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

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 patients...

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Bibliographic Details
Published in:Scientific reports Vol. 12; no. 1; pp. 1 - 10
Main Authors: Nishikawa, Miyu, Murose, Naruhiro, Mano, Hiroki, Yasuda, Kaori, Isogai, Yasuhiro, Kittaka, Atsushi, Takano, Masashi, Ikushiro, Shinichi, Sakaki, Toshiyuki
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22-07-2022
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Subjects:
631/154
631/337
692/163
692/699
Affinity
Calcitriol
Calcium
Calcium homeostasis
Gene regulation
Homeostasis
Humanities and Social Sciences
Ligands
multidisciplinary
Osteogenesis
Quality of life
Rickets
Science
Science (multidisciplinary)
Vitamin D
Vitamin D receptors
Vitamin D-dependent rickets
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Summary: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).
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-16819-7