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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Intracellular Accumulation of Advanced Glycation End Products Induces Osteoblast Apoptosis Via Endoplasmic Reticulum Stress
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Intracellular Accumulation of Advanced Glycation End Products Induces Osteoblast Apoptosis Via Endoplasmic Reticulum Stress

机译：晚期糖化末端产物的细胞内积聚诱导成骨细胞凋亡通过内质网胁迫

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摘要

Osteoporosis is an aging-associated disease that is attributed to excessive osteoblast apoptosis. It is known that the accumulation of advanced glycation end products (AGEs) in bone extracellular matrix deteriorates osteoblast functions. However, little is known about the interaction between intracellular AGE accumulation and the induction of osteoblast apoptosis. In this study, we investigated the effect of intracellular AGE accumulation on osteoblast apoptosis in vitro and in vivo. In vitro, murine osteoblastic MC3T3-E1 cells were treated with glycolaldehyde (GA), an AGE precursor. GA-induced intracellular AGE accumulation progressed in time- and dose-dependent manners, followed by apoptosis induction. Intracellular AGE formation also activated endoplasmic reticulum (ER) stress-related proteins (such as glucose-regulated protein 78, inositol-requiring protein-1 alpha (IRE1 alpha), and c-Jun N-terminal kinase) and induced apoptosis. In agreement, treatment with the ER stress inhibitor 4-phenylbutyric acid and knocking down IRE1 alpha expression ameliorated osteoblast apoptosis. Furthermore, the ratio between AGE- and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive osteoblasts in human vertebral bodies was significantly higher in an elderly group than in a younger group. A positive linear correlation between the ratio of AGE-positive and TUNEL-positive osteoblasts (r = 0.72) was also observed. Collectively, these results indicate that AGEs accumulated in osteoblasts with age and that intracellular AGE accumulation induces apoptosis via ER stress. These findings offer new insight into the mechanisms of osteoblast apoptosis and age-related osteoporosis. (c) 2020 American Society for Bone and Mineral Research.
机译：骨质疏松症是一种与衰老相关的疾病，其原因是成骨细胞过度凋亡。众所周知，晚期糖基化终产物（AGEs）在骨细胞外基质中的积累会恶化成骨细胞的功能。然而，关于细胞内年龄积累与成骨细胞凋亡诱导之间的相互作用知之甚少。在本研究中，我们在体外和体内研究了细胞内年龄积累对成骨细胞凋亡的影响。在体外，小鼠成骨细胞MC3T3-E1细胞被AGE前体乙醇醛（GA）处理。GA诱导的细胞内AGE积累以时间和剂量依赖性方式进行，然后是凋亡诱导。细胞内AGE形成还激活内质网（ER）应激相关蛋白（如葡萄糖调节蛋白78、肌醇需要蛋白-1α（IRE1α）和c-Jun N-末端激酶）并诱导细胞凋亡。与此一致的是，内质网应激抑制剂4-苯基丁酸治疗和抑制IRE1α表达改善了成骨细胞凋亡。此外，老年人椎体中年龄和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性成骨细胞之间的比率显著高于年轻人。年龄阳性和TUNEL阳性成骨细胞比率之间也存在正线性相关（r=0.72）。总的来说，这些结果表明，随着年龄的增长，成骨细胞中的age逐渐积累，细胞内的age积累通过内质网应激诱导细胞凋亡。这些发现为成骨细胞凋亡和年龄相关骨质疏松症的机制提供了新的见解。（c） 2020年美国骨与矿物研究学会。

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