A proposed mechanism of the inhibitory action of IL-18 on osteoclast differentiation. IL-18 secreted from osteoblasts acts on T lymphocytes, which generate granulocyte–macrophage colony-stimulating factor (GM-CSF) and IFN-γ. Both GM-CSF and IFN-γ are potent inhibitors of osteoclast formation, at least in vitro. When GM-CSF binds its receptor, GM-CSFR (present in osteoclast progenitors), osteoclast formation is completely inhibited. In contrast, the target molecule of IFN-γ is TNF receptor-associated factor 6 (TRAF6). The degradation of TRAF6 by IFN-γ leads to the inhibition of osteoclastogenesis. The inhibitory action of IL-18 on osteoclast differentiation occurs via GM-CSF, but not via IFN-γ.