Journal
MOLECULAR ENDOCRINOLOGY
Volume 19, Issue 3, Pages 771-780Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2004-0161
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Funding
- NIAMS NIH HHS [AR46523, AR46852, AR48812, AR48853, AR32788] Funding Source: Medline
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Cell/matrix detachment is a general inducer of programmed cell death, an event mediated by loss of integrin/ligand association. Because alpha(v)beta(3) 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)beta(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 alpha(v)beta(3) ligand, vitronectin. To further explore the role of alpha(v)beta(3) in osteoclast apoptosis, wild-type and beta(3)(-/-) preosteoclasts were suspended and apoptosis determined, with time. beta(3)(-/-) preosteoclasts, in suspension, undergo a rate of apoptosis only 40 - 60% of that of their wild-type counterparts, indicating that unoccupied alpha(v)beta(3) 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)beta(3) is mediated by capsase-9. We have shown that the resorptive defect of beta(3)(-/-) osteoclasts is rescued by wild-type beta(3) cDNA but not by one bearing a (SP)-P-752 mutation. To determine whether the same holds true regarding osteoclast apoptosis, we constructed lentivirus vectors encoding green fluorescent protein, wild- type beta(3), or beta(3)(S752P). Once again, native beta(3)(-/-) preosteoclasts were protected against apoptosis. Similar to its effect on bone resorption, transduced wild- type beta(3) normalizes the apoptotic rate of beta(3)(-/-) preosteoclasts. Unexpectedly, however, beta(3)(S752P) transductants also die at a rate indistinguishable from wild type. Thus, unoccupied alpha(v)beta(3) integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption.
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