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.

Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the autosomal recessive disorder sitosterolemia. Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxysterol receptors liver X receptor (LXR) ␣ and LXR␤. Diets containing high cholesterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine. This increase was also observed using synthetic ligands of LXR and its heterodimeric partner, the retinoid X receptor. In situ hybridization analyses of tissues from LXR agonisttreated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation. In addition, expression of the LXR target gene ABCA1, previously implicated in the control of cholesterol absorption, was also dramatically up-regulated in jejunal enterocytes upon exposure to LXR agonists. These changes in ABC transporter gene expression were not observed in mice lacking LXRs. Furthermore, in the rat hepatoma cell line FTO2B, LXRdependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by LXRs. The addition of ABCG5 and ABCG8 to the growing list of LXR target genes further supports the notion that LXRs serve as sterol sensors to coordinately regulate sterol catabolism, storage, efflux, and elimination.Cholesterol homeostasis is maintained by a series of regulatory pathways to control the synthesis of endogenous cholesterol, the absorption of dietary sterol, and the elimination of cholesterol and its catabolic end products, bile acids. Transcriptional control of many genes vital to these processes can be attributed to two families of transcription factors: the sterolregulatory element-binding proteins (SREBPs), 1 especially SREBP-2, which control the production of key enzymes in cholesterol biosynthesis (for review, see Ref. 1), and the liver X receptors LXR␣ and LXR␤, which regulate the expression of genes involved in cholesterol efflux, storage, catabolism, and elimination (for review, see Ref.2). LXRs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. LXRs are bound and activated by a specific class of naturally occurring oxysterols (3-5) as well as a recently described nonsteroidal synthetic agonist, T0901317 (6, 7). LXRs bind DNA as obligate heterodimers with the retinoid X receptors (RXRs) and can be activated by either LXR agonists or RXR ligands. The RXR/LXR heterodimer binds to a DNA sequence comprised of two direct repeats of the hexanucleotide motif AGGTCA separated by four bases, referred to as an LXR response element of the DR4 type (8). Upon binding ligand, LXR undergoes a conformational change that recruits coactivator proteins and enhances transcription of the target gene. Increasing evidence suggests that the RXR/LXR heterodimer serves as a sensor that responds to high intracellular sterol concentrations by increasing the expression of genes that reduce the cellular stero...