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

Research output: Contribution to journalArticle

80 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

Fingerprint

S-Adenosylmethionine
Osteoclasts
Metabolic Networks and Pathways
Bone
Bone and Bones
DNA Methylation
Metabolism
Osteogenesis
Epigenetic Repression
Genetic Epigenesis
Cytoplasmic and Nuclear Receptors
Osteoporosis
DNA methyltransferase 3A
Homeostasis
Transcription Factors
Genes
Cytokines
Ligands

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nishikawa, K., Iwamoto, Y., Kobayashi, Y., Katsuoka, F., Kawaguchi, S. I., Tsujita, T., ... 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

DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. / Nishikawa, Keizo; Iwamoto, Yoriko; Kobayashi, Yasuhiro; Katsuoka, Fumiki; Kawaguchi, Shin Ichi; Tsujita, Tadayuki; Nakamura, Takashi; Kato, Shigeaki; Yamamoto, Masayuki; Takayanagi, Hiroshi; Ishii, Masaru.

In: Nature Medicine, Vol. 21, No. 3, 2015, p. 281-287.

Research output: Contribution to journalArticle

Nishikawa, K, Iwamoto, Y, Kobayashi, Y, Katsuoka, F, Kawaguchi, SI, 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, vol. 21, no. 3, pp. 281-287. https://doi.org/10.1038/nm.3774
Nishikawa, Keizo ; Iwamoto, Yoriko ; Kobayashi, Yasuhiro ; Katsuoka, Fumiki ; Kawaguchi, Shin Ichi ; Tsujita, Tadayuki ; Nakamura, Takashi ; Kato, Shigeaki ; Yamamoto, Masayuki ; Takayanagi, Hiroshi ; Ishii, Masaru. / DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. In: Nature Medicine. 2015 ; Vol. 21, No. 3. pp. 281-287.
@article{39aecff99e7e47ccbc7d67987601a333,
title = "DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway",
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.",
author = "Keizo Nishikawa and Yoriko Iwamoto and Yasuhiro Kobayashi and Fumiki Katsuoka and Kawaguchi, {Shin Ichi} and Tadayuki Tsujita and Takashi Nakamura and Shigeaki Kato and Masayuki Yamamoto and Hiroshi Takayanagi and Masaru Ishii",
year = "2015",
doi = "10.1038/nm.3774",
language = "English",
volume = "21",
pages = "281--287",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway

AU - Nishikawa, Keizo

AU - Iwamoto, Yoriko

AU - Kobayashi, Yasuhiro

AU - Katsuoka, Fumiki

AU - Kawaguchi, Shin Ichi

AU - Tsujita, Tadayuki

AU - Nakamura, Takashi

AU - Kato, Shigeaki

AU - Yamamoto, Masayuki

AU - Takayanagi, Hiroshi

AU - Ishii, Masaru

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84924370236&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924370236&partnerID=8YFLogxK

U2 - 10.1038/nm.3774

DO - 10.1038/nm.3774

M3 - Article

C2 - 25706873

AN - SCOPUS:84924370236

VL - 21

SP - 281

EP - 287

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -