Jin Zixue, Wei Wei, Huynh HoangDinh, Wan Yihong
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Mol Endocrinol. 2015 May;29(5):730-8. doi: 10.1210/me.2014-1365. Epub 2015 Mar 20.
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.
最近的研究表明，II类组蛋白去乙酰化酶（HDAC）9在新陈代谢和免疫等生理过程中发挥着重要作用。在此，我们报告HDAC9还通过抑制破骨细胞分化和骨吸收来控制骨转换。在破骨细胞生成过程中，HDAC9的表达下调。体外破骨细胞分化在HDAC9缺失时加速，但在HDAC9过表达时减弱。HDAC9基因敲除小鼠表现出骨吸收增加和骨量降低。骨髓移植显示，破骨细胞生成缺陷是造血谱系固有的，因为在接受HDAC9基因缺失骨髓的野生型（WT）小鼠中可出现过度骨吸收表型，而在接受WT骨髓的HDAC9基因缺失小鼠中该表型可得到挽救。机制上，HDAC9与过氧化物酶体增殖物激活受体γ（PPARγ）和核因子κB受体激活剂配体（RANKL）信号形成负调控环。一方面，PPARγ和核因子κB抑制HDAC9的表达，另一方面，HDAC9与视黄酸和甲状腺激素受体沉默介质（SMRT）/核受体辅阻遏蛋白协同抑制PPARγ活性。这些发现确定HDAC9是骨重塑和骨骼稳态中一种新的、重要的且与生理相关的调节因子。
