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Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is

Katsunari Makino1, Masatoshi Jinnin, Jun Aoi

  • 1Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.

The Journal of Investigative Dermatology
|July 27, 2012
PubMed

Insights

Systemic sclerosis involves excess collagen due to TGF-β. Discoidin domain receptor 2 (DDR2) is decreased in SSc, potentially impairing a negative feedback pathway involving microRNA-196a and collagen expression.

Area of Science:

  • Fibroblast biology
  • Connective tissue diseases
  • Molecular mechanisms of fibrosis

Background:

  • Systemic sclerosis (SSc) is marked by excessive collagen deposition.
  • Transforming growth factor-β (TGF-β) activation is a key driver of fibrosis in SSc.
  • The role of discoidin domain receptor 2 (DDR2) in SSc pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the expression and function of DDR2 in systemic sclerosis (SSc).
  • To elucidate the relationship between DDR2, TGF-β, microRNA-196a, and type I collagen in SSc fibroblasts.

Main Methods:

  • Quantitative analysis of DDR2 mRNA and protein expression in SSc dermal fibroblasts.
  • Experimental manipulation of TGF-β levels and DDR2 expression via knockdown.
  • Assessment of microRNA-196a expression and type I collagen levels.

Main Results:

  • DDR2 expression was significantly reduced in SSc dermal fibroblasts.
  • TGF-β knockdown restored DDR2 expression in SSc fibroblasts.
  • DDR2 knockdown in normal fibroblasts increased microRNA-196a and decreased type I collagen.
  • In SSc fibroblasts, microRNA-196a levels were decreased, and TGF-β signaling downregulated DDR2.

Conclusions:

  • Decreased DDR2 expression in SSc fibroblasts may impair a negative feedback loop involving microRNA-196a.
  • The DDR2-microRNA-196a pathway's impairment is potentially implicated in the pathogenesis of systemic sclerosis.
  • TGF-β signaling plays a crucial role in regulating DDR2 and collagen expression in SSc.

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