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DNA methylation by Dnmt3a regulates osteoclastogenesis
DOI:10.1038/bonekey.2015.93
Nishikawa et al. investigated the epigenetic factors that underpin differentiation of osteoclasts and that link osteoclastogenesis with changes in cellular metabolism.
Their genome-wide screen for mRNAs expressed in osteoclast precursors (bone marrow-derived monocyte-macrophage precursor cells) showed that osteoclasts expressed mRNA for the Dnmt protein Dnmt3a continuously when stimulated by RANKL when macrophage colony-stimulating factor was present. In contrast, osteoblasts did not express Dnmt3a.
Dnmt3a was identified as the transcription factor, under the direction of RANKL, which couples osteoclastogenesis to a shift towards an oxidative metabolic state. A significant rise in production of S-adenosylmethionine (SAM) was also observed; DNA methylation by Dnmt3a, mediated by SAM, was shown to regulate osteoclastogenesis by epigenetic repression of anti-osteoclastogenic genes.
Mice that lack Dnmt3a specifically in their osteoclasts show elevated bone mass, confirming the role of Dnmt3a in bone homeostasis. Blocking the activity of this protein, suggest the authors, could have the potential to treat bone metastases and osteoporosis.
Editor's comment: Possibly the most interesting finding was that use of theaflavin 3,3′-digallate to inhibit DNA methylation prevented bone loss in ovariectomized mice. Targeting DNA methylation therapeutically in osteoporosis and a wide range of other disorders of bone resorption is worthy of further exploration.
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