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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.

ABSTRACT: Active vitamin D form 1α,25-dihydroxtvitamin D₃ (1,25(OH)₂D₃) 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)D₃. Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)₂D_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)₂D₃ of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D₃. In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)₂D₃ (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D₃ and 1,25(OH)₂D₃. 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)D₃ 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).

SUBMITTER: Nishikawa M

PROVIDER: S-EPMC9307643 | biostudies-literature |

REPOSITORIES: biostudies-literature

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