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J. Biol. Chem., Vol. 282, Issue 43, 31601-31609, October 26, 2007

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Investigating the Interaction between Osteoprotegerin and Receptor Activator of NF-B or Tumor Necrosis Factor-related Apoptosis-inducing Ligand

EVIDENCE FOR A PIVOTAL ROLE FOR OSTEOPROTEGERIN IN REGULATING TWO DISTINCT PATHWAYS^*

From the Academic Unit of Bone Biology, Section of Musculoskeletal Science and the Section of Infection, Inflammation and Immunity, University of Sheffield School of Medical and Biomedical Sciences, Beech Hill Road, Sheffield, Yorkshire S10 2RX, United Kingdom

Osteoprotegerin (OPG) binds the ligand for receptor activator of nuclear factor B (RANKL) to prevent association with its receptor RANK and inhibit osteoclast-mediated bone resorption. OPG has been reported, recently, to inhibit tumor necrosis factor-related apoptosis-induced ligand (TRAIL)-induced tumor cell apoptosis. This raises the possibility that OPG may play a unique role in regulating these two signaling pathways. However, there are little data on the interactions between OPG, RANKL, and TRAIL, and the relative affinity of OPG for these two ligands is unknown. In the present study we examined the ability of OPG to bind native human TRAIL and RANKL under physiological conditions. Native TRAIL was expressed in Escherichia coli, purified to homogeneity, and shown to induce human myeloma cell apoptosis. OPG inhibited native TRAIL from binding the TRAILR1 at 37 °C in vitro. Similarly, OPG prevented RANKL from binding to RANK. TRAIL also prevented OPG-mediated inhibition of RANKL from binding RANK. The affinity of OPG for native TRAIL and RANKL at 37 °C was determined by plasmon surface resonance analysis. OPG had a binding affinity for TRAIL of 45 nM, whereas the affinity of OPG for RANKL was 23 nM. These data suggest that OPG can bind both RANKL and TRAIL and that the affinity of OPG for these two ligands is of a similar order of magnitude. Furthermore, OPG prevented TRAIL-mediated reductions in cell viability, whereas TRAIL inhibited OPG-mediated inhibition of osteoclastogenesis in vitro. This highlights the pivotal role of OPG in regulating the biology of both RANKL and TRAIL.

Received for publication, July 24, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 44-114-271-2414; Fax: 44-114-271-1711; E-mail: p.croucher{at}sheffield.ac.uk.

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