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Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.


ABSTRACT: The bioactive vitamin D3, 1?,25(OH)2D3, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1?,25(OH)2D3 synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1?,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1?,25(OH)2D3-induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1?,25(OH)2D3-induced hypercalcemia.

SUBMITTER: Rovito D 

PROVIDER: S-EPMC7721737 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.

Rovito Daniela D   Belorusova Anna Y AY   Chalhoub Sandra S   Rerra Anna-Isavella AI   Guiot Elvire E   Molin Arnaud A   Linglart Agnès A   Rochel Natacha N   Laverny Gilles G   Metzger Daniel D  

Nature communications 20201207 1


The bioactive vitamin D<sub>3</sub>, 1α,25(OH)<sub>2</sub>D<sub>3</sub>, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D<sub>3</sub> leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)<sub>2</sub>D<sub>3</sub> synthesis, but are poorly efficie  ...[more]

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