Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts

J Invest Dermatol. 2013 Jan;133(1):110-9. doi: 10.1038/jid.2012.252. Epub 2012 Jul 26.

Abstract

Systemic sclerosis (SSc) is characterized by excess collagen deposition in the skin, due to intrinsic transforming growth factor-β (TGF-β) activation. We tried to determine the expression and the role of discoidin domain receptor 2 (DDR2) in SSc. The expression of DDR2 mRNA and protein was significantly decreased in SSc dermal fibroblasts, which was recovered by knocking down TGF-β. The knockdown of DDR2 in normal fibroblasts induced microRNA-196a expression, which led to type I collagen downregulation, indicating that DDR2 itself has a negative effect on microRNA-196a expression and inducible effect on collagen expression. In SSc fibroblasts, however, the DDR2 knockdown did not affect TGF-β signaling and microRNA-196a expression. The microRNA-196a levels were significantly decreased in normal fibroblasts treated with TGF-β and in SSc fibroblasts. Taken together our data indicate that, in SSc fibroblasts, intrinsic TGF-β stimulation induces type I collagen expression, and also downregulates DDR2 expression. This probably acts as a negative feedback mechanism against excess collagen expression, as a decreased DDR2 expression is supposed to stimulate the microRNA-196a expression and further change the collagen expression. However, in SSc fibroblasts the microRNA-196a expression was downregulated by TGF-β signaling. DDR2-microRNA-196a pathway may be a previously unreported negative feedback system, and its impairment may be involved in the pathogenesis of SSc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Collagen Type I / biosynthesis*
  • Dermis / drug effects
  • Dermis / metabolism*
  • Dermis / pathology
  • Discoidin Domain Receptors
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Gene Knockdown Techniques
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Mitogen / genetics
  • Receptors, Mitogen / metabolism*
  • Scleroderma, Systemic / drug therapy
  • Scleroderma, Systemic / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology

Substances

  • Collagen Type I
  • MIRN196 microRNA, human
  • MicroRNAs
  • Receptors, Mitogen
  • Transforming Growth Factor beta
  • Discoidin Domain Receptors
  • Receptor Protein-Tyrosine Kinases