title: Estrogen-Related Receptor γ Plays a Key Role in Vascular Calcification Through the Upregulation of BMP2 Expression.
abstract: OBJECTIVE
  Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)γ is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERRγ in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERRγ in vascular calcification.
  
  
  RESULTS
  Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERRγ expression in vascular smooth muscle cells was induced during calcification medium-induced vascular calcification. Adenovirus-mediated overexpression of ERRγ in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of α-smooth muscle actin. Adenovirus-mediated overexpression of ERRγ induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERRγ promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERRγ expression or activity using a specific siRNA or the selective inverse agonist GSK5182 attenuated vascular calcification and osteogenic gene expression in vitro and in vivo.
  
  
  CONCLUSIONS
  The present results indicate that ERRγ plays a key role in vascular calcification by upregulating the BMP2 signaling pathway, suggesting that inhibition of ERRγ is a potential therapeutic strategy for the prevention of vascular calcification.
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Yeon-Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Do
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Chae-Myeong
authors.initials: CM
authors.lastname: Ha
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Won-Kee
authors.initials: WK
authors.lastname: Lee
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.).
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.). leei@knu.ac.kr kpark@knu.ac.kr.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.). leei@knu.ac.kr kpark@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001665:Binding Sites; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D054337:Cell Dedifferentiation; D002460:Cell Line; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; C490916:Esrrg protein, mouse; C493778:Esrrg protein, rat; C583041:GSK5182; D011960:Receptors, Estrogen; D013629:Tamoxifen
keywords: BMP2; ERRγ; vascular calcification; vascular smooth muscle cells