Molecular Mechanisms of the Biphasic Effects of Interferon-γ on Osteoclastogenesis

Although interferon-gamma (IFN-gamma) potently inhibits osteoclastogenesis, the suppressive effect is significantly reduced when osteoclast precursors are pre-exposed to the receptor activator of NF-kappa B (RANK) ligand (RANKL). However, the molecular mechanism underlying the biphasic effects of IFN-gamma on osteoclastogenesis remains elusive. Here, we recapitulate the biphasic functions of IFN-gamma in osteoclastogenesis in both tissue culture dishes and on bone slices. We further demonstrate that IFN-gamma markedly suppresses the RANKL-induced expression of nuclear factor of activated T-cells c1 (NFATc1) in normal, but not RANKL-pretreated bone marrow macrophages (BMMs). Similarly, IFN-gamma impairs the activation of the nuclear factor-kappa B (NF-kappa B) and c-Jun N-terminal kinase (JNK) pathways in normal, but not RANKL-pretreated, BMMs. These findings indicate that IFN-gamma inhibits osteoclastogenesis partially by suppressing the expression of NFATc1 and the activation of the NF-kappa B and JNK pathways. Moreover, IFN-gamma inhibits the RANKL-induced expression of osteoclast genes, but RANKL pretreatment reprograms osteoclast genes into a state in which they can no longer be suppressed by IFN-gamma, indicating that IFN-gamma inhibits osteoclastogenesis by blocking the expression of osteoclast genes. Finally, the IVVY(535-538) motif in the cytoplasmic domain of RANK is responsible for rendering BMMs refractory to the inhibitory effect of IFN-gamma. Taken together, these findings provide important mechanistic insights into the biphasic effects of IFN-gamma on osteoclastogenesis.