Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition
Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition
复制标题
Sirt1 在间充质干细胞中的过度表达通过 FOXO3a 脱乙酰化和氧化应激抑制来防止小鼠骨质流失
DOI：
10.1016/j.metabol.2018.06.006
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发表时间：
2018-11-01
影响因子：
9.8
通讯作者：
Miao, Dengshun
中科院分区：
文献类型：
--
作者：
Sun, Wen;Qiao, Wanxin;Miao, Dengshun
目的：B细胞特异性Moloney鼠白血病病毒整合位点1（Bmi-1）缺陷（Bmi-1（-/-））导致Sirt 1蛋白表达显著下调的细胞表型。Sirtuin 1（Sirt 1）单倍不足通过减少骨形成导致骨丢失;然而，尚不清楚Sirt 1在间充质干细胞（MSC）中的过表达是否起抗骨质疏松作用。该研究的目的是确定在MSC中Sirt 1的过表达是否可以恢复Bmi-1缺陷小鼠的骨骼生长迟缓和骨质疏松症。我们使用我们新产生的转基因小鼠模型，在其MSC中过表达Sirt 1，（Sirt 1（TG））与Bmi-1（-/-）小鼠杂交以产生在MSC中Sirt 1过表达的Bmi-1（-/-）小鼠，并将它们的骨骼代谢与它们的Bmi-1（-/-）和野生型（WT）同窝仔的骨骼代谢进行比较使用成像、组织病理学、免疫组织化学、组织形态计量学、细胞和分子方法，对4周龄时的小鼠（每个基因型6只小鼠）进行检测。Sift]的表达水平在Sirt 1（TG）小鼠的骨骼组织中明显高于WT小鼠。与野生型小鼠相比，Sirt 1（TG）小鼠的体重和体型、骨骼大小、骨体积、成骨细胞数量、碱性磷酸酶和I型胶原阳性面积、成骨相关基因表达水平均显著增加。Sirt 1在Bmi-1（-/-）小鼠间充质干细胞中的过表达通过刺激Bmi-1（-/-）小鼠成骨细胞骨形成和抑制骨细胞骨吸收而导致更长的寿命，改善骨骼生长和显著增加骨量，尽管缺陷没有完全恢复。此外，Sirt 1在MSC中的过表达降低了FOXO 3a（Forkhead box O3 a）的乙酰化水平，增加了骨组织中FOXO 3a和SOD 2（超氧化物歧化酶2）的表达水平，增强了骨生成并减少了成骨细胞衰老。我们还表明，烟酰胺，Sirt 1抑制剂，阻断Sirt 1在骨髓间充质干细胞的过度表达对成骨和成骨细胞senescence.Conclusions的影响：两者合计，这些结果表明，Sirt 1在骨髓间充质干细胞过度表达增加成骨细胞骨形成和部分恢复骨生长和骨生成的缺陷Bmi-1（-/-）小鼠通过FOXO 3a脱乙酰化和氧化应激抑制。我们的数据支持Sirt 1作为治疗骨质疏松症的合成代谢方法是促进骨形成的靶点的提议。(C)2018由Elsevier Inc.出版
Objective: B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) deficiency (Bmi-1(-/-)) leads to an osteoporotic phenotype with a significant downregulation of Sirt1 protein expression. Sirtuin 1 (Sirt1) haploinsufficiency results in a bone loss by decreased bone formation; however, it is unclear whether Sirt1 over expression in mesenchymal stem cells (MSCs) plays an anti-osteoporotic role. The aim of the study is to identify whether the overexpression of Sirt1 in MSCs could restore skeletal growth retardation and osteoporosis in Bmi-1 deficient mice.Methods: We used our new generated transgenic mouse model that overexpresses Sirt1 in its MSCs (Sirt1(TG)) to cross with Bmi-1(-/-) mice to generate Bmi-1(-/-) mice with Sirt1 overexpression in MSCs, and compared their skeletal metabolism with those of their Bmi-1(-/-) and wild-type (WT) littermates (6 mice for each genotype) at 4 weeks of age using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods.Results: The levels of expression for Sift] were noticeably higher in the skeletal tissue of Sirt1(TG) mice than in those of WT mice. In Comparison to WT mice, the body weight and size, skeletal size, bone volume, osteoblast number, alkaline phosphatase and type I collagen positive areas, osteogenic related gene expression levels were all significantly increased in the Sirt1(TG) mice. Overexpression of Sirt1 in Bmi-1(-/-) mouse MSCs resulted in a longer lifespan, improved skeletal growth and significantly increased bone mass by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in the Bmi-1(-/-) mice, although the defects were not completely restored. Furthermore, Sirt1 overexpression in MSCs reduced the acetylation level of FOXO3a (Forkhead box O3a), increasing levels of expression for FOXO3a and SOD2 (Superoxide dismutase 2) in bony tissue, enhanced osteogenesis and reduced osteogenic cell senescence. We also demonstrated that nicotinamide, a Sirt1 inhibitor, blocks the effect of overexpression of Sirt1 in MSCs on osteogenesis and osteogenic cell senescence.Conclusions: Taken together, these results demonstrate that Sirt1 overexpression in MSCs increased the osteoblastic bone formation and partially restores the defects in skeletal growth and osteogenesis in Bmi-1(-/-) mice by FOXO3a deacetylation and oxidative stress inhibition. Our data support the proposal that Sirt1 is a target for promoting bone formation as an anabolic approach for the treatment of osteoporosis. (C) 2018 Published by Elsevier Inc.