A novel RANKL-targeted selenyl quinolinamide alleviates ovariectomy-induced bone loss through inhibiting ROS, MAPK and NF-κB signaling pathways

The osteoclast is the only bone cell responsible for bone resorption, intracellular Reactive Oxygen Species (ROS) are key signaling factors that regulate RANKL-induced osteoclast differentiation. Organoselenium compounds have been demonstrated with good antioxidant activity by scavenging ROS. However, these compounds exerting anti-osteoclastogenesis activity by reducing ROS levels have not been reported. In this study, a series of selenyl quinolinamides were synthesized using a novel, simple, and metal-free method at room temperature, and their osteoclastogenesis inhibitory effects in vitro were tested. The most promising compound 3w with an IC₅₀ value of 0.577 μM, markedly inhibited RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes and proteins expressions in vitro. Additionally, 3w suppressed RANKL-stimulated intracellular ROS levels by inhibition of ROS production and promotion of ROS scavenging, and inhibited downstream MAPK and NF-κB signaling pathways. In vivo, 3w significantly prevented bone loss in ovariectomized osteoporosis mice. Moreover, 3w could bind to RANKL and interfere with RANKL-RANK interaction. Our findings may offer a valuable direction for the development of novel organoselenium-based antiosteoporosis agents.