The estrogen-related receptor. modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis

초록

Estrogen-related receptor gamma (ERR gamma), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERR. has become an attractive target for treating diverse metabolic disorders. We recently reported that ERR. acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-kappa B ligand (RANKL). In the present study, we explored the effects of an ERR.-specific modulator, GSK5182, on ERR gamma-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERR. protein levels much as does GSK4716, which is an ERR. 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 kappa B alpha, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-kappa 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. modulator, may have potential in treating disorders related to bone resorption.

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