Oxidative Stress and Metabolic Reprogramming in Osteoclastogenesis: Molecular Mechanisms and Antioxidant Therapy for...

Osteoclasts are the primary bone-resorbing cells responsible for maintaining skeletal homeostasis through balanced bone remodeling. Accumulating evidence suggests that oxidative stress is an emerging regulator of osteoclast differentiation, metabolic reprogramming, and bone resorption, arising from excessive reactive oxygen species (ROS) and insufficient antioxidant defenses. Dysregulated redox signaling contributes to osteoporosis, rheumatoid arthritis, periodontitis, periapical lesions, and other osteolytic disorders. This review summarizes recent advances in the molecular mechanisms linking oxidative stress to osteoclast metabolism, focusing on ROS sources, mitochondrial dysfunction, redox-sensitive signaling pathways, endogenous antioxidant systems, and emerging antioxidant-based therapies. Oxidative stress regulates osteoclastogenesis through interconnected signaling networks, including NF-κB, MAPKs, PI3K/Akt, AMPK, mTOR, NFATc1, and Keap1/Nrf2. Under both physiological and pathological conditions, osteoclast function is regulated by mitochondrial dynamics, mitophagy, and epigenetic mechanisms. Although both synthetic and natural antioxidants have been shown to reduce pathological osteoclast activity in preclinical studies, limitations in bioavailability, target specificity, and long-term efficacy hinder clinical translation. Advances in multi-omics technologies, single-cell analyses, biomarker discovery, precision medicine, and targeted antioxidant delivery may facilitate the development of effective therapies for oxidative stress-related bone disorders.