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

The bioactive vitamin D-3, 1 alpha ,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 1 alpha ,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 1 alpha ,25(OH)(2)D-3-intoxicated mice. As ZK168281 also blunts 1 alpha ,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 1 alpha ,25(OH)(2)D-3-induced hypercalcemia. Current therapeutic strategies for vitamin D-induced hypercalcemia are poorly efficient. Here the authors identify a new interaction between the vitamin D receptor (VDR) and WBP4 controlling the subcellular localization of VDR and show that ZK168281, a VDR antagonist, enhances the interaction between VDR and WBP4 blunting VDR signalling and normalizing calcium levels in vitamin D-intoxicated mice.