APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress.
APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress.
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DOI：
10.1038/s41419-018-1123-7
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发表时间：
2018-10-22
影响因子：
9
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Pan JX;Tang F;Xiong F;Xiong L;Zeng P;Wang B;Zhao K;Guo H;Shun C;Xia WF;Mei L;Xiong WC
淀粉样前体蛋白（APP）广泛表达于包括骨细胞在内的各种类型的细胞中。 App 基因突变会导致早发性阿尔茨海默病 (AD)。然而，对其在骨稳态中的生理功能知之甚少。在这里，我们提供了 APP 在促进骨形成方面的作用的证据。敲除 App 基因 (APP−/−) 的小鼠表现出骨质疏松样缺陷，包括小梁骨和皮质骨量减少。这种缺陷很可能在很大程度上是由于成骨细胞（OB）介导的骨形成减少所致，因为在突变小鼠中检测到的骨吸收几乎没有变化。 APP−/− OB 的进一步机械研究表明线粒体功能受损，并伴有活性氧 (ROS) 和细胞凋亡增加。有趣的是，这些缺陷与表达瑞典突变体 APP (APPswe) 的 Tg2576 AD 动物模型中的缺陷类似，通过抗氧化剂 NAC（n-乙酰基-l-半胱氨酸）治疗得到了减少，揭示了 ROS 是一个关键的潜在机制。总而言之，这些结果确定了 APP 在促进 OB 存活和骨形成方面未被认识的生理功能，表明 APPswe 是显性负因子，并揭示了 NAC 在治疗 AD 相关骨质疏松症中的潜在临床价值。
Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer’s disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP’s role in promoting bone formation. Mice that knocked out App gene (APP−/−) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP−/− OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.
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影响因子：
9
作者：
Rehklau K;Hoffmann L;Gurniak CB;Ott M;Witke W;Scorrano L;Culmsee C;Rust MB
通讯作者：
Rust MB
影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
肿瘤抑制因子 SIRT3 脱乙酰并激活锰超氧化物歧化酶清除 ROS
影响因子：
7.7
作者：
Chen, Yaohui;Zhang, Jinye;Lin, Yan;Lei, Qunying;Guan, Kun-Liang;Zhao, Shimin;Xiong, Yue
通讯作者：
Xiong, Yue
影响因子：
29
作者：
Qiu, Xiaolei;Brown, Katharine;Chen, Danica
通讯作者：
Chen, Danica
影响因子：
6.2
作者：
Cui, Shun;Xiong, Fei;Hong, Yan;Jung, Ji-Ung;Li, Xing-Sheng;Liu, Jian-Zhong;Yan, Riqiang;Mei, Lin;Feng, Xu;Xiong, Wen-Cheng
通讯作者：
Xiong, Wen-Cheng