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Unoccupied _vß₃ Integrin Regulates Osteoclast Apoptosis by Transmitting a Positive Death Signal

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Steven L. Teitelbaum, M.D., Washington University School of Medicine, Department of Pathology and Immunology, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: teitelbs{at}wustl.edu.

Cell/matrix detachment is a general inducer of programmed cell death, an event mediated by loss of integrin/ligand association. Because _vß₃ is the major integrin expressed by the osteoclast, we asked whether its occupancy promotes survival of the resorptive cell. Thus, we generated wild-type preosteoclasts and placed them on selective matrix proteins. Consistent with the posture that _vß₃ occupancy promotes survival, preosteoclasts plated on native collagen, a matrix not recognized by the integrin, undergo apoptosis 4-fold faster than those on the _vß₃ ligand, vitronectin. To further explore the role of _vß₃ in osteoclast apoptosis, wild-type and ß₃^–/– preosteoclasts were suspended and apoptosis determined, with time. ß₃^–/– preosteoclasts, in suspension, undergo a rate of apoptosis only 40–60% of that of their wild-type counterparts, indicating that unoccupied _vß₃ transmits a positive death signal that we find regulated by caspase-8. Attesting to specificity of the unoccupied integrin-transmitted death signal, apoptosis in the absence of _vß₃ is mediated by capsase-9. We have shown that the resorptive defect of ß₃^–/– osteoclasts is rescued by wild-type ß₃ cDNA but not by one bearing a S⁷⁵²P mutation. To determine whether the same holds true regarding osteoclast apoptosis, we constructed lentivirus vectors encoding green fluorescent protein, wild-type ß₃, or ß₃^S752P. Once again, native ß₃^–/– preosteoclasts were protected against apoptosis. Similar to its effect on bone resorption, transduced wild-type ß₃ normalizes the apoptotic rate of ß₃^–/– preosteoclasts. Unexpectedly, however, ß₃^S752P transductants also die at a rate indistinguishable from wild type. Thus, unoccupied _vß₃ integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption.

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