Agonist-activated αvβ3 on platelets and lymphocytes binds to the matrix protein osteopontin

Abstract

The phosphorylated acidic glycoprotein osteopontin is present in the extracellular matrix of atherosclerotic plaques and the wall of injured but not normal arteries. To determine if osteopontin could serve as a substrate for platelet adhesion, we measured the adherence of resting and agonist- stimulated human platelets to immobilized recombinant human osteopontin. Agonist-stimulated but not resting platelets bound to osteopontin by a process that was mediated primarily by αvβ3. αvβ3-mediated adherence occurred at physiologic concentrations of calcium and was inhibited by an αvβ3-selective cyclic peptide. Assays using phorbol myristate acetate- stimulated transfected B lymphocytes expressing both αvβ3 and αIIbβ3 confirmed that activated αvβ3 not activated αIIbβ3 was responsible for the cellular adherence we measured. These studies indicate that αvβ3 can reside on the cell surface in an inactive state and can be converted to a ligand binding conformation by cellular agonists. Moreover, they suggest that platelet adherence to osteopontin mediated by activated αvβ3 could play a role in anchoring platelets to disrupted atherosclerotic plaques and the walls of injured arteries. By inhibiting αvβ3 function, it may be possible to inhibit platelet-mediated vascular occlusion with a minimal effect on primary hemostasis.