Relevance of the vitamin d receptor in complications associated with crohn's disease

Resumen

Crohn’s disease (CD) is a chronic gastrointestinal inflammatory disorder with an unknown aetiology with alternating periods of relapses and remissions. The transmural involvement of CD leads to complications, such as strictures or fistulas, that often require surgery. Fibrosis is usually detected in CD and is characterized by a dysregulation of the equilibrium between the production and the degradation of the extracellular matrix. There is no effective treatment for intestinal fibrosis in CD, which makes a better understanding of the etiopathogenesis of CD essential. GWAS studies have revealed single nucleotide polymorphisms (SNP) in different genes associated with CD. Among them, TaqI SNP in the vitamin D receptor (VDR) gene has been reported as a risk factor for CD. VDR is a member of the nuclear receptor family of transcription factors, and vitamin D constitutes its main ligand. VD deficiency and defective signalling have been reported in CD patients. In recent years, PDIA3 has emerged as a vitamin D receptor. The aim of this work was to analyse the relevance of genetic polymorphisms and the VD/VDR/PDIA3 pathway in CD complications. First, we detected that homozygosity for the C allele in CD patients was associated with reduced VDR protein levels and higher expression of IL-1β in PBMCs, as well as an elevated lymphocyte activation and a higher probability of deriving towards a penetrating phenotype. We also observed a lower expression of VDR and a higher expression of PDIA3 in intestinal resections and in isolated intestinal fibroblasts from CD patients vs controls. PDIA3 levels correlated with COL1A1 levels in intestinal tissue, and down-regulation of the PDIA3 receptor in control fibroblasts was associated with decreased COL1A1 expression and increased VDR protein levels. In addition, a reduced expression of VDR and an increase in PDIA3 were detected in fibroblasts from control subjects who were homozygous for the C allele in the TaqI SNP of VDR, providing strong evidence of a crosstalk between the two VD receptors. VD treatment increased VDR protein levels in control fibroblasts. VD also induced a slight increase in VDR expression and a decrease in PDIA3 in fibroblasts isolated from the damaged mucosa of CD patients. Finally, the systemic treatment of mice with VD prevented intestinal fibrosis induced by the heterotopic transplant model. The effects of VD were mediated by modulation of the immune system and a direct action of VD on intestinal fibroblasts. In summary, this study demonstrates reduced VDR protein levels in PBMCs and fibroblasts from CD patients carrying the TaqI SNP of the VDR gene, and shows that these patients are more prone to develop a penetrating phenotype. VD increased VDR and decreased PDIA3 expression in intestinal fibroblasts from CD patients, which correlates with a reduced expression of markers of fibrosis. These effects may be involved in the anti-fibrotic effect of VD demonstrated in the in vivo murine model.