Role of Rac1 in a Bleomycin-Induced Scleroderma Model Using Fibroblast-Specific Rac1-knockout Mice

Arthritis Rheum. 2008 Jul;58(7):2189-95. doi: 10.1002/art.23595.

Abstract

Objective: Activated adhesive signaling is a hallmark of fibroblasts isolated from the scars of scleroderma (systemic sclerosis [SSc]) lesions. Rac1 plays a key role in adhesive signaling. The aim of the present study was to examine the role of Rac1 in bleomycin-induced scleroderma, using mice with a fibroblast-specific deletion of Rac1.

Methods: Cutaneous sclerosis was induced by subcutaneous injection of bleomycin. Control groups were treated with phosphate buffered saline. Mice with a fibroblast-specific deletion of Rac1 and control mice were investigated. Dermal thickness, inflammation, collagen production, and the number of alpha-smooth muscle actin-positive cells were determined. The quantity of the collagen-specific amino acid hydroxyproline was also measured.

Results: Bleomycin treatment induced marked cutaneous thickening, inflammation, and fibrosis in control mice. Conversely, deletion of Rac1 resulted in resistance to bleomycin-induced fibrosis and inflammation.

Conclusion: Rac1 expression by fibroblasts is required for fibrogenesis. Inhibition of Rac1 may be a viable method to alleviate the development of cutaneous sclerosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Bleomycin / adverse effects
  • Disease Models, Animal
  • Fibroblasts / metabolism*
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuropeptides / genetics*
  • Scleroderma, Localized / chemically induced
  • Scleroderma, Localized / genetics*
  • Scleroderma, Localized / pathology
  • rac GTP-Binding Proteins / genetics*
  • rac1 GTP-Binding Protein

Substances

  • Antibiotics, Antineoplastic
  • Neuropeptides
  • Rac1 protein, mouse
  • Bleomycin
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein