Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: Role in the interactions with receptor activator of nuclear factor {kappa}B ligand (RANKL) and RANK
- INSERM, ERI 7, Nantes, F-44035 (France)
- IFR26, Institut de Biologie, Nantes Hospital (France)
- Department of Medical Oncology, PICR, Christie Hospital NHS Trust, Wilmslow Rd, Manchester M20 4BX (United Kingdom)
- CNRS, UMR 5086, UCBL, Institut de Biologie et Chimie des Proteines, 7 passage du Vercors 69367 Lyon Cedex 07 (France)
- INSERM, ERI 7, Nantes, F-44035 (France) and Universite de Nantes, Laboratoire de Physiopathologie de la Resorption Osseuse et Therapie des Tumeurs Osseuses Primitives, EA3822, Nantes F-44035 (France)
Osteoprotegerin (OPG) is a decoy receptor for receptor activator of nuclear factor {kappa}B ligand (RANKL), a key inducer of osteoclastogenesis via its receptor RANK. We previously showed that RANK, RANKL, and OPG are able to form a tertiary complex and that OPG must be also considered as a direct effector of osteoclast functions. As OPG contains a heparin-binding domain, the present study investigated the interactions between OPG and glycosaminoglycans (GAGs) by surface plasmon resonance and their involvement in the OPG functions. Kinetic data demonstrated that OPG binds to heparin with a high-affinity (K {sub D}: 0.28 nM) and that the pre-incubation of OPG with heparin inhibits in a dose-dependent manner the OPG binding to the complex RANK-RANKL. GAGs from different structure/origin (heparan sulfate, dermatan sulfate, and chondroitin sulfate) exert similar activity on OPG binding. The contribution of the sulfation pattern and the size of the oligosaccharide were determined in this inhibitory mechanism. The results demonstrated that sulfation is essential in the OPG-blocking function of GAGs since a totally desulfated heparin loses its capacity to bind and to block OPG binding to RANKL. Moreover, a decasaccharide is the minimal structure that totally inhibits the OPG binding to the complex RANK-RANKL. Western blot analysis performed in 293 cells surexpressing RANKL revealed that the pre-incubation of OPG with these GAGs strongly inhibits the OPG-induced decrease of membrane RANKL half-life. These data support an essential function of the related glycosaminoglycans heparin and heparan sulfate in the activity of the triad RANK-RANKL-OPG.
- OSTI ID:
- 20854425
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 347, Issue 2; Other Information: DOI: 10.1016/j.bbrc.2006.06.120; PII: S0006-291X(06)01420-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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