Nox4 Expression Is Not Required for OVX-Induced Osteoblast Senescence and Bone Loss in Mice

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, 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 (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. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.