Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

Current pharmacological intervention for the treatment of osteolytic bone diseases such as osteoporosis focuses on the prevention of excessive osteoclastic bone resorption but does not enhance osteoblast‐mediated bone formation. In our study, we have shown that 4‐iodo‐6‐phenylpyrimidine (4‐IPP), an irreversible inhibitor of macrophage migration inhibitory factor (MIF), can inhibit receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis and potentiate osteoblast‐mediated mineralization and bone nodule formation in vitro . Mechanistically, 4‐IPP inhibited RANKL‐induced p65 phosphorylation and nuclear translocation by preventing the interaction of MIF with thioredoxin‐interacting protein—p65 complexes. This led to the suppression of late osteoclast marker genes such as nuclear factor of activated T cells cytoplasmic 1, resulting in impaired osteoclast formation. In contrast, 4‐IPP potentiated osteoblast differentiation and mineralization also through the inhibition of the p65/NF‐κB signaling cascade. In the murine model of pathologic osteolysis induced by titanium particles, 4‐IPP protected against calvarial bone destruction. Similarly, in the murine model of ovariectomy‐induced osteoporosis, 4‐IPP treatment ameliorated the bone loss associated with estrogen deficiency by reducing osteoclastic activities and enhancing osteoblastic bone formation. Collectively, these findings provide evidence for the pharmacological targeting of MIF for the treatment of osteolytic bone disorders.—Zheng, L., Gao, J., Jin, K., Chen, Z., Yu, W., Zhu, K., Huang, W., Liu, F., Mei, L., Lou, C., He, D. Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway. FASEB J. 33, 7667–7683 (2019). www.fasebj.org