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

Daniela Rovito, Anna Y. Belorusova, Sandra Chalhoub, Anna-Isavella Rerra, Elvire Guiot, Arnaud Molin, Agnès Linglart, Natacha Rochel, Gilles Laverny () and Daniel Metzger ()
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Daniela Rovito: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Anna Y. Belorusova: Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca
Sandra Chalhoub: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Anna-Isavella Rerra: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Elvire Guiot: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Arnaud Molin: Université de Normandie, UNICAEN, CHU de Caen Normandie, Service de Génétique
Agnès Linglart: Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR)
Natacha Rochel: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Gilles Laverny: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Daniel Metzger: Institut de Génétique et de Biologie Moléculaire et Cellulaire

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The bioactive vitamin D3, 1α,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 1α,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 1α,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1α,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 1α,25(OH)2D3-induced hypercalcemia.

Date: 2020
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DOI: 10.1038/s41467-020-20069-4

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