TY - JOUR
T1 - HDAC9 inhibits osteoclastogenesis via mutual suppression of PPARγ/RANKL signaling
AU - Jin, Zixue
AU - Wei, Wei
AU - Huynh, HoangDinh
AU - Wan, Yihong
N1 - Publisher Copyright:
© 2015 by the Endocrine Society.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1210/me.2014-1365
DO - 10.1210/me.2014-1365
M3 - Article
C2 - 25793404
AN - SCOPUS:84930514795
SN - 0888-8809
VL - 29
SP - 730
EP - 738
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 5
ER -