title: The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Paulius
authors.initials: P
authors.lastname: Venalis
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nevskaya
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D051921:Fos-Related Antigen-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta