Unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis by transmitting a positive death signal.
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Zhao H., Ross F.P., Teitelbaum S.L.
Cell/matrix detachment is a general inducer of programmed cell death, an event mediated by loss of integrin/ligand association. Because alpha(v)beta3 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 alpha(v)beta3 occupancy promotes survival, preosteoclasts plated on native collagen, a matrix not recognized by the integrin, undergo apoptosis 4-fold faster than those on the alpha(v)beta3 ligand, vitronectin. To further explore the role of alpha(v)beta3 in osteoclast apoptosis, wild-type and beta3-/-preosteoclasts were suspended and apoptosis determined, with time. Beta3-/-preosteoclasts, in suspension, undergo a rate of apoptosis only 40-60% of that of their wild-type counterparts, indicating that unoccupied alpha(v)beta3 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 alpha(v)beta3 is mediated by capsase-9. We have shown that the resorptive defect of beta3-/-osteoclasts is rescued by wild-type beta3 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 beta3, or beta3S752P. Once again, native beta3-/-preosteoclasts were protected against apoptosis. Similar to its effect on bone resorption, transduced wild-type beta3 normalizes the apoptotic rate of beta3-/-preosteoclasts. Unexpectedly, however, beta3S752P transductants also die at a rate indistinguishable from wild type. Thus, unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption.