Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL*
- John G. Emery‡,
- Peter McDonnell‡,
- Michael Brigham Burke¶,
- Keith C. Deen‖,
- Sally Lyn‡,
- Carol Silverman**,
- Edward Dul‡,
- Edward R. Appelbaum‡,
- Chris Eichman‖,
- Rocco DiPrinzio‖,
- Robert A. Dodds§§,
- Ian E. James§§,
- Martin Rosenberg¶¶,
- John C. Lee§§ and
- Peter R. Young‡§
- From the Departments of ‡Molecular Biology,¶Structural Biology, ‖Molecular and Cellular Immunology,**Protein Biochemistry, ‡Gene Expression Sciences, and §§Bone and Cartilage Biology at SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406 and the ¶¶Department of Anti-infectives at SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania 19426
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.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ To whom correspondence should be addressed: Dept. of Molecular Biology, Mail Code UW2101, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406. Tel.: 610-270-7691; Fax: 610-270-5114; E-mail: Peter_R_Young{at}sbphrd.com.
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↵1 The abbreviations used are: TNF, tumor necrosis factor; OPG, osteoprotegerin; ELISA, enzyme-linked immunosorbent assay; TRAP, tartrate-resistant acid phosphatase.
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↵2 P. Hensley, unpublished data.
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↵4 J. A. Harrop, P. C. McDonnell, M. Brigham-Burke, S. D. Lyn, J. Minton, K. B. Tan, K. Dede, J. Spampanato, C. Silverman, P. Hensley, R. DiPrinzio, J. G. Emery, C. Eichman, M. Chabot-Fletcher, A. Truneh, and P. R. Young, submitted for publication.
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↵3 S. Kumar, S. Holmes, J. Fox, S. Gluck, T. Chadderton, and K. B. Tan, unpublished data.
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- Received January 26, 1998.
- Revision received March 9, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
