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Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

Active vitamin D form 1α,25-dihydroxtvitamin D(3) (1,25(OH)(2)D(3)) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patient...

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Autores principales: Nishikawa, Miyu, Murose, Naruhiro, Mano, Hiroki, Yasuda, Kaori, Isogai, Yasuhiro, Kittaka, Atsushi, Takano, Masashi, Ikushiro, Shinichi, Sakaki, Toshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307643/
https://www.ncbi.nlm.nih.gov/pubmed/35869242
http://dx.doi.org/10.1038/s41598-022-16819-7
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author Nishikawa, Miyu
Murose, Naruhiro
Mano, Hiroki
Yasuda, Kaori
Isogai, Yasuhiro
Kittaka, Atsushi
Takano, Masashi
Ikushiro, Shinichi
Sakaki, Toshiyuki
author_facet Nishikawa, Miyu
Murose, Naruhiro
Mano, Hiroki
Yasuda, Kaori
Isogai, Yasuhiro
Kittaka, Atsushi
Takano, Masashi
Ikushiro, Shinichi
Sakaki, Toshiyuki
author_sort Nishikawa, Miyu
collection PubMed
description Active vitamin D form 1α,25-dihydroxtvitamin D(3) (1,25(OH)(2)D(3)) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patients with VDDR-II are hardly responsive to physiological doses of 1,25(OH)D(3). Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)(2)D(3,) have limited success and fail to improve the quality of life of affected patients. Thus, various vitamin D analogues have been developed as therapeutic options. In our previous study, we generated genetically modified rats with mutated Vdr(R270L), an ortholog of human VDR(R274L) isolated from the patients with VDDR-II. The significant reduced affinity toward 1,25(OH)(2)D(3) of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D(3). In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)(2)D(3) (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D(3) and 1,25(OH)(2)D(3). A robust osteogenic activity of AH-1 was observed in Vdr(R270L) rats. Only a 40-fold lower dose of AH-1 than that of 25(OH)D(3) was effective in ameliorating rickets symptoms in Vdr(R270L) rats. Therefore, AH-1 may be promising for the therapy of VDDR-II with VDR(R274L).
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spelling pubmed-93076432022-07-24 Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats Nishikawa, Miyu Murose, Naruhiro Mano, Hiroki Yasuda, Kaori Isogai, Yasuhiro Kittaka, Atsushi Takano, Masashi Ikushiro, Shinichi Sakaki, Toshiyuki Sci Rep Article Active vitamin D form 1α,25-dihydroxtvitamin D(3) (1,25(OH)(2)D(3)) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patients with VDDR-II are hardly responsive to physiological doses of 1,25(OH)D(3). Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)(2)D(3,) have limited success and fail to improve the quality of life of affected patients. Thus, various vitamin D analogues have been developed as therapeutic options. In our previous study, we generated genetically modified rats with mutated Vdr(R270L), an ortholog of human VDR(R274L) isolated from the patients with VDDR-II. The significant reduced affinity toward 1,25(OH)(2)D(3) of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D(3). In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)(2)D(3) (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D(3) and 1,25(OH)(2)D(3). A robust osteogenic activity of AH-1 was observed in Vdr(R270L) rats. Only a 40-fold lower dose of AH-1 than that of 25(OH)D(3) was effective in ameliorating rickets symptoms in Vdr(R270L) rats. Therefore, AH-1 may be promising for the therapy of VDDR-II with VDR(R274L). Nature Publishing Group UK 2022-07-22 /pmc/articles/PMC9307643/ /pubmed/35869242 http://dx.doi.org/10.1038/s41598-022-16819-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Nishikawa, Miyu
Murose, Naruhiro
Mano, Hiroki
Yasuda, Kaori
Isogai, Yasuhiro
Kittaka, Atsushi
Takano, Masashi
Ikushiro, Shinichi
Sakaki, Toshiyuki
Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title_full Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title_fullStr Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title_full_unstemmed Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title_short Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
title_sort robust osteogenic efficacy of 2α-heteroarylalkyl vitamin d analogue ah-1 in vdr (r270l) hereditary vitamin d-dependent rickets model rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307643/
https://www.ncbi.nlm.nih.gov/pubmed/35869242
http://dx.doi.org/10.1038/s41598-022-16819-7
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