Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis

Arthritis Rheum. 2007 Dec;56(12):4203-15. doi: 10.1002/art.23074.


Objective: Insufficient angiogenesis with tissue ischemia and accumulation of extracellular matrix are hallmarks of systemic sclerosis (SSc). Based on the severely decreased oxygen levels in the skin of patients with SSc, we aimed to investigate the role of hypoxia in the pathogenesis of SSc.

Methods: Subtractive hybridization was used to compare gene expression in dermal fibroblasts under hypoxic and normoxic conditions. Dermal fibroblasts were further characterized by exposure to different concentrations of oxygen and for different time periods as well as by interference with hypoxia-inducible factor 1alpha (HIF-1alpha). The systemic normobaric hypoxia model in mice was used for in vivo analyses.

Results: Several extracellular matrix proteins and genes involved in extracellular matrix turnover, such as thrombospondin 1, proalpha2(I) collagen, fibronectin 1, insulin-like growth factor binding protein 3, and transforming growth factor beta-induced protein, were induced by hypoxia in SSc and healthy dermal fibroblasts. The induction of these genes was time- and dose-dependent. Experiments with HIF-1alpha-knockout mouse embryonic fibroblasts, deferoxamine/cobalt ions as chemical stabilizers of HIF-1alpha, and HIF-1alpha small interfering RNA consistently showed that extracellular matrix genes are induced in dermal fibroblasts by HIF-1alpha-dependent, as well as HIF-1alpha-independent, mechanisms. Using the systemic normobaric hypoxia mouse model, we demonstrated that dermal hypoxia leads to the induction of the identified extracellular matrix genes in vivo after both short exposure and prolonged exposure to hypoxia.

Conclusion: These data show that hypoxia contributes directly to the progression of fibrosis in patients with SSc by increasing the release of major extracellular matrix proteins. Targeting of hypoxia pathways might therefore be of therapeutic value in patients with SSc.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Biopsy
  • Cell Hypoxia / physiology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Oxygen / metabolism
  • Oxygen / pharmacology
  • RNA, Messenger / metabolism
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Scleroderma, Systemic / physiopathology
  • Skin / pathology
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Extracellular Matrix Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • Oxygen