Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis

Rick B. Vega, Koichi Matsuda, Junyoung Oh, Ana C. Barbosa, Xiangli Yang, Eric Meadows, John McAnally, Chris Pomajzl, John M. Shelton, James A. Richardson, Gerard Karsenty, Eric N. Olson

Research output: Contribution to journalArticle

573 Scopus citations

Abstract

Histone deacetylases (HDACs) modulate cell growth and differentiation by governing chromatin structure and repressing the activity of specific transcription factors. We showed previously that HDAC9 acts as a negative regulator of cardiomyocyte hypertrophy and skeletal muscle differentiation. Here we report that HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2, a transcription factor necessary for chondrocyte hypertrophy. HDAC4-null mice display premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, mimicking the phenotype that results from constitutive Runx2 expression in chondrocytes. Conversely, overexpression of HDAC4 in proliferating chondrocytes in vivo inhibits chondrocyte hypertrophy and differentiation, mimicking a Runx2 loss-of-function phenotype. These results establish HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis and suggest general roles for class II HDACs in the control of cellular hypertrophy.

Original languageEnglish (US)
Pages (from-to)555-566
Number of pages12
JournalCell
Volume119
Issue number4
DOIs
StatePublished - Nov 12 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., Karsenty, G., & Olson, E. N. (2004). Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell, 119(4), 555-566. https://doi.org/10.1016/j.cell.2004.10.024