Absence of Dap12 and the αvβ3 integrin causes severe osteopetrosis

In vitro, ligand occupancy of alpha v beta 3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only alpha v beta 3, Dap12(-/-) mice exhibited a slight increase in bone mass, but Dap12(-/-) mice, lacking another ITAM protein, FcR gamma, were severely osteopetrotic. The mechanism by which FcR gamma compensates for Dap12 deficiency is unknown. We find that co-deletion of FcR gamma did not exacerbate the skeletal phenotype of beta 3(-/-) mice. In contrast, beta 3/Dap12 double-deficient (DAP/beta 3(-/-))mice (but not beta 1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking alpha v beta 3 or Dap12 alone. Activation of OSCAR, the FcR gamma co-receptor, rescued Dap12(-/-) but not DAP/beta 3(-/-) osteoclasts. Thus, the absence of alpha v beta 3 precluded compensation for Dap12 deficiency by FcR gamma. In keeping with this, Syk phosphorylation did not occur in OSCAR-activated DAP/beta 3(-/-) osteoclasts. Thus, FcR gamma requires the osteoclast alpha v beta 3 integrin to normalize the Dap12-deficient skeleton.