HDAC9 Inhibits Osteoclastogenesis via Mutual Suppression of PPARγ/RANKL Signaling.
Mol Endocrinol
; 29(5): 730-8, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25793404
ABSTRACT
Recent studies suggest that the class II histone deacetylase (HDAC)9 plays important roles in physiology such as metabolism and immunity. Here, we report that HDAC9 also controls bone turnover by suppressing osteoclast differentiation and bone resorption. HDAC9 expression is down-regulated during osteoclastogenesis. Ex vivo osteoclast differentiation is accelerated by HDAC9 deletion but diminished by HDAC9 overexpression. HDAC9 knockout mice exhibit elevated bone resorption and lower bone mass. Bone marrow transplantation reveal that the osteoclastogenic defects are intrinsic to the hematopoietic lineage, because the excessive bone resorption phenotype can be conferred in wild-type (WT) mice receiving HDAC9-null bone marrow, and rescued in HDAC9-null mice receiving WT bone marrow. Mechanistically, HDAC9 forms a negative regulatory loop with peroxisome proliferator-activated receptor gamma (PPARg) and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. On one hand, PPARγ and nuclear factor κB suppress HDAC9 expression, on the other hand, HDAC9 inhibits PPARγ activity in synergy with silencing mediator of retinoic acid and thyroid hormone receptors (SMRT)/NCoR corepressors. These findings identify HDAC9 as a novel, important and physiologically relevant modulator of bone remodeling and skeletal homeostasis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoclastos
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Proteínas Repressoras
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PPAR gama
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Ligante RANK
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Histona Desacetilases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Endocrinol
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENDOCRINOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article