Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation

Sangyong Lee; Hyuk Soon Kim; Myoung Jun Kim; Keun Young Min; Wahn Soo Choi; Jueng Soo You

doi:10.1016/j.bone.2020.115836

Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation

Bone. 2021 Apr:145:115836. doi: 10.1016/j.bone.2020.115836. Epub 2020 Dec 29.

Authors

Sangyong Lee¹, Hyuk Soon Kim², Myoung Jun Kim¹, Keun Young Min¹, Wahn Soo Choi³, Jueng Soo You⁴

Affiliations

¹ School of Medicine, Konkuk University, Seoul, South Korea.
² Department of Biomedical Sciences, College of Natural Science, Dong-A University, Busan, South Korea; Department of Health Sciences, The Graduate School of Dong-A University, Busan, South Korea.
³ School of Medicine, Konkuk University, Seoul, South Korea; Research Institute of Medical Science, KU Open Innovation Center, Konkuk University, Seoul, South Korea.
⁴ School of Medicine, Konkuk University, Seoul, South Korea; Research Institute of Medical Science, KU Open Innovation Center, Konkuk University, Seoul, South Korea. Electronic address: jsyou@kku.ac.kr.

PMID: 33383217
DOI: 10.1016/j.bone.2020.115836

Abstract

Osteoclasts (OCs) have been well-known involved in the exacerbation of bone-related diseases. However, the role of metabolites on osteoclastogenesis has not been well characterized. Herein, we found osteoclastogenesis was negatively regulated by α-ketoglutarate (αKG) in vitro and in vivo (C57BL/6 mouse). Kinetic transcriptome analysis revealed the upregulation of solute carrier family 7 member 11 (Slc7a11), a subunit of the cysteine/glutamate antiporter, as well as the downregulation of typical OC maker genes through αKG treatment. Given that Slc7a11 could control ROS level through glutathione import, we measured intracellular ROS, then RANKL-induced ROS production was inhibited by αKG. Notably, we highlight that αKG plays an epigenetic co-factor at the Slc7a11 promoter by demethylating repressive histone H3K9 methylation and simultaneously increasing the nuclear factor erythroid 2-related factor (Nrf2) binding, a critical transcription factor through chromatin immunoprecipitation (ChIP) analysis. Together, we suggested that αKG could be a therapeutic strategy for OC activated diseases.

Keywords: Alpha-ketoglutarate; Epigenetics; Nrf2; Osteoclast; Osteoporosis; Slc7a11.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Epigenesis, Genetic
Glutamine
Ketoglutaric Acids
Mice
Mice, Inbred C57BL
Osteoclasts* / metabolism
RANK Ligand* / metabolism

Substances

Ketoglutaric Acids
RANK Ligand
Glutamine