title: Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis.
abstract: BACKGROUND
  Microvascular damage is one of the first pathological changes in systemic sclerosis. In this study, we investigated the role of Fos-related antigen-2 (Fra-2), a transcription factor of the activator protein-1 family, in the peripheral vasculopathy of systemic sclerosis and examined the underlying mechanisms.
  
  
  RESULTS
  Expression of Fra-2 protein was significantly increased in skin biopsies of systemic sclerosis patients compared with healthy controls, especially in endothelial and vascular smooth muscle cells. Fra-2 transgenic mice developed a severe loss of small blood vessels in the skin that was paralleled by progressive skin fibrosis at 12 weeks of age. The reduction in capillary density was preceded by a significant increase in apoptosis in endothelial cells at week 9 as detected by immunohistochemistry. Similarly, suppression of Fra-2 by small interfering RNA prevented human microvascular endothelial cells from staurosporine-induced apoptosis and improved both the number of tubes and the cumulative tube lengths in the tube formation assay. In addition, cell migration in the scratch assay and vascular endothelial growth factor-dependent chemotaxis in a modified Boyden chamber assay were increased after transfection of human microvascular endothelial cells with Fra-2 small interfering RNA, whereas proliferation was not affected.
  
  
  CONCLUSIONS
  Fra-2 is present in human systemic sclerosis and may contribute to the development of microvasculopathy by inducing endothelial cell apoptosis and by reducing endothelial cell migration and chemotaxis. Fra-2 transgenic mice are a promising preclinical model to study the mechanisms and therapeutic approaches of the peripheral vasculopathy in systemic sclerosis.
authors.affiliation: Center of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Nicole
authors.initials: N
authors.lastname: Busch
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.forename: Margarita
authors.initials: M
authors.lastname: Pileckyte
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Jörg
authors.initials: J
authors.lastname: Distler
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002464:Cell Migration Inhibition / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D051921:Fos-Related Antigen-2 / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016491:Peripheral Vascular Diseases / Q000378:metabolism* / Q000473:pathology*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology*
chemical_list: D051921:Fos-Related Antigen-2