4 research departments
750 employees
45 nationalities
55 research teams
16 ERC laureates
260 publications per year
24000 m² lab area

Support us through

Fondation universite de Strasbourg

Communication Service

Tél. +33(0) 3 88 65 35 47

Quick Links

Science & society

Key figures 2014

11 ERC grants
16 prizes and distinctions
3 public events
23 major scientific news

Scientific news

Discovery of a dark side of vitamin D deficiency: the repressive activity of its receptor

© IGBMC

The Vitamin D receptor (VDR) activates numerous genes following binding of bioactive vitamin D (calcitriol, A).
Gemini
analog bound to the mutated receptor VDRgem have similar effects (B).
On the other hand, VDRgem cannot bind calcitriol (C). This induces a repression of numerous genes and leads to rickets that are more severe than in the absence of the receptor.

A vitamin d receptor selectively activated by gemini analogs reveals ligand dependent and independent effects.

Huet T(1), Laverny G(2), Ciesielski F(1), Molnár F(1), Ramamoorthy TG(2), Belorusova AY(1), Antony P(1), Potier N(3), Metzger D(4), Moras D(1), Rochel N(5).

Cell Rep Feb. 3, 2015


Jan. 22, 2015

Having identified precisely how vitamin D binds to its receptor, a study coordinated by Natacha Rochel and Dino Moras (Department of Integrated Structural Biology, IGBMC) and Daniel Metzger (Department of Functional Genomics and Cancer, IGBMC) explains the severe skeletal defects of patients carrying mutations of this receptor and osteoporosis due to vitamin D deficiency.

The researchers indeed showed that the absence of Vitamin D binding to its receptor leads to a more severe calcium deficiency than in the absence of receptor. Their results, published on January 22nd 2015 in Cell Reports, also pave a way to identify Vitamin D analogs for the treatment of various pathologies like osteoporosis, neuro-degenerative and autoimmune diseases, as well as cancer.

 

Vitamin D and its receptor: a duet with multiple effects

Vitamin D - under its active form termed calcitriol [1 α, 25-dihydroxyvitamine D3] is a key hormone for the regulation of calcium levels which controls the expression of numerous genes, in various cell types, via its nuclear receptor, VDR.
Calcitriol deficiency - induced by low sunlight exposure or dysfunction of the enzyme inducing its synthesis – causes  hypocalcemia and bone decalcification. VDR mutations are responsible for a rare hereditary disease, Vitamin D Resistant Rickets (HVDRR), associated with alopecia in case of total VDR loss-of-function.
At low doses, calcitriol reduces hypocalcemia and skeletal decalcification. At high doses, it could represent a treatment for neuro-degenerative and autoimmune diseases, as well as cancer, due to its anti-proliferative and anti-inflammatory activities. Nevertheless, the required doses induce then calcification of organs like kidney, heart and blood vessels.
To dissociate the effects of vitamin D, numerous academic laboratories and pharmaceutical companies synthesized calcitriol derivatives, termed analogs. However, the reduced therapeutic window of these compounds limits their clinical use.


Back to the basis: from the Vitamin D Receptor structure to its activity
To characterize the molecular and cellular mechanisms underlying the effects of Vitamin D, a multidisciplinary study was led by two complementary IGBMC teams.
Having collected and analyzed very precise structural data of VDR complexes with calcitriol and with analogs of the Gemini family, the researchers produced a new Vitamin D receptor – termed VDRgem - that binds Gemini but not calcitriol.
They analyzed the effects of VDRgem and showed that its presence impairs much more calcium homeostasis than in the absence of Vitamin D receptor, but does not affect hair cycle.
This result indicates that alopecia does not reflect the severity of Vitamin D Resistant Rickets (HVDRR).
These studies also showed that:
- the presence of  VDR alone (without vitamin D bound to it) has a repressive activity on numerous genes regulating calcium homeostasis;
- the expression of VDR target genes and the levels of calcium are restored in mice expressing VDRgem by administration of Gemini analogs.


Towards new Vitamin D analogs as drugs
Beyond these first results, the VDRgem receptor will facilitate the identification of the various effects controlled by vitamin D, in particular those inducing hypercalcemia.
Thus, the results published today should allow to identify Vitamin D analogs as drugs  for various pathologies.

Imprimer Envoyer

Université de Strasbourg
INSERM
CNRS

IGBMC - CNRS UMR 7104 - Inserm U 964
1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX / France Tél +33 (0)3 88 65 32 00 / Fax +33 (0)3 88 65 32 01 / directeur.igbmc@igbmc.fr