Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis

Mol Endocrinol. 2012 May;26(5):798-808. doi: 10.1210/me.2011-1287. Epub 2012 Mar 15.

Abstract

Runx2, a runt-related transcriptional factor family member, is involved in the regulation of osteoblast differentiation. Interestingly, it is abundant in growth-arrested 3T3-L1 preadipocytes and was dramatically down-regulated during adipocyte differentiation. Knockdown of Runx2 expression promoted 3T3-L1 adipocyte differentiation, whereas overexpression inhibited adipocyte differentiation and promoted the trans-differentiation of 3T3-L1 preadipocytes to bone cells. Runx2 was down-regulated specifically by dexamethasone (DEX). Only type I Runx2 was expressed in 3T3-L1 preadipocytes. Using luciferase assay and chromatin immunoprecipitation-quantitative PCR analysis, it was found that DEX repressed this type of Runx2 at the transcriptional level through direct binding of the glucocorticoid receptor (GR) to a GR-binding element in the Runx2 P2 promoter. Further studies indicated that GR recruited histone deacetylase 1 to the Runx2 P2 promoter which then mediated the deacetylation of histone H4 and down-regulated Runx2 expression. Runx2 might play its repressive role through the induction of p27 expression, which blocked 3T3-L1 adipocyte differentiation by inhibiting mitotic clonal expansion. Taken together, we identified Runx2 as a new downstream target of DEX and explored a new pathway between DEX, Runx2, and p27 which contributed to the mechanism of the 3T3-L1 adipocyte differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects*
  • Adipogenesis / drug effects*
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Transdifferentiation / drug effects
  • Core Binding Factor Alpha 1 Subunit / antagonists & inhibitors
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Dexamethasone / pharmacology*
  • Down-Regulation / drug effects*
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Mice
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Promoter Regions, Genetic / drug effects
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Response Elements / drug effects
  • Up-Regulation / drug effects

Substances

  • Anti-Inflammatory Agents
  • Cdkn1b protein, mouse
  • Core Binding Factor Alpha 1 Subunit
  • Protein Isoforms
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Recombinant Proteins
  • Runx2 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p27
  • Dexamethasone
  • Hdac1 protein, mouse
  • Histone Deacetylase 1