Metabolic-epigenetic coupling in osteoclast differentiation

Abstract

Osteoclasts are required for bone resorption. A new study in mice indicates that osteoclast differentiation is stabilized by DNA methylation at Irf8 (encoding interferon regulatory factor 8) mediated by DNA methyltransferase 3a (Dnmt3a), which suppresses Irf8 gene expression. The activity of Dnmt3 in osteoclasts requires elevated oxidative metabolism.

Figure 1

The role of DNA methylation in osteoclast differentiation. RANKL is a regulator of osteoclastogenesis. Nishikawa et al. show in mouse osteoclast precursor cells that it induces the expression of the de novo DNA methyltransferase Dnmt3a and increases oxidative metabolism to provide the SAM substrate for Dnmt3a. After RANKL-induced signaling, the expression of Irf8, a negative regulator of osteoclastogenesis is repressed. Dnmt3a maintains this repression by methylating CpG motifs in putative regulatory elements downstream of the Irf8 gene body, thereby promoting osteoclast differentiation and bone resorption. RANK, receptor activator of NF-κB.