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Blood, 15 July 2007, Vol. 110, No. 2, pp. 536-543.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2007-01-068395.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo

Giorgio Zauli1, Federica Corallini1, Fleur Bossi2, Fabio Fischetti2, Paolo Durigutto2, Claudio Celeghini1, Francesco Tedesco2, and Paola Secchiero3

Departments of1 Biomedicine and 2 Physiology & Pathology, University of Trieste, Italy; 3 Department of Morphology and Embryology, University of Ferrara, Italy

Recombinant osteoprotegerin (OPG) promoted the adhesion of both primary polymorphonuclear neutrophils (PMNs) and leukemic HL60 cells to endothelial cells. Leukocyte/endothelial cell adhesion was promoted by short (peak at 1 hour) preincubation of either endothelial cells or PMNs with OPG, and the peak of proadhesive activity was observed in the same range of OPG concentrations detected in the sera of patients affected by cardiovascular diseases. Although the cognate high-affinity ligands for OPG, membrane receptor activator of nuclear factor-{kappa}B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were detected at significant levels on both PMNs and HL60 cells, they were not expressed on the surface of endothelial cells. However, preincubation of OPG with heparin abrogated its proadhesive activity, whereas pretreatment of endothelial cells with chondroitinase plus heparinases significantly decreased the proadhesive activity of OPG. Taken together, these findings suggest the involvement of both the ligand binding and the N-terminal heparin-binding domains of OPG in mediating its pro-adhesive activity. The relevance of these in vitro findings was underscored by in vivo experiments, in which the topical administration of recombinant OPG increased leukocyte rolling and adhesion to rat mesenteric postcapillary venules. Our data suggest that a pathological increase of OPG serum levels might play an important role in promoting leukocyte/endothelial cell adhesion.


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