DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway

Keizo Nishikawa, Yoriko Iwamoto, Yasuhiro Kobayashi, Fumiki Katsuoka, Shin Ichi Kawaguchi, Tadayuki Tsujita, Takashi Nakamura, Shigeaki Kato, Masayuki Yamamoto, Hiroshi Takayanagi, Masaru Ishii

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94 Citations (Scopus)

Abstract

Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3′-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.

Original languageEnglish
Pages (from-to)281-287
Number of pages7
JournalNature Medicine
Volume21
Issue number3
DOIs
Publication statusPublished - 2015 Jan 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Nishikawa, K., Iwamoto, Y., Kobayashi, Y., Katsuoka, F., Kawaguchi, S. I., Tsujita, T., Nakamura, T., Kato, S., Yamamoto, M., Takayanagi, H., & Ishii, M. (2015). DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. Nature Medicine, 21(3), 281-287. https://doi.org/10.1038/nm.3774