Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice
Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice
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Sirt1 通过 Bmi1 激活促进小鼠成骨分化并增加牙槽骨量
DOI：
10.1002/jbmr.3677
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Sun, Wen
中科院分区：
文献类型：
--
作者：
Wang, Hua;Hu, Zixuan;Sun, Wen
Sirtuin 1（Sirt 1）是一种蛋白质脱乙酰酶，是骨代谢的新靶点。为了研究Sirt 1在下颌骨间充质干细胞（M-MSCs）中的过表达是否增加了体内牙槽骨质量，我们产生了Sirt 1转基因小鼠（Sirt 1（TG）），其中Sirt 1基因表达由代表间充质谱系的Prx 1基因驱动。我们的研究结果表明，M-MSC中Sirt 1的过表达增加了1个月大，9个月大，和18个月大的Sirt 1（TG）小鼠与年龄匹配的野生型（WT）小鼠相比，和卵巢切除Sirt 1（TG）小鼠与卵巢切除WT小鼠相比，通过刺激M-MSC分化为成骨细胞的牙槽骨体积。白藜芦醇，一种Sirt 1激活剂，治疗增加Sirt 1与Bmi 1的结合，并以剂量依赖性的方式减少Bmi 1乙酰化在M-MSC培养中证明。在M-MSC培养物中用白藜芦醇处理和在M-MSC离体培养物中过表达Sirt 1都增加了Bmi 1的核转位。此外，我们证明了Bmi 1的缺失阻断了Sirt 1（TG）小鼠牙槽骨体积的增加。Sirt 1激活剂白藜芦醇抑制人MSC衰老并促进其向成骨细胞分化，这与上调Sirt 1的表达水平和Bmi 1的核转位有关。Sirt 1通过促进Bmi 1的去乙酰化和核转位，促进MSC增殖和成骨分化，抑制MSC衰老，增加牙槽骨体积。因此，我们的研究阐明了Sirt 1增加牙槽骨质量的机制，这些发现对于Sirt 1激活剂白藜芦醇促进牙槽骨形成和预防牙槽骨丢失的临床应用具有重要意义。(c)2019年美国骨与矿物质研究学会。
Sirtuin 1 (Sirt1), a protein deacetylase, is a novel target for bone metabolism. To investigate whether overexpression of Sirt1 in mandibular mesenchymal stem cells (M-MSCs) increased alveolar bone mass in vivo, we generated Sirt1 transgenic mice (Sirt1(TG)), with Sirt1 gene expression driven by the Prx1 gene, which represents the mesenchymal lineage. Our results demonstrated that overexpression of Sirt1 in M-MSCs increased the alveolar bone volume in 1-month-old, 9-month-old, and 18-month-old Sirt1(TG) mice compared with age-matched wild-type (WT) mice, and in ovariectomized Sirt1(TG) mice compared with ovariectomized WT mice by stimulating M-MSC differentiation into osteoblasts. Treatment with resveratrol, a Sirt1 activator, increased Sirt1 binding with Bmi1 and reduced Bmi1 acetylation in a dose-dependent manner demonstrated in M-MSC cultures. Both treatment with resveratrol in M-MSC cultures and overexpressed Sirt1 in M-MSCs ex vivo cultures increased nuclear translocation of Bmi1. Furthermore, we demonstrated that deletion of Bmi1 blocked the increased alveolar bone volume in Sirt1(TG) mice. The Sirt1 activator resveratrol inhibited human MSC senescence and promoted their differentiation into osteoblasts, which were associated with upregulating the expression levels of Sirt1 and nuclear translocation of Bmi1. The present results suggested that Sirt1 promotes MSC proliferation and osteogenic differentiation, inhibits MSC senescence to increase alveolar bone volume by promoting the deacetylation and nuclear translocation of Bmi1. Thus, our study elucidated the mechanism by which Sirt1 increases alveolar bone mass, and these findings are important for the clinical application of the Sirt1 activator resveratrol for the promotion of alveolar bone formation and prevention of alveolar bone loss. (c) 2019 American Society for Bone and Mineral Research.