Yu Katsuma

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.

Regulatory T cells (Tregs) maintain peripheral immune tolerance and are involved in various oral diseases with markedly different characteristics. In the oral field, Tregs have largely been discussed through reports on their distribution and numbers, and interpretations of whether their role is protective or pathogenic. Current identification markers do not directly assess the suppressive function, and reports on this function remain limited. This review focuses on the suppressive function of Tregs in the organization of oral diseases. Cells may express FOXP3 without exerting stable suppressive function, and the suppressive capacity of the same FOXP3⁺ cells may vary with TSDR status and the inflammatory environment. In Sjögren’s disease, oral lichen planus, periodontitis, and peri-implantitis, inflammation does not resolve even when Treg numbers are increased or maintained. In contrast, Treg suppressive function is enhanced in oral squamous cell carcinoma. Medication-related osteonecrosis of the jaw differs in that a reduction in Tregs induced by the causative drugs is itself what governs the condition. Attending to the functional state allows these conditions to be organized coherently and supports a therapeutic conception of Treg control that differs in direction according to the disease: weakening the function where it is enhanced, and restoring it where it is impaired.

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.