| First Author | Rovito D | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 6249 |
| PubMed ID | 33288743 | Mgi Jnum | J:300970 |
| Mgi Id | MGI:6504559 | Doi | 10.1038/s41467-020-20069-4 |
| Citation | Rovito D, et al. (2020) Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia. Nat Commun 11(1):6249 |
| abstractText | The bioactive vitamin D3, 1alpha,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 1alpha,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 1alpha,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1alpha,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 1alpha,25(OH)2D3-induced hypercalcemia. |
