HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression

Emi Shimizu, Nagarajan Selvamurugan, Jennifer J. Westendorf, Eric N. Olson, Nicola Partridge

Research output: Contribution to journalArticle

Abstract

Parathyroid hormone (PTH) is a hormone regulating bone remodeling through its actions on both bone formation and bone resorption. Previously we reported that PTH induces matrix metalloproteinase-13 (MMP-13) transcription in osteoblastic cells. Here, we show that histone deacetylase 4 (HDAC4) interacts with Runx2, binds the MMP-13 promoter, and suppresses MMP-13 gene transcription in the rat osteoblastic cell line, UMR 106-01. PTH induces the rapid cAMP-dependent protein kinase-dependent release of HDAC4 from the MMP-13 promoter and subsequent transcription of MMP-13. Knock-out of HDAC4 either by siRNA in vitro or by gene deletion in vivo leads to an increase in MMP-13 expression, and overexpression of HDAC4 decreases the PTH induction of MMP-13. All of these observations indicate that HDAC4 represses MMP-13 gene transcription in bone. Moreover, PTH stimulates HDAC4 gene expression and enzymatic activity at times corresponding to the reassociation of HDAC4 with the MMP-13 promoter and a decline in its transcription. Thus, HDAC4 is a basal repressor of MMP-13 transcription, and PTH regulates HDAC4 to control MMP-13 promoter activity. These data identify a novel and discrete mechanism of regulating HDAC4 levels and, subsequently, gene expression.

Original languageEnglish (US)
Pages (from-to)9616-9626
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number13
DOIs
StatePublished - Mar 26 2010

Fingerprint

Matrix Metalloproteinase 13
Histone Deacetylases
Transcription
Parathyroid Hormone
Bone
Genes
Gene expression
Gene Expression
Bone and Bones
Bone Remodeling
Gene Deletion
Bone Resorption
Cyclic AMP-Dependent Protein Kinases
Osteogenesis
Small Interfering RNA
Rats

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression. / Shimizu, Emi; Selvamurugan, Nagarajan; Westendorf, Jennifer J.; Olson, Eric N.; Partridge, Nicola.

In: Journal of Biological Chemistry, Vol. 285, No. 13, 26.03.2010, p. 9616-9626.

Research output: Contribution to journalArticle

Shimizu, Emi ; Selvamurugan, Nagarajan ; Westendorf, Jennifer J. ; Olson, Eric N. ; Partridge, Nicola. / HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 13. pp. 9616-9626.
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