Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor (TNF) receptor family that inhibits osteoclastogenesis and increases bone density. This study identifies OPG as a fifth TRAIL receptor, demonstrating that OPG binds TRAIL with an affinity of 3.0 nM. OPG inhibits TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks OPG's anti-osteoclastogenic activity. These findings suggest a potential cross-regulatory mechanism between OPG and TRAIL. TRAIL is a TNF-related ligand that induces apoptosis by binding to death domain-containing receptors DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, act as decoy receptors without functional death domains. OPG, a secreted TNF receptor homologue, inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity slightly weaker than TRID-Fc or DR5-Fc. OPG blocks TRAIL-induced apoptosis, while TRAIL inhibits OPG's anti-osteoclastogenic activity. The TNF ligand and receptor superfamilies regulate various biological processes, including apoptosis and immune responses. TRAIL, along with FasL and TNFα, induces apoptosis by binding to death domain-containing receptors. OPG, a soluble receptor, may neutralize a TNF-related ligand that promotes osteoclast differentiation or bind a membrane-anchored TNF-related ligand that regulates osteoclastogenesis via reverse signaling. The study identified a novel interaction between OPG and TRAIL through receptor-Fc fusion protein screening. OPG binds TRAIL in vitro and can block TRAIL-induced apoptosis. Conversely, TRAIL blocks OPG's anti-osteoclastogenic activity. These results suggest that OPG and TRAIL may function to inhibit each other. The affinity of TRAIL for its receptors was determined using surface plasmon resonance, showing that OPG-Fc binds TRAIL with an affinity of 3.0 nM, slightly weaker than TRID-Fc and DR5-Fc. OPG inhibits TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks OPG's anti-osteoclastogenic activity. These findings suggest that OPG may act as a soluble antagonist for TRAIL, similar to how secreted TNF receptors inhibit TNFα. OPG inhibits osteoclastogenesis in vitro, and TRAIL was shown to block OPG's inhibitory effect on osteoclastogenesis. This suggests that soluble TRAIL may regulate OPG activity. The study also indicates that OPG may inhibit osteoclastogenesis by binding to a pro-osteoclastogenic TNF-related ligand, though this ligand is not TRAIL. Further experiments are needed to fully define the role of TRAIL in osteoclastogenesisOsteoprotegerin (OPG) is a secreted member of the tumor necrosis factor (TNF) receptor family that inhibits osteoclastogenesis and increases bone density. This study identifies OPG as a fifth TRAIL receptor, demonstrating that OPG binds TRAIL with an affinity of 3.0 nM. OPG inhibits TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks OPG's anti-osteoclastogenic activity. These findings suggest a potential cross-regulatory mechanism between OPG and TRAIL. TRAIL is a TNF-related ligand that induces apoptosis by binding to death domain-containing receptors DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, act as decoy receptors without functional death domains. OPG, a secreted TNF receptor homologue, inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity slightly weaker than TRID-Fc or DR5-Fc. OPG blocks TRAIL-induced apoptosis, while TRAIL inhibits OPG's anti-osteoclastogenic activity. The TNF ligand and receptor superfamilies regulate various biological processes, including apoptosis and immune responses. TRAIL, along with FasL and TNFα, induces apoptosis by binding to death domain-containing receptors. OPG, a soluble receptor, may neutralize a TNF-related ligand that promotes osteoclast differentiation or bind a membrane-anchored TNF-related ligand that regulates osteoclastogenesis via reverse signaling. The study identified a novel interaction between OPG and TRAIL through receptor-Fc fusion protein screening. OPG binds TRAIL in vitro and can block TRAIL-induced apoptosis. Conversely, TRAIL blocks OPG's anti-osteoclastogenic activity. These results suggest that OPG and TRAIL may function to inhibit each other. The affinity of TRAIL for its receptors was determined using surface plasmon resonance, showing that OPG-Fc binds TRAIL with an affinity of 3.0 nM, slightly weaker than TRID-Fc and DR5-Fc. OPG inhibits TRAIL-induced apoptosis in Jurkat cells, while TRAIL blocks OPG's anti-osteoclastogenic activity. These findings suggest that OPG may act as a soluble antagonist for TRAIL, similar to how secreted TNF receptors inhibit TNFα. OPG inhibits osteoclastogenesis in vitro, and TRAIL was shown to block OPG's inhibitory effect on osteoclastogenesis. This suggests that soluble TRAIL may regulate OPG activity. The study also indicates that OPG may inhibit osteoclastogenesis by binding to a pro-osteoclastogenic TNF-related ligand, though this ligand is not TRAIL. Further experiments are needed to fully define the role of TRAIL in osteoclastogenesis