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

Am J Pathol. 2009 Feb;174(2):519-33. doi: 10.2353/ajpath.2009.080574. Epub 2009 Jan 15.


The nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, originally identified as a key mediator of adipogenesis, is expressed widely and implicated in diverse biological responses. Both natural and synthetic agonists of PPAR-gamma abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-beta in vitro. To characterize the role of PPAR-gamma 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-beta. Rosiglitazone-driven adipogenic differentiation of both fibroblasts and preadipocytes was abrogated in the presence of TGF-beta; this effect was accompanied by the concomitant down-regulation of cellular PPAR-gamma mRNA expression. Collectively, these results indicate that rosiglitazone treatment attenuates inflammation, dermal fibrosis, and subcutaneous lipoatrophy via PPAR-gamma in a mouse model of scleroderma and suggest that pharmacological PPAR-gamma ligands, widely used as insulin sensitizers in the treatment of type-2 diabetes mellitus, may be potential therapies for scleroderma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Collagen / drug effects
  • Female
  • Fibrosis / chemically induced
  • Fibrosis / drug therapy
  • Fibrosis / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression / drug effects
  • Hypoglycemic Agents / pharmacology*
  • Immunohistochemistry
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred BALB C
  • PPAR gamma / drug effects
  • PPAR gamma / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rosiglitazone
  • Scleroderma, Systemic / chemically induced
  • Scleroderma, Systemic / drug therapy*
  • Scleroderma, Systemic / metabolism*
  • Stem Cells / cytology
  • Thiazolidinediones / pharmacology*
  • Transforming Growth Factor beta1 / drug effects
  • Transforming Growth Factor beta1 / metabolism


  • Antibiotics, Antineoplastic
  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • Transforming Growth Factor beta1
  • Rosiglitazone
  • Bleomycin
  • Collagen