Cell/matrix detachment is a general inducer of programmed cell death, an event mediated by loss of integrin/ligand association. Because αvβ3 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 αvβ 3 occupancy promotes survival, preosteoclasts plated on native collagen, a matrix not recognized by the integrin, undergo apoptosis 4-fold faster than those on the αvβ3 ligand, vitronectin. To further explore the role of αvβ 3 in osteoclast apoptosis, wild-type and β3 -/- preosteoclasts were suspended and apoptosis determined, with time. β3-/- preosteoclasts, in suspension, undergo a rate of apoptosis only 40-60% of that of their wild-type counterparts, indicating that unoccupied αvβ3 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 αvβ3 is mediated by capsase-9. We have shown that the resorptive defect of β3-/- osteoclasts is rescued by wild-type β3 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 β3, or β3 S752P. Once again, native β3-/- preosteoclasts were protected against apoptosis. Similar to its effect on bone resorption, transduced wild-type β3 normalizes the apoptotic rate of β3-/- preosteoclasts. Unexpectedly, however, β3S752P transductants also die at a rate indistinguishable from wild type. Thus, unoccupied αvβ 3 integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption.

Original languageEnglish
Pages (from-to)771-780
Number of pages10
JournalMolecular Endocrinology
Issue number3
StatePublished - Mar 2005


Dive into the research topics of 'Unoccupied αvβ3 integrin regulates osteoclast apoptosis by transmitting a positive death signal'. Together they form a unique fingerprint.

Cite this