Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.
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.
Vega
Rick B
RB
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Matsuda
Koichi
K
Oh
Junyoung
J
Barbosa
Ana C
AC
Yang
Xiangli
X
Meadows
Eric
E
McAnally
John
J
Pomajzl
Chris
C
Shelton
John M
JM
Richardson
James A
JA
Karsenty
Gerard
G
Olson
Eric N
EN
D000818:Animals; D002454:Cell Differentiation; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology*; D050659:Core Binding Factor Alpha 1 Subunit; D006655:Histone Deacetylases / Q000502:physiology*; D006984:Hypertrophy / Q000201:enzymology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009999:Ossification, Heterotopic / Q000473:pathology; D010012:Osteogenesis; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D050659:Core Binding Factor Alpha 1 Subunit; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C400300:HDAC4 protein, human; D006655:Histone Deacetylases