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.