Imbalance of Bone Homeostasis Caused by Nrf2 Deficiency Leads to Bone Loss in OVX Rats

Objective: Postmenopausal osteoporosis (PMOP) is a common bone metabolic disorder in middle-aged and elderly women, yet its pathogenesis remains unclear. This study investigates the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on bone homeostasis to provide insight into the mechanisms underlying PMOP. Methods: Sixteen female SD rats were randomly assigned to Sham and ovariectomized (OVX) groups. After 12 weeks, bone homeostasis disruption and Nrf2-mediated oxidative stress responses in bone tissue cells were assessed. Nrf2 expression was modulated in UMR-106 osteoblast-like cells and RAW264.7 macrophage-derived osteoclast precursor cells through knockdown or pharmacological activation. The effects on osteogenic function and osteoclast differentiation under oxidative stress were then evaluated. Results: The OVX group of rats exhibited a disruption in bone homeostasis, potentially attributable to the reduced expression of Nrf2 and its downstream antioxidant enzymes, coupled with elevated levels of oxidative stress. Nrf2 knockdown impaired osteogenic capacity in UMR-106 cells and enhanced osteoclast differentiation in RAW264.7 cells. In contrast, activation of Nrf2 using tert-butylhydroquinone (TBHQ) promoted bone formation and suppressed osteoclast differentiation and bone resorption. Conclusion: Nrf2 deficiency may contribute to PMOP by disrupting bone homeostasis. Activation of Nrf2 may represent a potential therapeutic strategy for restoring bone balance and treating PMOP.