Sirt6 cooperates with Blimp1 to positively regulate osteoclast differentiation.
Sirt6 cooperates with Blimp1 to positively regulate osteoclast differentiation.
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DOI：
10.1038/srep26186
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发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Lee SY
中科院分区：
文献类型：
--
作者：
Park SJ;Huh JE;Shin J;Park DR;Ko R;Jin GR;Seo DH;Kim HS;Shin HI;Oh GT;Kim HS;Lee SY
小鼠中编码核组蛋白去乙酰化酶sirtuin 6（Sirt 6）的基因的全局缺失导致骨质减少，由于骨形成受损而具有低骨转换。但Sirt 6是否调节破骨细胞分化尚不清楚。在这里，我们表明，Sirt 6的功能作为一个转录调节直接抑制抗破骨细胞基因的表达。造血细胞（包括破骨细胞前体）中Sirt 6的靶向消融导致破骨细胞数量减少引起的骨体积增加。Sirt 6的过表达导致破骨细胞形成增加，而Sirt 6缺陷的破骨细胞前体细胞不能有效地进行破骨细胞分化。此外，我们发现，Sirt 6，诱导RANKL依赖性NFATc 1的表达，形成一个复合物与B淋巴细胞诱导的成熟蛋白-1（Blimp 1）负调控抗破骨细胞基因的表达，如Maf B。这些发现确定Sirt 6作为一种新的破骨细胞生成的调节因子，作为一个转录抑制剂。
Global deletion of the gene encoding a nuclear histone deacetylase sirtuin 6 (Sirt6) in mice leads to osteopenia with a low bone turnover due to impaired bone formation. But whether Sirt6 regulates osteoclast differentiation is less clear. Here we show that Sirt6 functions as a transcriptional regulator to directly repress anti-osteoclastogenic gene expression. Targeted ablation of Sirt6 in hematopoietic cells including osteoclast precursors resulted in increased bone volume caused by a decreased number of osteoclasts. Overexpression of Sirt6 led to an increase in osteoclast formation, and Sirt6-deficient osteoclast precursor cells did not undergo osteoclast differentiation efficiently. Moreover, we showed that Sirt6, induced by RANKL-dependent NFATc1 expression, forms a complex with B lymphocyte-induced maturation protein-1 (Blimp1) to negatively regulate expression of anti-osteoclastogenic gene such as Mafb. These findings identify Sirt6 as a novel regulator of osteoclastogenesis by acting as a transcriptional repressor.