Diminished Vitamin D Receptor Protein Levels in Crohn's Disease Fibroblasts: Effects of Vitamin D.

Laura Gisbert-Ferrándiz,Dolores Ortiz-Masiá,Jesús Cosín-Roger,Juan V Esplugues,Joaquín Hinojosa,María D Barrachina,Francisco Navarro,Sara Calatayud,Dulce C Macias-Ceja,Pedro Salvador,Carlos Hernández

doi:10.3390/nu12040973

Abstract

Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.

Highlights

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by transmural inflammation, which often leads to intestinal fibrosis and the formation of strictures.Current pharmacological anti-inflammatory treatment does not prevent fibrosis in susceptible patients, and surgery is required in a high percentage of patients which, does not rule out recurrence [1,2].In recent years, a better knowledge of the fibrotic pathways has emerged from other organs [3,4], and the assessment of some anti-fibrotic therapies has been proposed for CD patients [5,6]
Vitamin D receptor (VDR) Expression Is Diminished in Intestinal Resections of CD Patients
In epithelial crypts isolated from intestinal resections from CD patients, we found a diminution in protein levels of VDR (51.5 ± 29.2%) compared with those obtain from control tissue (Figure 1c)

Summary

Introduction

Current pharmacological anti-inflammatory treatment does not prevent fibrosis in susceptible patients, and surgery is required in a high percentage of patients which, does not rule out recurrence [1,2]. A better knowledge of the fibrotic pathways has emerged from other organs [3,4], and the assessment of some anti-fibrotic therapies has been proposed for CD patients [5,6]. The lack of current clinical trials forces us to better understand the etiopathogenesis of intestinal fibrosis. Clinical studies report serum Vitamin D (VD) levels lower than 20 ng/mL or 50 nmol/L in CD patients, a situation that has been qualified as VD deficiency and explained by the reduced food intake or malnutrition characteristic of these patients [9,10,11]. Little is known about the mechanistic basis that explicates both how VD deficiency contributes to the pathogenesis of CD and the beneficial effects of VD in these patients

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