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http://dx.doi.org/10.5483/BMBRep.2021.54.5.243

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)
Publication Information
BMB Reports / v.54, no.5, 2021 , pp. 266-271 More about this Journal
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
Apoptosis; $ERR{\gamma}$; GSK5182; NFATc1; Osteoclast;
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