Histone deacetylase 3 interacts with Runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation

Tania M. Schroeder, Rachel A. Kahler, Xiaodong Li, Jennifer J Westendorf

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

The Runt domain transcription factor Runx2 (AML-3, and Cbfa1) is essential for osteoblast development, differentiation, and bone formation. Runx2 positively or negatively regulates osteoblast gene expression by interacting with a variety of transcription cofactor complexes. In this study, we identified a trichostatin A-sensitive autonomous repression domain in the amino terminus of Runx2. Using a candidate approach, we found that histone deacetylase (HDAC) 3 interacts with the amino terminus of Runx2. In transient transfection assays, HDAC3 repressed Runx2-mediated activation of the osteocalcin promoter. HDAC inhibitors and HDAC3-specific short hairpin RNAs reversed this repression. In vivo, Runx2 and HDAC3 associated with the osteocalcin promoter. These data indicate that HDAC3 regulates Runx2-mediated transcription of osteoblast genes. Suppression of HDAC3 in HC3T3 preosteoblasts by RNA interference accelerated the expression of Runx2 target genes, osteocalcin, osteopontin, and bone sialoprotein but did not significantly alter Runx2 levels. Matrix mineralization also occurred earlier in HDAC3-suppressed cells, but alkaline phosphatase expression was not affected. Thus, HDAC3 regulates osteoblast differentiation and bone formation. Although HDAC3 is likely to affect the activity of multiple proteins in osteoblasts, our data show that it actively regulates the transcriptional activity of the osteoblast master protein, Runx2.

Original languageEnglish (US)
Pages (from-to)41998-42007
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number40
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

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Osteocalcin
Osteoblasts
Transcription
Osteogenesis
Core Binding Factor Alpha 1 Subunit
Core Binding Factor alpha Subunits
trichostatin A
Bone
Genes
Integrin-Binding Sialoprotein
Osteopontin
Histone Deacetylase Inhibitors
RNA Interference
Gene expression
Small Interfering RNA
Transfection
Alkaline Phosphatase
histone deacetylase 3
Assays
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Histone deacetylase 3 interacts with Runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. / Schroeder, Tania M.; Kahler, Rachel A.; Li, Xiaodong; Westendorf, Jennifer J.

In: Journal of Biological Chemistry, Vol. 279, No. 40, 01.10.2004, p. 41998-42007.

Research output: Contribution to journalArticle

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