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The estrogen-related receptor ャ modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis
Hyun-Ju Kim 1,* (Research professor), Hye-Jin Yoon1 (Research worker), Dong-Kyo Lee1 (Graduate student), Xian Jin1 (Graduate student), Xiangguo Che1 (Research professor), Je-Yong Choi 1 (Professor)
1Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, KNU Convergence Med, Kyungpook National University
Estrogen-related receptor ャ(ERRャ), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERRャ has become an attractive target for treating diverse metabolic disorders. We recently reported that ERRャacts as a negative regulator of receptor activator of nuclear factor-リB ligand (RANKL)-induced osteoclastogenesis. In the present study, we explored the effects of an ERRャ-specific modulator, GSK5182, on ERRャ-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERRャprotein levels similar to GSK4716, which is known as an ERRャagonist. GSK5182 inhibited osteoclast generation from bone marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of c-Fos 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 the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IリBメ, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-リB 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 ERRャmodulator, may have potential in treating bone resorption-related disorders.
Abstract, Accepted Manuscript(in press) [Submitted on November 4, 2020, Accepted on December 14, 2020]
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