Nox4 Expression Is Not Required for OVX-Induced Osteoblast Senescence and Bone Loss in Mice
Nox4 Expression Is Not Required for OVX-Induced Osteoblast Senescence and Bone Loss in Mice
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DOI：
10.1002/jbm4.10376
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发表时间：
2020-08-01
期刊：
影响因子：
3.8
通讯作者：
Ronis, Martin J. J.
中科院分区：
文献类型：
--
作者：
Chen, Jin-Ran;Lazarenko, Oxana P.;Ronis, Martin J. J.
雌激素缺乏和衰老在骨的病理生理学中起关键作用，这是由于氧化应激增加。已经提出，预防ROS的NADPH氧化酶-（Nox-）依赖性积累可能是潜在地最小化由这些病症引起的骨丢失的方法。我们使用卵巢切除（OVX）和Nox 4基因缺失的小鼠模型，研究了Nox 4在OVX诱导的骨丢失和成骨细胞衰老信号传导中的作用。将6月龄WT C57 B16小鼠分配至假手术对照组、OVX和OVX加E2治疗组，持续8周。与假手术对照组相比，OVX组的骨量（包括BMD和BMC）降低（p < 0.05）; E2治疗完全逆转了OVX诱导的骨丢失。有趣的是，E2对OVX诱导的骨丢失的预防与OVX组骨成骨细胞中增加的衰老信号的消除有关。E2减弱了OVX诱导的p53和p21的过度表达，但对p16和Nox 4无影响。另外，将8月龄和11月龄的Nox 4 KO雌性小鼠OVX 8周。与假手术动物相比，不仅在Nox 4 KO OVX小鼠中发生显著的骨丢失和骨成骨细胞衰老信号传导增加，而且在11月龄的Nox 4 KO假手术小鼠中与8月龄的Nox 4 KO假手术小鼠相比也发生显著的骨丢失和骨成骨细胞衰老信号传导增加（p < 0.05）。这些数据表明，在骨成骨细胞中，Nox 4介导的ROS可能与性类固醇缺乏诱导的骨丢失和衰老有关。(C)2020作者出版社：Wiley Periodicals，Inc.美国骨与矿物质研究协会（American Society for Bone and Mineral Research）
Estrogen deficiency and aging play critical roles in the pathophysiology of bone as a result of increased oxidative stress. It has been suggested that prevention of NADPH oxidase- (Nox-) dependent accumulation of ROS may be an approach to potentially minimize bone loss caused by these conditions. Using ovariectomized (OVX) and Nox4 gene-deletion mouse models, we investigated the role of Nox4 in OVX-induced bone loss and osteoblast senescence signaling. Six-month-old WT C57Bl6 mice were allocated to a sham control group, OVX, and OVX plus E2 treatment group for 8 weeks. Decreased bone mass including BMD and BMC were found in the OVX group compared with the sham control (p < 0.05); E2 treatment completely reversed OVX-induced bone loss. Interestingly, the prevention of OVX-induced bone loss by E2 was associated with the elimination of increased senescence signaling in bone osteoblastic cells from the OVX group. E2 blunted OVX-induced p53 and p21 overexpression, but not p16 and Nox4 in bone. In addition, 8and 11-month-old Nox4 KO female mice were OVX for 8 weeks. Significant bone loss and increased bone osteoblastic cell senescence signaling occurred not only in Nox4 KO OVX mice compared with sham-operated animals, but also in 11-month-old Nox4 KO sham mice compared with 8-month-old Nox4 KO sham mice (p < 0.05). These data suggest that Nox4-mediated ROS in bone osteoblastic cells may be dispensable for sex steroid deficiency-induced bone loss and senescence. (C) 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.