Histone deacetylase 3 suppresses Erk phosphorylation and matrix metalloproteinase (Mmp)-13 activity in chondrocytes

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Abstract

Histone deacetylase (Hdac3) inhibitors are emerging therapies for many diseases including cancers and neurological disorders; however, these drugs are teratogens to the developing skeleton. Hdac3 is essential for proper endochondral ossification as its deletion in chondrocytes increases cytokine signaling and the expression of matrix remodeling enzymes. Here we explored the mechanism by which Hdac3 controls matrix metalloproteinase (Mmp)-13 expression in chondrocytes. In Hdac3-depleted chondrocytes, extracellular signal-regulated kinase (Erk)1/2 as well as its downstream substrate, Runx2, were hyperphosphorylated as a result of decreased expression and activity of the Erk1/2 specific phosphatase, Dusp6. Erk1/2 kinase inhibitors and Dusp6 adenoviruses reduced Mmp13 expression and partially rescued matrix production in Hdac3-deficient chondrocytes. Postnatal chondrocyte-specific deletion of Hdac3 with an inducible Col2a1-Cre caused premature production of pErk1/2 and Mmp13 in the growth plate. Thus, Hdac3 controls the temporal and spatial expression of tissue-remodeling genes in chondrocytes to ensure proper endochondral ossification during development.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalConnective Tissue Research
DOIs
StateAccepted/In press - Nov 5 2016

Fingerprint

Matrix Metalloproteinase 13
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Chondrocytes
Teratogens
Histone Deacetylases
Mitogen-Activated Protein Kinase 3
Phosphoric Monoester Hydrolases
Phosphotransferases
Genes
Tissue
Cytokines
Osteogenesis
Substrates
Enzymes
Pharmaceutical Preparations
Histone Deacetylase Inhibitors
Growth Plate
Mitogen-Activated Protein Kinase 1
Nervous System Diseases

Keywords

  • Cartilage
  • Dusp6
  • Erk1/2
  • Hdac3
  • MAPK
  • Runx2

ASJC Scopus subject areas

  • Rheumatology
  • Biochemistry
  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "Histone deacetylase (Hdac3) inhibitors are emerging therapies for many diseases including cancers and neurological disorders; however, these drugs are teratogens to the developing skeleton. Hdac3 is essential for proper endochondral ossification as its deletion in chondrocytes increases cytokine signaling and the expression of matrix remodeling enzymes. Here we explored the mechanism by which Hdac3 controls matrix metalloproteinase (Mmp)-13 expression in chondrocytes. In Hdac3-depleted chondrocytes, extracellular signal-regulated kinase (Erk)1/2 as well as its downstream substrate, Runx2, were hyperphosphorylated as a result of decreased expression and activity of the Erk1/2 specific phosphatase, Dusp6. Erk1/2 kinase inhibitors and Dusp6 adenoviruses reduced Mmp13 expression and partially rescued matrix production in Hdac3-deficient chondrocytes. Postnatal chondrocyte-specific deletion of Hdac3 with an inducible Col2a1-Cre caused premature production of pErk1/2 and Mmp13 in the growth plate. Thus, Hdac3 controls the temporal and spatial expression of tissue-remodeling genes in chondrocytes to ensure proper endochondral ossification during development.",
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