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Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL
J G Emery1, P McDonnell, M B Burke
1Department of Molecular Biology, King of Prussia, Pennsylvania 19406, USA.
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 in vivo. 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.
Insights
Osteoprotegerin (OPG) acts as a novel receptor for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), inhibiting TRAIL-induced apoptosis. TRAIL also counteracts OPG
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) induces apoptosis via death receptors DR4 and DR5.
- Other TRAIL receptors, TRID/DcR1 and DcR2, act as decoy receptors.
- Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclastogenesis and increases bone density.
Purpose of the Study:
- To identify and characterize novel receptors for TRAIL.
- To investigate the interaction between OPG and TRAIL.
- To explore potential cross-regulatory mechanisms between OPG and TRAIL.
Main Methods:
- Binding assays to determine OPG-Fc and TRAIL interaction affinity.
- Apoptosis assays using Jurkat cells to assess OPG's effect on TRAIL-induced apoptosis.
- Functional assays to evaluate TRAIL's impact on OPG's anti-osteoclastogenic activity.
Main Results:
- Osteoprotegerin (OPG) was identified as a fifth TRAIL receptor.
- OPG-Fc binds TRAIL with an affinity of 3.0 nM.
- OPG inhibits TRAIL-induced apoptosis in Jurkat cells.
- TRAIL blocks the anti-osteoclastogenic activity of OPG.
Conclusions:
- Osteoprotegerin (OPG) functions as a novel TRAIL receptor.
- A cross-regulatory relationship exists between OPG and TRAIL, impacting both apoptosis and osteoclastogenesis.
- These findings suggest new therapeutic targets and strategies involving OPG and TRAIL.