Chen Jin-Ran, Lazarenko Oxana P, Zhao Haijun, Wankhade Umesh D, Pedersen Kim, Watt James, Ronis Martin J J
Department of Pediatrics University of Arkansas for Medical Sciences Little Rock AR USA.
Arkansas Children's Nutrition Center Little Rock AR USA.
JBMR Plus. 2020 Jul 23;4(8):e10376. doi: 10.1002/jbm4.10376. eCollection 2020 Aug.
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 ( < 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, 8- and 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 ( < 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. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
雌激素缺乏和衰老由于氧化应激增加在骨骼病理生理学中起关键作用。有人提出，预防烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）依赖性活性氧（ROS）积累可能是一种潜在的方法，可将这些情况导致的骨质流失降至最低。我们使用去卵巢（OVX）和Nox4基因缺失小鼠模型，研究了Nox4在OVX诱导的骨质流失和成骨细胞衰老信号传导中的作用。将6个月大的野生型C57Bl6小鼠分为假手术对照组、OVX组和OVX加E2治疗组，为期8周。与假手术对照组相比，OVX组的骨量包括骨密度（BMD）和骨矿含量（BMC）降低（P<0.05）；E2治疗完全逆转了OVX诱导的骨质流失。有趣的是，E2预防OVX诱导的骨质流失与消除OVX组骨成骨细胞中增加的衰老信号有关。E2减弱了OVX诱导的p53和p21过表达，但对骨中的p16和Nox4没有影响。此外，将8个月和11个月大的Nox4基因敲除雌性小鼠去卵巢8周。与假手术动物相比，Nox4基因敲除OVX小鼠不仅出现了明显的骨质流失和骨成骨细胞衰老信号增加，而且与8个月大的Nox4基因敲除假手术小鼠相比，11个月大的Nox4基因敲除假手术小鼠也出现了这种情况（P<0.05）。这些数据表明，骨成骨细胞中Nox4介导的ROS对于性类固醇缺乏诱导的骨质流失和衰老可能是不必要的。©2020作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
