Nrf2 signaling in bone health: unlocking new avenues for osteoporosis management.

Abstract

Osteoporosis (OP) is a progressive skeletal disorder characterized by reduced bone mass, structural deterioration, and increased fracture risk, particularly in postmenopausal women and the elderly. Oxidative stress and inflammation are key contributors to the disruption of bone remodeling in OP. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular redox homeostasis, has gained attention for its role in bone metabolism. This review explores Nrf2's regulatory influence on osteoblast (OB) and osteoclast (OC) activity. In OBs, moderate Nrf2 activation protects against reactive oxygen species (ROS)-induced apoptosis, enhances differentiation, and supports bone formation. In contrast, both insufficient and excessive Nrf2 expression may impair OB function. In OCs, Nrf2 suppresses ROS-mediated pathways such as MAPK and NF-κB, thereby inhibiting differentiation and resorptive activity. Nrf2 also attenuates inflammation by downregulating pro-inflammatory mediators and inhibiting NF-κB nuclear translocation. Nrf2 knockout animal models exhibit age-related bone loss, reduced bone mineral density, impaired trabecular structure, and delayed fracture healing. These effects are exacerbated by increased oxidative stress and inflammation. Notably, sex-specific differences have been observed, with female mice showing greater susceptibility to Nrf2 deficiency, potentially due to interactions with estrogen signaling. Nrf2 also regulates osteocyte-specific gene expression, further reinforcing its role in bone maintenance and mechanotransduction. Therapeutic activation of Nrf2 using agents such as bardoxolone methyl, sulforaphane, quercetin, and curcumin shows promise in mitigating bone loss. However, precise modulation is crucial to avoid potential adverse effects. Overall, Nrf2 represents a promising target for the prevention and treatment of OP and related musculoskeletal disorders.