The study identifies osteoprotegerin (OPG) as a fifth receptor for the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, a secreted TNF receptor homologue, inhibits osteoclastogenesis and increases bone density. The research demonstrates that OPG binds to TRAIL with an affinity of 3.0 nM, slightly weaker than the interactions of TRID/DeR1 and DR5/Fc with TRAIL. OPG can block TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks the anti-osteoclastogenic activity of OPG. These findings suggest that OPG and TRAIL may function to inhibit each other, potentially through cross-regulatory mechanisms. The study also explores the binding kinetics and affinity of TRAIL for its receptors using surface plasmon resonance and examines the effects of TRAIL on osteoclastogenesis in vitro. The results indicate that TRAIL blocks the inhibitory effect of OPG on osteoclast formation, suggesting that soluble TRAIL may regulate OPG activity.The study identifies osteoprotegerin (OPG) as a fifth receptor for the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, a secreted TNF receptor homologue, inhibits osteoclastogenesis and increases bone density. The research demonstrates that OPG binds to TRAIL with an affinity of 3.0 nM, slightly weaker than the interactions of TRID/DeR1 and DR5/Fc with TRAIL. OPG can block TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks the anti-osteoclastogenic activity of OPG. These findings suggest that OPG and TRAIL may function to inhibit each other, potentially through cross-regulatory mechanisms. The study also explores the binding kinetics and affinity of TRAIL for its receptors using surface plasmon resonance and examines the effects of TRAIL on osteoclastogenesis in vitro. The results indicate that TRAIL blocks the inhibitory effect of OPG on osteoclast formation, suggesting that soluble TRAIL may regulate OPG activity.