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

Date publication

décembre 2020

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel , Dr ROCHEL-GUIBERTEAU Natacha , Dr LAVERNY Gilles

Tous les auteurs :
Rovito D, Belorusova AY, Chalhoub S, Rerra AI, Guiot E, Molin A, Linglart A, Rochel N, Laverny G, Metzger D

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33288743

Résumé

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

Référence

Nat Commun. 2020 12 7;11(1):6249