Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33288743.
- Also identified by DOI 10.1038/s41467-020-20069-4 and PMC identifier 7721737.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The bioactive vitamin D<sub>3</sub>, 1α,25(OH)<sub>2</sub>D<sub>3</sub>, 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<sub>3</sub> leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub>-intoxicated mice. As ZK168281 also blunts 1α,25(OH)<sub>2</sub>D<sub>3</sub>-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)<sub>2</sub>D<sub>3</sub>-induced hypercalcemia.
Medical subject headings
- Calcium
- Hypercalcemia
- Receptors, Calcitriol
- Vitamin D