Mitogen activated protein kinase-dependent inhibition of osteocalcin gene expression by transforming growth factor-β1

Sukyee Kwok, Nicola C. Partridge, Narasaimhan Srinivasan, Shantikumar V. Nair, Nagarajan Selvamurugan

Research output: Contribution to journalArticle

Abstract

TGF-β (transforming growth factor-beta) plays a key role in osteoblast differentiation and bone development. While the ability of TGF-β to inhibit the expression of osteoblast differentiation genes has been well documented, the mechanism of this inhibition is not yet completely characterized. Runx2, a transcription factor necessary for expression of osteoblast differentiation genes is a central target of inhibition by TGF-β. In this study, we found that TGF-β1 inhibits expression of osteoblast differentiation genes without altering expression of Runx2. Transient transfection experiments determined that TGF-β1 inhibited osteocalcin promoter activity and this effect is mediated through Runx2. We further identified that there was no change in protein expression, cellular localization, or DNA binding affinity of Runx2 after TGF-β1-treatment of osteoblasts, suggesting that Runx2 undergoes post-translational modifications following TGF-β1 treatment. Coimmunoprecipitation experiments identified increased phosphorylation of Runx2 when differentiating osteoblasts were treated with TGF-β1. Mitogen activated protein kinase (MAPK) inhibitors relieved the TGF-β1-inhibitory effect of Runx2-mediated osteocalcin expression. Thus, our results suggest that TGF-β1-inhibition of osteoblast differentiation is dependent on the MAPK pathway and this effect is most likely mediated by post-translational modification of Runx2 such as phosphorylation rather than other regulatory mechanisms. J. Cell. Biochem. 106: 161-169, 2009. copy; 2008 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)161-169
Number of pages9
JournalJournal of Cellular Biochemistry
Volume106
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Osteoblast
  • Osteocalcin
  • Runx2
  • Tgf-β

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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