Stimulation of Osteoclast Formation by RANKL Requires Interferon Regulatory Factor-4 and Is Inhibited by Simvastatin in a Mouse Model of Bone Loss
Figure 5
Model of osteoclastogenesis acceleration by IRF4.
In osteoclast precursors, differentiation is regulated by epigenetic modification of the IRF4 and NFATc1 genes, and demethylation of H3K27me3 by Jmjd3 plays a critical role in this process. RANKL induces upregulation of IRF4, thereby augmenting IRF4 expression in the nucleus. We examined the mechanism of the increase in NFATc1 expression with RANKL. Stimulation of osteoclast precursors by RANKL results in activation of NF-κB which binds the NFATc1 promoter, cooperating with activated IRF4 and NFATc2 to induce initial induction of NFATc1. The increase in NFATc1 and IRF4 expression and decreased H3K27me3 detection could be coincidental and not causal.