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

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Tytuł:: Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.
Autorzy:: Rovito D; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France.; Université de Strasbourg, Illkirch, France.
Belorusova AY; Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Chalhoub S; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France.; Université de Strasbourg, Illkirch, France.
Rerra AI; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France.; Université de Strasbourg, Illkirch, France.
Guiot E; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France.; Université de Strasbourg, Illkirch, France.
Molin A; Université de Normandie, UNICAEN, CHU de Caen Normandie, Service de Génétique, EA 7450 BIOTARGEN, Caen, France.; Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Paris, France.
Linglart A; Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Paris, France.; Université de Paris Saclay, AP-HP, Hôpital Bicêtre, DMU SEA, INSERM, U1185, Le Kremlin Bicêtre, France.
Rochel N; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France.; Université de Strasbourg, Illkirch, France.
Laverny G; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. .; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. .; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France. .; Université de Strasbourg, Illkirch, France. .
Metzger D; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. .; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. .; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France. .; Université de Strasbourg, Illkirch, France. .
Źródło:: Nature communications [Nat Commun] 2020 Dec 07; Vol. 11 (1), pp. 6249. Date of Electronic Publication: 2020 Dec 07.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Calcium/*metabolism
Hypercalcemia/*metabolism
Receptors, Calcitriol/*metabolism
Vitamin D/*pharmacology
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
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Substance Nomenclature:: 0 (Nuclear Proteins)
0 (RNA-Binding Proteins)
0 (Receptors, Calcitriol)
0 (Vdr protein, mouse)
0 (ZK 168281)
1406-16-2 (Vitamin D)
FXC9231JVH (Calcitriol)
SY7Q814VUP (Calcium)
Entry Date(s):: Date Created: 20201208 Date Completed: 20201228 Latest Revision: 20201228
Update Code:: 20240104
PubMed Central ID:: PMC7721737
DOI:: 10.1038/s41467-020-20069-4
PMID:: 33288743
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The bioactive vitamin D 3 , 1α,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 1α,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 1α,25(OH) 2 D 3 -intoxicated mice. As ZK168281 also blunts 1α,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 1α,25(OH) 2 D 3 -induced hypercalcemia.

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