Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis

Costimulatory signals are required for activation of immune cells1, but it is not known whether they contribute to other biological systems. The development and homeostasis of the skeletal system depend on the balance between bone formation and resorption2,3. Receptor activator of NF-κB ligand (RANKL) regulates the differentiation of bone-resorbing cells, osteoclasts, in the presence of macrophage-colony stimulating factor (M-CSF)4,5. But it remains unclear how RANKL activates the calcium signals that lead to induction of nuclear factor of activated T cells c1, a key transcription factor for osteoclastogenesis6. Here we show that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)7-harbouring adaptors8,9,10, Fc receptor common γ subunit (FcRγ) and DNAX-activating protein (DAP)12, exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple immunoreceptors11,12,13,14,15 and activate calcium signalling through phospholipase Cγ. Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. These results reveal that RANKL and M-CSF are not sufficient to activate the signals required for osteoclastogenesis.