SIRT6 deficiency culminates in low-turnover osteopenia.
SIRT6 deficiency culminates in low-turnover osteopenia.
复制标题
DOI：
10.1016/j.bone.2015.07.018
复制
发表时间：
2015-12
期刊：
影响因子：
4.1
通讯作者：
Hruska KA
中科院分区：
文献类型：
--
作者：
Sugatani T;Agapova O;Malluche HH;Hruska KA
SIRT6（一种染色质相关的去乙酰化酶）在小鼠中缺乏会显示严重的早衰表型，包括骨质减少。然而，SIRT6在骨代谢中的潜在分子机制尚不清楚。在这里，我们表明SIRT6缺乏小鼠产生低周换率骨质减少，由骨形成和骨吸收受损引起，其机制类似于与年龄相关的骨质流失。在机制上，SIRT6与runt相关转录因子2 （Runx2）和osterix （Osx）相互作用，这是成骨细胞发生的两个关键转录调节因子，并使组蛋白H3在其启动子上的赖氨酸9 （H3K9）去乙酰化。因此，SIRT6−/−成骨细胞中Runx2和Osx的过度升高导致成骨细胞生成受损。此外，SIRT6缺乏会导致dickkopf相关蛋白1 （Dkk1）启动子H3K9的超乙酰化，Dkk1是成骨细胞形成的有效负调节因子，而骨保护素是破骨细胞形成的抑制剂。因此，由此导致的Dkk1和骨保护素水平上调有助于骨重塑受损，导致sirt6缺陷小鼠骨减少和低骨转换。这些结果在SIRT6与骨重塑之间建立了新的联系，SIRT6积极调节成骨细胞发生和破骨细胞发生。
Deficiency of Sirtuin 6 (SIRT6), a chromatin-related deacetylase, in mice reveals severe premature aging phenotypes including osteopenia. However, the underlying molecular mechanisms of SIRT6 in bone metabolism are unknown. Here we show that SIRT6 deficiency in mice produces low-turnover osteopenia caused by impaired bone formation and bone resorption, which are mechanisms similar to those of age-related bone loss. Mechanistically, SIRT6 interacts with runt-related transcription factor 2 (Runx2) and osterix (Osx), which are the two key transcriptional regulators of osteoblastogenesis, and deacetylates histone H3 at Lysine 9 (H3K9) at their promoters. Hence, excessively elevated Runx2 and Osx in SIRT6−/− osteoblasts lead to impaired osteoblastogenesis. In addition, SIRT6 deficiency produces hyperacetylation of H3K9 in the promoter of dickkopf-related protein 1 (Dkk1), a potent negative regulator of osteoblastogenesis, and osteoprotegerin, an inhibitor of osteoclastogenesis. Therefore, the resulting up-regulation of Dkk1 and osteoprotegerin levels contribute to impaired bone remodeling, leading to osteopenia with a low bone turnover in SIRT6-deficient mice. These results establish a new link between SIRT6 and bone remodeling that positively regulates osteoblastogenesis and osteoclastogenesis.