KMID : 0624620210540050266
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BMB Reports 2021 Volume.54 No. 5 p.266 ~ p.271
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The estrogen-related receptor ¥ã modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis
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Kim Hyun-Ju
Yoon Hye-Jin Lee Dong-Kyo Jin Xian Che Xiangguo Choi Je-Yong
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Abstract
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Estrogen-related receptor ¥ã (ERR¥ã), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERR¥ã has become an attractive target for treating diverse metabolic disorders. We recently reported that ERR¥ã acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-¥êB ligand (RANKL). In the present study, we explored the effects of an ERR¥ã-specific modulator, GSK5182, on ERR¥ã-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERR¥ã protein levels much as does GSK4716, which is an ERR¥ã 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 with the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of I¥êB¥á, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-¥êB 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¥ã modulator, may have potential in treating disorders related to bone resorption.
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KEYWORD
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Apoptosis, ERR¥ã, GSK5182, NFATc1, Osteoclast
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