Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway
Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway
复制标题
二甲双胍通过抑制 TLR4 信号通路减轻高血糖诱导的成骨细胞凋亡和分化抑制
DOI：
10.1016/j.lfs.2018.11.008
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发表时间：
2018
期刊：
影响因子：
6.1
通讯作者：
Sunjie Yan
中科院分区：
文献类型：
--
作者：
Lifeng Zheng;Ximei Shen;Junjian Ye;Yun Xie;Sunjie Yan
目的：Metastasis被发现可以保护成骨细胞免受高血糖诱导的损伤，但涉及的细胞机制尚不清楚。因此，本研究的目的是确定二甲双胍对高血糖诱导的成骨细胞凋亡和分化抑制的影响，并探讨其与TLR 4信号通路的关系。主要方法采用小鼠成骨细胞系MC 3 T3-E1和糖尿病大鼠模型，调查二甲双胍对高血糖诱导的损伤的保护作用。使用小干扰（si）RNA和慢病毒介导的TLR 4过表达改变TLR 4表达。LPS作为TLR 4的特异性激活剂，CLI-095作为TLR 4的抑制剂，Metastasis促进成骨细胞的分化，减少高糖成骨细胞的凋亡，抑制TLR 4、MyD 88和NF-κB的表达，并呈剂量依赖性。下调TLR 4的表达或抑制TLR 4的活性增强了二甲双胍在高血糖条件下对成骨细胞分化、细胞活力和细胞凋亡的保护作用，而上调TLR 4的表达或激活TLR 4的活性则具有相反的作用。激活NF-κB抑制二甲双胍的保护作用，而抑制NF-κB活性则具有相反的作用。二甲双胍可增加糖尿病大鼠股骨组织ALP和OCN的分泌，促进BMP-2的表达，提高骨密度，降低TLR 4、MyD 88和NF-κ B的水平。
AimsMetformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear. Therefore, the aim of this study was to determine the effect of metformin on hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts and to explore its relationships with the TLR4 signaling pathway.Main methodsA mouse osteoblast cell line, MC3T3-E1, and a diabetic rat model were used to survey the protective effects of metformin on hyperglycemia-induced injury. TLR4 expression was altered using small interfering (si)RNA and lentivirus-mediated TLR4 overexpression. LPS was used as a specific TLR4 activator, and CLI-095 was used as a TLR4 inhibitor.Key findingsMetformin improved osteoblast differentiation, reduced apoptosis in hyperglycemic osteoblasts, and inhibited TLR4, MyD88 and NF-κB expression in a dose-dependent manner. Down-regulating the expression or inhibiting the activity of TLR4 enhanced these protective effects of metformin on osteoblast differentiation, cell viability and cell apoptosis in hyperglycemic conditions, whereas up-regulating the expression or activating the activity of TLR4 had the opposite effects. Activating NF-κB suppressed the protective effects of metformin, while inhibiting NF-κB activity had the opposite effects. Metformin increased ALP and OCN secretion, enhanced BMP-2 expression, improved bone mineral density (BMD), and decreased TLR4, MyD88 and NF-κB levels in the femur tissues of diabetic rats.SignificanceTaken together our experimentation support the hypothesis that metformin may alleviate hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts by inhibiting the TLR4/MyD88/NF-κB signaling pathway.