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

Abstract

The bioactive vitamin D3, 1α,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 1α,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 1α,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1α,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 1α,25(OH)2D3-induced hypercalcemia.

Design, Synthesis, Evaluation and Structure of Allenic 1α,25‐Dihydroxyvitamin D3 Analogs with Locked Mobility at C‐17

“…To determine the effects of 2 d in vivo, wild type mice were daily treated with various doses of 2 d and 1 for 5 days. In agreement with previous results, [24] 1 μg/kg of 1 induced hypercalcemia and the transcript levels of the vitamin D target genes Cyp24a1 and S100g in the kidney (Figure 3, D-E). However, the renal transcript levels were similar in mice treated with 2 d and with vehicle (Figure 3, D-E).…”

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3

“…The docking data were substantially corroborated by the crystal structures of 3a and 3b in complex with zebrafish (z) VDR LBD and a peptide encompassing the second LXXLL motif of NCoA1 solved by X-ray crystallography to a resolution of 2.6 Å. Note that we have previously shown that the binding of 1,25D 3 to zVDR LBD is similar to that of hVDR LBD , and to that of full-length hVDR . The detailed statistics of diffraction data collection and structural refinement are summarized in Table S1.…”

“…Note that we have previously shown that the binding of 1,25D 3 to zVDR LBD is similar to that of hVDR LBD 68,69 and to that of full-length hVDR. 70 The detailed statistics of diffraction data collection and structural refinement are summarized in Table S1. Both VDR complexes adopt the active conformation with H12 in agonist position, forming together with helices H3 and H4 the coactivator binding site.…”

Advances in Vitamin D Receptor Function and Evolution Based on the 3D Structure of the Lamprey Ligand-Binding Domain

“…(C) Averaged equilibrium dissociation constants for the interactions of VDR LBDs with the hRXRα LBD from two to three independent experiments. *From ref .…”