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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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The estrogen-related receptor γ modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis

  • Kim, Hyun-Ju (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Yoon, Hye-Jin (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Lee, Dong-Kyo (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Jin, Xian (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Che, Xiangguo (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Choi, Je-Yong (Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University)
  • Received : 2020.11.04
  • Accepted : 2020.12.14
  • Published : 2021.05.31
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Abstract

Estrogen-related receptor γ (ERRγ), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERRγ has become an attractive target for treating diverse metabolic disorders. We recently reported that ERRγ acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL). In the present study, we explored the effects of an ERRγ-specific modulator, GSK5182, on ERRγ-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERRγ protein levels much as does GSK4716, which is an ERRγ agonist. GSK5182 inhibited osteoclast generation from bone-marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of cFos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), pivotal transcription factors for osteoclastogenesis. Arrested osteoclast differentiation was associated with reduced RANK expression, but not with the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IκBα, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-κB promoter activity in a dose-dependent manner. In addition to osteoclastogenesis, GSK5182 accelerated osteoclast apoptosis by caspase-3 activation. Together, these results suggest that GSK5182, a synthetic ERRγ modulator, may have potential in treating disorders related to bone resorption.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (No. 2018R1A2B6001298); the Basic Science Research Program of NRF grant funded by the Ministry of Education, Science, and Technology (NRF-2015R1D1A1A01056666); and the Bio & Medical Technology Development Program (NRF-2017R1A5A2015391).

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