DAP12 and FcRgamma are typical immunoreceptor signal activator proteins that associate with multiple immunoglobulin-like receptors (IgLR) on various immune cells. DAP12-deficient (DAP12-/-) mice develop a mild osteopetrosis in vivo, whereas the in vitro osteoclast induction from DAP12-/- bone marrow cells yields immature cells with greatly attenuated bone resorption activity. Mice deficient in FcRgamma did not show any remarkable osteopetrosis. However, those animals doubly deficient in DAP12 and FcRgamma exhibit much more severe osteopetrosis than DAP12-/- mice, suggesting that either DAP12 or FcRgamma is required for normal bone remodeling in vivo. Thus, activation signals initiated by multiple IgLR associating with DAP12 and FcRgamma are indispensable for the development of osteoclast in concert with RANKL and M-CSF.