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Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.
- Source :
-
Nature communications [Nat Commun] 2020 Dec 07; Vol. 11 (1), pp. 6249. Date of Electronic Publication: 2020 Dec 07. - Publication Year :
- 2020
-
Abstract
- The bioactive vitamin D <subscript>3</subscript> , 1α,25(OH) <subscript>2</subscript> D <subscript>3</subscript> , 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 <subscript>3</subscript> leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH) <subscript>2</subscript> D <subscript>3</subscript> 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) <subscript>2</subscript> D <subscript>3</subscript> -intoxicated mice. As ZK168281 also blunts 1α,25(OH) <subscript>2</subscript> D <subscript>3</subscript> -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) <subscript>2</subscript> D <subscript>3</subscript> -induced hypercalcemia.
- Subjects :
- Animals
Calcitriol analogs & derivatives
Calcitriol pharmacology
Cell Line
Cell Line, Tumor
Cytosol metabolism
Gene Expression drug effects
HeLa Cells
Humans
Hypercalcemia genetics
Hypercalcemia prevention & control
Male
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins genetics
Nuclear Proteins metabolism
Protein Binding
RNA-Binding Proteins genetics
RNA-Binding Proteins metabolism
Rats
Receptors, Calcitriol genetics
Vitamin D analogs & derivatives
Calcium metabolism
Hypercalcemia metabolism
Receptors, Calcitriol metabolism
Vitamin D pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33288743
- Full Text :
- https://doi.org/10.1038/s41467-020-20069-4