The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis

Arthritis Rheum. 2010 Jan;62(1):280-90. doi: 10.1002/art.25056.

Abstract

Objective: Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis.

Methods: Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2-transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor beta (TGFbeta), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors.

Results: Fra-2-transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFbeta and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGFbeta and PDGF and decreased the release of collagen from SSc fibroblasts.

Conclusion: We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFbeta and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dermis / metabolism*
  • Dermis / pathology
  • Disease Models, Animal
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fluorescent Antibody Technique, Indirect
  • Fos-Related Antigen-2 / deficiency
  • Fos-Related Antigen-2 / genetics
  • Fos-Related Antigen-2 / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Platelet-Derived Growth Factor / pharmacology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Transforming Growth Factor beta / pharmacology

Substances

  • FOSL2 protein, human
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Platelet-Derived Growth Factor
  • RNA, Small Interfering
  • Transforming Growth Factor beta