title: Transcriptional activation of the wild-type and mutant vitamin D receptors by vitamin D3 analogs.
abstract: The active form of vitamin D3 (1α,25(OH)2D3, also known as calcitriol) controls the expression of target genes via the vitamin D receptor (VDR). Vitamin D-dependent rickets type II (VDDRII) is a congenital disease caused by inactivating mutations in the VDR The condition is treated with high doses of calcitriol, but the therapeutic effects of other synthetic VD3 analogs have not yet been investigated. In the present study, we analyzed the transcriptional activity of seven different VD3 analogs with VDRs carrying ligand-binding domain mutations identified in VDDRII patients. Wild-type VDR (WT-VDR) and seven mutant VDRs were expressed in TSA201 human embryonic kidney cells, HepG2 human liver cancer cells, and MC3T3-E1 mouse calvaria cells, and their transcriptional activation with VD3 analogs were analyzed by performing transient expression assays, western blotting, and quantitative real-time PCR. The results demonstrated that falecalcitriol stimulated significantly higher transcriptional activation of the WT-VDR and some mutant VDRs than did calcitriol. Calcitriol showed almost no transcriptional activation of the VDR with the I268T mutation identified in a severe case of VDDRII, whereas falecalcitriol caused a dose-dependent increase in the activation of this mutant VDR. Our findings demonstrate that falecalcitriol has a VDR activation profile distinct from that of calcitriol and may exhibit therapeutic effects even on difficult-to-treat VDDRII cases resistant to calcitriol. It is also possible that VDDRII patients responding to high doses of calcitriol could be appropriately treated with low doses of falecalcitriol.
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan kumif@mukogawa-u.ac.jp.
authors.forename: Kumi
authors.initials: K
authors.lastname: Futawaka
authors.affiliation: Clinical Research Institute for Endocrine and Metabolic DiseasesNational Hospital Organization Kyoto Medical Center, Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tagami
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Koyama
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nushida
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nezu
authors.affiliation: Department of Health and NutritionFaculty of Human Life, Jin-ai University, Fukui, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Nephrology and Blood PurificationInstitute of Biomedical Research and Innovation, Kobe Medical Frontier Center, Kobe, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Imamoto
authors.affiliation: Department of Nephrology and Blood PurificationInstitute of Biomedical Research and Innovation, Kobe Medical Frontier Center, Kobe, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.affiliation: Department of Medicine and Clinical ScienceFaculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan Clinical Research Institute for Endocrine and Metabolic DiseasesNational Hospital Organization Kyoto Medical Center, Kyoto, Japan Department of Nephrology and Blood PurificationInstitute of Biomedical Research and Innovation, Kobe Medical Frontier Center, Kobe, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Moriyama
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D005466:Fluorocarbons
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002762:Cholecalciferol; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C040488:26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3; D005466:Fluorocarbons; C051883:maxacalcitol
keywords: calcitriol; falecalcitriol; transcription; vitamin D receptor; vitamin D-dependent rickets type II