PDF(Pubmed)
Abstract：
The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.
摘要：
沉默信息调节因子T1（SIRT1）与寿命有关，并且是成骨细胞功能的关键介体。我们使用他莫昔芬诱导的成骨细胞特异性Sirt1条件敲除（cKO）小鼠研究了Sirt1在体内骨建模和重塑阶段的直接作用。cKO小鼠在股骨远端表现出较低的小梁和皮质骨量。这些表型与较低的骨形成和骨吸收相关。代谢组学分析显示，cKO小鼠中参与糖酵解的代谢物显着减少。对定量乙酰基组的进一步分析显示，cKO小鼠的股骨和颅骨中11种蛋白质的乙酰化水平上调。交叉分析确定了cKO小鼠股骨和颅骨中具有相同上调赖氨酸乙酰化位点的四种蛋白质。代谢组和乙酰基组的联合分析，以及免疫沉淀，基因敲除,和位点突变实验，显示Sirt1缺失通过直接结合并增加谷氨酰胺草酰乙酸转氨酶1（GOT1）的乙酰化水平来抑制糖酵解。总之,我们的研究表明，Sirt1通过其对GOT1的去乙酰化酶活性，在调节成骨细胞代谢以维持骨稳态中起着至关重要的作用。这些发现为成骨细胞代谢的潜在靶向治疗骨相关疾病提供了新的见解。
