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, Daniel METZGER
Abstract
Abstract The bioactive vitamin D 3 , 1α,25(OH) 2 D 3 , 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 3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH) 2 D 3 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) 2 D 3 -intoxicated mice. As ZK168281 also blunts 1α,25(OH) 2 D 3 -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) 2 D 3 -induced hypercalcemia.