Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models

Osteoporosis is a metabolic bone disease characterized by a disruption in the balance between bone resorption and formation. The specific role and mechanism of stomatin (STOM), a major component of lipid rafts, in regulating bone physiology remain unclear. This research identifies increased STOM expression in bone tissue of osteoporosis patients and ovariectomized mice. STOM-deficient mice show higher bone mass under both normal conditions and after ovariectomy. Furthermore, we clarify that STOM is a positive regulator of osteoclast differentiation. Through transcriptomic and bioinformatics approaches, our research reveals that inhibiting STOM increases antioxidant proteins and suppresses ROS-mediated transcriptional pathways in osteoclasts. Mechanistically, STOM interacts with Prdx1, promoting its degradation through the lysosomal pathway and boosting intracellular ROS production, thereby activating osteoclastogenesis. Ultimately, targeted inhibition of macrophage STOM expression in mice alleviates ovariectomized-induced bone loss. Overall, these findings show STOM directly regulates osteoclasts, suggesting that targeting it may modulate pathological bone remodeling.