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Runx2/Smad3 complex negatively regulates TGF-β-induced connective tissue growth factor gene expression in vascular

Yoshiaki Ohyama1, Toru Tanaka, Takehisa Shimizu

  • 1Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Journal of Atherosclerosis and Thrombosis
|October 12, 2011
PubMed
Abstract

Insights

Runx2, a transcription factor, negatively regulates connective tissue growth factor (CTGF) gene expression in vascular smooth muscle cells (VSMCs) by interacting with Smad3. This finding clarifies the role of Runx2 in atherosclerosis development.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research
  • Cell Biology

Background:

  • Connective tissue growth factor (CTGF) is implicated in atherosclerosis development and is a target of transforming growth factor-β (TGF-β) signaling.
  • Runx2, a transcription factor crucial for osteoblast differentiation, influences vascular smooth muscle cell (VSMC) phenotype.
  • Previous work demonstrated Runx2's role in VSMC osteogenic conversion and dedifferentiation.

Purpose of the Study:

  • To investigate if Runx2 modulates CTGF gene expression through TGF-β signaling.
  • To elucidate the molecular mechanisms underlying Runx2's regulation of CTGF.

Main Methods:

  • Cultured human aortic smooth muscle cells (HASMCs) and C3H10T1/2 cells were used to study gene expression.
  • TGF-β treatment was applied to assess its effect on Runx2 and CTGF levels.
  • Runx2 expression was manipulated using forced expression and small interfering RNA (siRNA).
  • CTGF promoter analysis, site-directed mutagenesis, immunoblots, and chromatin immunoprecipitation (ChIP) were employed.
  • Immunohistochemistry was used to examine Runx2 and CTGF expression in human atherosclerotic plaques.

Main Results:

  • TGF-β decreased Runx2 expression while increasing CTGF mRNA levels in HASMCs and C3H10T1/2 cells.
  • Overexpression of Runx2 reduced CTGF expression, whereas Runx2 knockdown enhanced it.
  • Runx2 repressed CTGF promoter activity via the Smad-binding element (SBE).
  • Runx2 physically interacted with Smad3 at the SBE.
  • Runx2 and CTGF expression patterns were mutually exclusive in human atherosclerotic lesions.

Conclusions:

  • Runx2, in complex with Smad3, acts as a negative regulator of CTGF gene expression in VSMCs.
  • This Runx2/Smad3 complex inhibits both basal and TGF-β-induced CTGF expression.
  • Runx2 induction contributes to VSMC phenotypic modulation within the context of TGF-β/Smad signaling.

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