Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.
Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, Kumamoto, Japan.
J Bone Miner Res. 2020 Oct;35(10):1992-2003. doi: 10.1002/jbmr.4053. Epub 2020 Jun 5.
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-1α (IRE1α), and c-Jun N-terminal kinase) and induced apoptosis. In agreement, treatment with the ER stress inhibitor 4-phenylbutyric acid and knocking down IRE1α 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. © 2020 American Society for Bone and Mineral Research.
骨质疏松症是一种与衰老相关的疾病，其特征是成骨细胞凋亡过多。已知骨细胞外基质中晚期糖基化终产物 (AGEs) 的积累会损害成骨细胞的功能。然而，细胞内 AGE 积累与成骨细胞凋亡的诱导之间的相互作用知之甚少。在这项研究中，我们研究了细胞内 AGE 积累对体外和体内成骨细胞凋亡的影响。在体外，用糖醛 (GA)，一种 AGE 前体处理鼠成骨细胞 MC3T3-E1 细胞。GA 诱导的细胞内 AGE 积累呈时间和剂量依赖性进展，随后诱导细胞凋亡。细胞内 AGE 的形成也激活了内质网 (ER) 应激相关蛋白（如葡萄糖调节蛋白 78、需要肌醇的蛋白 1α (IRE1α) 和 c-Jun N-末端激酶）并诱导细胞凋亡。与此一致，用 ER 应激抑制剂 4-苯基丁酸处理和敲低 IRE1α 表达可改善成骨细胞凋亡。此外，在老年组中，人椎体中 AGE-和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记 (TUNEL) 阳性成骨细胞的比例明显高于年轻组。AGE 阳性和成骨细胞 TUNEL 阳性的比例之间存在正线性相关（r = 0.72）。总之，这些结果表明，随着年龄的增长，AGE 在成骨细胞中积累，细胞内 AGE 积累通过 ER 应激诱导细胞凋亡。这些发现为成骨细胞凋亡和与年龄相关的骨质疏松症的机制提供了新的见解。© 2020 美国骨矿研究协会。
