to)519-533
Number of pages15
JournalAmerican Journal of Pathology
Volume174
Issue number2
DOIs
StatePublished - Feb 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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