In vitro, ligand occupancy of αvβ3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only αvβ3, Dap12-/- mice exhibited a slight increase in bone mass, but Dap12-/- mice, lacking another ITAM protein, FCRγ, were severely osteopetrotic. The mechanism by which FCRγ compensates for Dap12 deficiency is unknown. We find that co-deletion of FCRγ did not exacerbate the skeletal phenotype of β3-/- mice. In contrast, β3/Dap12 double-deficient (DAP/β3-/-) mice (but not β1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking αvβ3 or Dap12 alone. Activation of OSCAR, the FCRγ co-receptor, rescued Dap12-/- but not DAP/ β3-/-osteoclasts. Thus, the absence of αvβ3 precluded compensation for Dap12 deficiency by FCRγ. In keeping with this, Syk phosphorylation did not occur in OSCARactivated DAP/β3-/- osteoclasts. Thus, FCRγ requires the osteoclast αvβ3 integrin to normalize the Dap12- deficient skeleton.

Original languageEnglish
Pages (from-to)125-136
Number of pages12
JournalJournal of Cell Biology
Issue number1
StatePublished - 2015


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