Sirt1 Is a Regulator of Bone Mass and a Repressor of Sost Encoding for Sclerostin, a Bone Formation Inhibitor
Sirt1 Is a Regulator of Bone Mass and a Repressor of Sost Encoding for Sclerostin, a Bone Formation Inhibitor
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DOI：
10.1210/en.2011-1128
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发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Dresner-Pollak, Rivka
中科院分区：
文献类型：
--
作者：
Cohen-Kfir, Einav;Artsi, Hanna;Dresner-Pollak, Rivka
Sirt1是酵母Sir2（沉默信息调节因子2）的哺乳动物同源基因，已被证明在代谢和年龄相关疾病中发挥重要作用，但其在骨骼稳态和骨质疏松症中的作用尚未被研究。研究人员使用Sirt1基因发生种系突变的129/Sv小鼠，发现Sirt1单倍体不足（Sirt1(+/-)）雌性小鼠表现出显著的骨量减少，其特征是骨形成减少和骨髓脂肪生成增加。重要的是，我们发现Sost编码硬化蛋白（一种骨形成的关键抑制剂）作为Sirt1的新靶点。通过染色质免疫沉淀分析，我们发现Sirt1通过在Sost启动子赖氨酸9处去乙酰化组蛋白3直接负向调节Sost基因的表达。在诱导成骨的Sirt1（+/-）骨髓间充质干细胞中，通过小干扰RNA下调Sost和给药硬化蛋白中和抗体可恢复骨钙素和骨唾液蛋白的基因表达以及矿化结节的形成。这些发现揭示了Sirt1在骨中作为骨量的调节因子和硬化蛋白的抑制因子的新作用，并有潜在的意义表明Sirt1是促进骨形成的靶点，作为治疗骨质疏松症的合成代谢方法。（内分泌学152:4514-4524,2011）
Sirt1, the mammalian ortholog of the yeast Sir2 (silent information regulator 2), was shown to play an important role in metabolism and in age-associated diseases, but its role in skeletal homeostasis and osteoporosis has yet not been studied. Using 129/Sv mice with a germline mutation in the Sirt1 gene, we demonstrate that Sirt1 haplo-insufficient (Sirt1(+/-)) female mice exhibit a significant reduction in bone mass characterized by decreased bone formation and increased marrow adipogenesis. Importantly, we identify Sost, encoding for sclerostin, a critical inhibitor of bone formation, as a novel target of Sirt1. Using chromatin immunoprecipitation analysis, we reveal that Sirt1 directly and negatively regulates Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter. Sost down-regulation by small interfering RNA and the administration of a sclerostin-neutralizing antibody restore gene expression of osteocalcin and bone sialoprotein as well as mineralized nodule formation in Sirt1(+/-) marrow-derived mesenchymal stem cells induced to osteogenesis. These findings reveal a novel role for Sirt1 in bone as a regulator of bone mass and a repressor of sclerostin, and have potential implications suggesting that Sirt1 is a target for promoting bone formation as an anabolic approach for treatment of osteoporosis. (Endocrinology 152: 4514-4524, 2011)