The estrogen-related receptor γ modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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 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 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.
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 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 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.
참고문헌 (37)
- Boyle WJ, "Osteoclast differentiation and activation", Nature, 423, pp.337~342 (2003)
- Teitelbaum SL, "Bone resorption by osteoclasts", Science, 289, pp.1504~1508 (2000)
- Tsukasaki M, "Osteoimmunology : evolving concepts in bone-immune interactions in health and disease", Nat Rev Immunol, 19, pp.626~642 (2019)
- Kong YY, "OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis", Nature, 397, pp.315~323 (1999)
- Lacey DL, "Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation", Cell, 93, pp.165~176 (1998)
- Wong BR, "TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells", J Biol Chem, 272, pp.25190~25194 (1997)
- Yasuda H, "Osteoclast differentiation factor is a ligand for osteoprotegerin", osteoclastogenesis-inhibitory factor and is identical to TRANCE, Proc Natl Acad Sci U S A, pp.1998, 95[DOI]
- Lee ZH, "Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts", Biochem Biophys Res Commun, 305, pp.211~214 (2003)
- 박진희, "Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation", Molecules and Cells, 40(10), pp.706~713 (2017), 한국분자세포생물학회[DOI]
- 김정하, "Regulation of NFATc1 in Osteoclast Differentiation", 대한골대사학회지, 21(4), pp.233~241 (2014), 대한골대사학회[DOI]
- Nakashima T, "New insights into osteoclastogenic signaling mechanisms", Trends Endocrinol Metab, 23, pp.582~590 (2012)
- Giguere V, "Transcriptional control of energy homeostasis by the estrogen-related receptors", Endocr Rev, 29, pp.677~696 (2008)
- Giguere V, "Identification of a new class of steroid hormone receptors", Nature, 331, pp.91~94 (1988)
- Hong H, "Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3", J Biol Chem, 274, pp.22618~22626 (1999)
- Misra J, "ERRgamma : a junior orphan with a senior role in metabolism", Trends Endocrinol Metab, 28, pp.261~272 (2017)
- Chao EY, "Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma", Bioorg Med Chem Lett, 16, pp.821~824 (2006)
- Kim DK, "Inverse agonist of nuclear receptor ERRgamma mediates antidiabetic effect through inhibition of hepatic gluconeogenesis", Diabetes, 62, pp.3093~3102 (2013)
- Kim JH, "Estrogen-related receptor gamma plays a key role in vascular calcification through the upregulation of BMP2 expression", Arterioscler Thromb Vasc Biol, 35, pp.2384~2390 (2015)
- Son YO, "Estrogen-related receptor gamma causes osteoarthritis by upregulating extracellular matrix-degrading enzymes", Nat Commun, 8, pp.2133~ (2017)
- Vernier M, "Estrogenrelated receptors are targetable ROS sensors", Genes Dev, 34, pp.544~559 (2020)
- Cardelli M, "ERRgamma is not required for skeletal development but is a RUNX2-dependent negative regulator of postnatal bone formation in male mice", PLoS One, 9, pp.e109592~ (2014)
- Cardelli M, "Cartilage-specific overexpression of ERRgamma results in Chondrodysplasia and reduced chondrocyte proliferation", PLoS One, 8, pp.e81511~ (2013)
- Jeong BC, "The orphan nuclear receptor estrogen receptor-related receptor gamma negatively regulates BMP2-induced osteoblast differentiation and bone formation", J Biol Chem, 284, pp.14211~14218 (2009)
- Kim HJ, "Estrogen-related receptor gamma negatively regulates osteoclastogenesis and protects against inflammatory bone loss", J Cell Physiol, 234, pp.1659~1670 (2019)
- Kim DK, "Inverse agonist of estrogen-related receptor gamma controls Salmonella typhimurium infection by modulating host iron homeostasis", Nat Med, 20, pp.419~424 (2014)
- Kim DK, "Estrogen-related receptor gamma(ERRgamma)is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling", J Biol Chem, 286, pp.38035~38042 (2011)
- Kim DK, "Orphan nuclear receptor estrogen-related receptor gamma(ERRgamma)is key regulator of hepatic gluconeogenesis", J Biol Chem, 287, pp.21628~21639 (2012)
- Bianco S, "Modulating estrogen receptor-related receptor-alpha activity inhibits cell proliferation", J Biol Chem, 284, pp.23286~23292 (2009)
- Johnson RS, "Pleiotropic effects of a null mutation in the c-fos proto-oncogene", Cell, 71, pp.577~586 (1992)
- Wang ZQ, "Bone and haematopoietic defects in mice lacking c-fos", Nature, 360, pp.741~745 (1992)
- Takayanagi H, "Induction and activation of the transcription factor NFATc1(NFAT2)integrate RANKL signaling in terminal differentiation of osteoclasts", Dev Cell, 3, pp.889~901 (2002)
- Asagiri M, "Autoamplification of NFATc1 expression determines its essential role in bone homeostasis", J Exp Med, 202, pp.1261~1269 (2005)
- Franzoso G, "Requirement for NF-kappaB in osteoclast and B-cell development", Genes Dev, 11, pp.3482~3496 (1997)
- Iotsova V, "Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2", Nat Med, 3, pp.1285~1289 (1997)
- Hyun-Ju Kim, "Oleoylethanolamide Exhibits GPR119-Dependent Inhibition of Osteoclast Function and GPR119-Independent Promotion of Osteoclast Apoptosis", Molecules and Cells, 43(4), pp.340~349 (2020), 한국분자세포생물학회
- Jung YK, "DICAM inhibits osteoclast differentiation through attenuation of the integrin alphaVbeta3 pathway", J Bone Miner Res, 27, pp.2024~2034 (2012)
- Takeshita S, "Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts", J Bone Miner Res, 15, pp.1477~1488 (2000)