1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells

The active metabolite of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 , acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which mimic vitamin D 3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation. Since VDR activated by 1,25(OH) 2 D 3 coordinates calcium absorption in the gut and bone remodeling to maintain adequate serum calcium concentrations, this ligand-dependent receptor function is important to prevent rickets, osteomalacia, and hypocalcemic tetany [6]. Thus, many 1,25(OH) 2 D 3 derivatives have been developed as drug candidates for these diseases [7][8][9]. However, VDR activation by high-dose treatment with those types of ligands leads to excessive skeletal calcium release, increases intestinal calcium absorption, and decreases renal calcium excretion, thereby resulting in lethal levels of calcium in the bloodstream, known as hypercalcemia [10].We developed a new type of ligand, 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which

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“…B). These data were in agreement with previous results indicating that DLAMs barely activate VDR function .…”

Section: Resultssupporting

confidence: 94%

“…In previous reports, the effects of several DLAMs on VDR function were validated under unsystematic conditions . To systematically investigate the effects of DLAMs in this study, the human promyelocytic leukemia HL‐60 and the human embryonic kidney HEK‐293 cell lines, in both of which VDR is functional, were treated with each DLAM.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the vitamin D receptor by vitamin D lactam derivatives

et al. 2016

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“…RXRα is the principal partner for VDR binding and formation of this heterodimer is an absolute requirement for translocation to the nucleus and the activation of gene transcription [35]. Prevention of VDR-RXR hetero-dimerization, and subsequent recruitment of transcriptional co-activators, has been observed to reduce 1,25(OH) 2 D 3 -stimulated monocytic differentiation of myeloid cell lines [34,36-38]. Similarly, preventing the association of the VDR/RXR heterodimer with VDREs, by co-expression of DR3-VDRE oligonucleotide decoys, reduced 1,25(OH) 2 D 3 -mediated monocytic differentiation of HL60 cells [39].…”

Section: Translocation Of Vitamin D Receptor (Vdr) To the Nucleus mentioning

confidence: 99%

Vitamin D3-driven signals for myeloid cell differentiation—Implications for differentiation therapy

et al. 2010

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Primitive myeloid leukemic cell lines can be driven to differentiate to monocyte-like cells by 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and, therefore, 1,25(OH) 2 D 3 may be useful in differentiation therapy of myeloid leukemia and myelodysplastic syndromes (MDS). Recent studies have provided important insights into the mechanism of 1,25(OH) 2 D 3 -stimulated differentiation. For myeloid progenitors to complete monocytic differentiation a complex network of intracellular signals has to be activated and/or inactivated in a precise temporal and spatial pattern. 1,25(OH) 2 D 3 achieves this change to the 'signaling landscape' by: i) direct genomic modulation of the level of expression of key regulators of cell signaling and differentiation pathways, and ii) activation of intracellular signaling pathways. An improved understanding of the mode of action of 1,25(OH) 2 D 3 is facilitating the development of new therapeutic regimens.

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“…To investigate this, a vitamin D receptor inhibitor (VDRI) was obtained from the Teijin Institute in Japan. This VDRI (TEI-9647) has been shown to antagonise the VDR in human osteoclasts and monocytes [58][59][60]. However, there is no evidence to date regarding the ability of TEI-9647 to inhibit the VDR in Caco-2 cells.…”

Section: Discussionmentioning

confidence: 99%

The effect of polymeric formula on enterocyte differentiation

et al. 2017

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Exclusive Enteral Nutrition (EEN) is commonly used in the management of Crohn's disease (CD). Polymeric formulae (PF), comprising whole proteins along with the daily requirements of vitamins and minerals, are commonly used for EEN. The mechanism by which several weeks of PF treatment induces remission is incompletely understood and appears to be a combination of modulation of the intestinal microbiota and antiinflammatory effects on the intestinal mucosa. These include a reduction in inflammatory cytokine production and improved barrier function.The hypothesis for the current work was that PF caused an increased rate of differentiation of enterocytes at physiological concentrations. This was tested using Caco-2 cell culture and murine enteroids as in vitro models of the intestine.When Caco-2 cells were treated with PF, it caused an increase in intestinal alkaline phosphatase (IAP) expression and activity, a marker of enterocyte differentiation. This was associated with a decrease in cell proliferation and viability. Murine enteroids dissociated after several hours of exposure to PF, possibly due to interference with Wnt signalling.It was hypothesised that the observed effect of PF on Caco-2 cells might be mediated via the vitamin D receptor (VDR). However, when the activity of this receptor was reduced through use of an inhibitor, no change in PF-induced IAP activity and/or decrease in proliferation was observed. This suggests that the VDR pathway is not the primary driver of the accelerated differentiation seen in PF-treated cells.ii Acknowledgement

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1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells

Abstract: Abstract

Cited by 16 publications

References 30 publications

Regulation of the vitamin D receptor by vitamin D lactam derivatives

Regulation of the vitamin D receptor by vitamin D lactam derivatives

Vitamin D3-driven signals for myeloid cell differentiation—Implications for differentiation therapy

The effect of polymeric formula on enterocyte differentiation

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