Nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is a key enzymatic source of reactive oxygen species (ROS) in bone tissue, and the ROS it generates serve as crucial signaling molecules that precisely regulate bone metabolism. However, the molecular mechanisms of NOX2 in skeletal physiological and pathological processes, its spatiotemporal regulatory networks, and interactions with other NOX subtypes remain incompletely elucidated. This review aims to integrate existing research advances, delve into the core mechanisms of NOX2 in maintaining bone homeostasis and in bone-related diseases, identify current research gaps, and provide targeted recommendations for future research directions and clinical translation strategies to advance the development of NOX2-targeted diagnostic and therapeutic technologies. Under physiological conditions, NOX2 maintains dynamic equilibrium in bone metabolism by precisely regulating the activation, differentiation, and functional activities of osteoblasts (OB) and osteoclasts (OC). Notably, NOX2 exhibits significant age-dependent regulation of bone formation: juvenile NOX2 deficiency promotes osteoblast differentiation and bone formation through compensatory upregulation of NOX4, whereas chronic NOX2 deficiency in the elderly accelerates osteoblast senescence, enhances inflammatory responses in the bone microenvironment, and ultimately inhibits bone formation. Furthermore, the MT-NOX2-TRPV4-CaMKII signaling pathway mediates mechanically stimulated osteogenesis, revealing NOX2′s crucial role in force sensing. For osteoclasts, physiological NOX2 knockout is functionally compensated by NOX1, causing minimal impact on bone resorption. However, under pathological conditions such as obesity, NOX2 deficiency increases inflammatory cytokine expression, significantly inhibiting osteoclast differentiation and bone resorption. Pathologically, NOX2 dysregulation is closely associated with multiple bone disorders. In osteoarthritis (OA), abnormal NOX2 activation promotes chondrocyte injury and extracellular matrix degradation. Different OA models exhibit subtype-specific mechanisms: Collagenase-induced OA (CiOA) relies on synovial macrophages to drive inflammation, where NOX2 deficiency can be compensated by NOX1/4; Whereas in the medial meniscus instability (DMM) model, synergistic NOX2/4 activity in chondrocytes and synovial cells promotes pathological progression. In osteoporosis (OP), NOX2 dysfunction disrupts the balance between bone formation and resorption, leading to bone mass loss; Under aging and diabetic conditions, daphnetin and PMS/PC improve bone mass and microarchitecture by suppressing NOX2 expression. In osteosarcoma (OS), NOX2-ROS drives malignant progression through dual mechanisms: Directly inducing DNA damage and impairing repair capacity to promote genomic instability and malignant proliferation; And activating EGFR and VEGFR signaling pathways to enhance cell invasion and angiogenesis while contributing to chemotherapy resistance development. Despite significant advances in NOX2 research, key scientific questions remain unresolved, including the precise molecular regulatory mechanisms of NOX2 in bone cells, synergistic/antagonistic interactions with other NOX subtypes, threshold definition for ROS concentration-dependent effects, and bottlenecks in translating basic research to clinical applications. Future research should focus on: (1) Utilizing single-cell sequencing and gene editing technologies to precisely decipher context-dependent regulatory networks of NOX2 in bone cell subpopulations; (2) Developing highly specific NOX2-targeted drugs to avoid off-target effects; (3) Conducting rigorously designed clinical trials targeting diseases such as OA, OP, and OS; (4) Exploring the diagnostic value of NOX2 as a biomarker for bone metabolic disorders. Through multidisciplinary integration, advancing the clinical translation of NOX2-targeting strategies will provide novel approaches for precision diagnosis and treatment of bone-related diseases.
TIAN et al. (Mon,) studied this question.