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Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome

Minghua Wu1, Denisa S Melichian, Eric Chang

  • 1Section of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA.

The American Journal of Pathology
|January 17, 2009
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, like rosiglitazone, reduce skin inflammation and fibrosis in a mouse model of scleroderma. This suggests PPAR-gamma ligands may offer new therapeutic options for scleroderma patients.

Area of Science:

  • Cell Biology
  • Dermatology
  • Endocrinology

Background:

  • Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear hormone receptor involved in adipogenesis and diverse biological responses.
  • PPAR-gamma agonists inhibit collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-beta in vitro.
  • Scleroderma is characterized by inflammation and fibrosis in the skin.

Purpose of the Study:

  • To investigate the role of PPAR-gamma in the fibrotic process in vivo using a mouse model of scleroderma.
  • To evaluate the therapeutic potential of the synthetic PPAR-gamma agonist rosiglitazone in treating scleroderma-related symptoms.

Main Methods:

  • A mouse model of scleroderma was induced using bleomycin.
  • Mice were treated with rosiglitazone, a synthetic PPAR-gamma agonist.
  • Skin inflammation, dermal fibrosis, collagen gene expression, myofibroblast accumulation, and lipoatrophy were assessed.
  • In vitro studies using explanted fibroblasts and skin organ cultures examined the effects of rosiglitazone on TGF-beta-induced responses.

Main Results:

  • Rosiglitazone treatment attenuated bleomycin-induced skin inflammation and dermal fibrosis.
  • Rosiglitazone reduced subcutaneous lipoatrophy and counteracted increased collagen gene expression and myofibroblast accumulation.
  • In vitro, rosiglitazone prevented TGF-beta-induced collagen gene transcription and cell migration.
  • Rosiglitazone-induced adipogenic differentiation was abrogated by TGF-beta, with concomitant down-regulation of PPAR-gamma mRNA.

Conclusions:

  • Rosiglitazone treatment attenuates inflammation, dermal fibrosis, and lipoatrophy via PPAR-gamma in a mouse model of scleroderma.
  • Pharmacological PPAR-gamma ligands, used for type-2 diabetes, may represent potential therapies for scleroderma.

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