RRC ID 62094
Author Futawaka K, Tagami T, Fukuda Y, Koyama R, Nushida A, Nezu S, Yamamoto H, Imamoto M, Kasahara M, Moriyama K.
Title Transcriptional activation of the wild-type and mutant vitamin D receptors by vitamin D3 analogs.
Journal J Mol Endocrinol
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.
Volume 57(1)
Pages 23-32
Published 2016-7-1
DOI 10.1530/JME-16-0048
PII JME-16-0048
PMID 27154546
MeSH 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics Animals Calcitriol / analogs & derivatives Calcitriol / pharmacology Cell Line Cholecalciferol / analogs & derivatives Cholecalciferol / pharmacology* Gene Expression Regulation / drug effects* Humans Mice Mutation* Promoter Regions, Genetic RNA, Messenger / genetics RNA, Messenger / metabolism Receptors, Calcitriol / genetics* Receptors, Calcitriol / metabolism Transcription, Genetic*
IF 3.562
Human and Animal Cells MC3T3-E1(RCB1126)