Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL

TLDR

TRAIL is a TNF‑related ligand that triggers apoptosis through death‑domain receptors DR4 and DR5, while decoy receptors TRID/DcR1 and DcR2 lack death domains and sequester TRAIL. The study identifies osteoprotegerin (OPG) as a fifth TRAIL receptor that binds TRAIL with nanomolar affinity, inhibits TRAIL‑induced apoptosis in Jurkat cells, and is itself inhibited by TRAIL, indicating reciprocal regulatory interactions.

Abstract

TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density <i>in vivo</i>. OPG-Fc binds TRAIL with an affinity of 3.0 nm, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.