Agonist-activated αvβ3 on Platelets and Lymphocytes Binds to the Matrix Protein Osteopontin*
- From the ‡ Hematology-Oncology Division, Department of Medicine and the
- ∥ Department of Biochemistry and Biophysics, the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and
- ¶ Dupont Merck Pharmaceuticals, Wilmington, Delaware 19880
- § To whom correspondence should be addressed: Hematology-Oncology Division, Stellar-Chance Laboratories, Rm. 1005, 422 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-662-4028; Fax: 215-662-7617; E-mail: bennetts{at}mail.med.upenn.edu
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.
Footnotes
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↵* This work was supported by National Institutes of Health Grants HL40387 (to J. S. B.) and HL51258 (to J. S. B.) and National Science Foundation Grant CHE-9634646 (to W. F. D.). 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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↵1 The abbreviations used are:
- PTCA
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percutaneous transluminal coronary angioplasty
- PMA
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phorbol myristate acetate
- mAb
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monoclonal antibody.
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↵2S. Mousa, unpublished observations.
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- Received November 21, 1996.
- Revision received January 27, 1997.
- © 1997 by The American Society for Biochemistry and Molecular Biology, Inc.
