Header

UZH-Logo

Maintenance Infos

Intestinal activation of pH-sensing receptor OGR1 (GPR68) contributes to fibrogenesis


Abstract

Background and aims pH-sensing ovarian cancer G-protein coupled receptor-1 (OGR1/GPR68) is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases (IBD) express increased mucosal levels of OGR1 compared to non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extra-cellular acidification leads to fibroblast activation and extracellular matrix remodeling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease (CD) patients, and the effect of Ogr1 deficiency in fibrogenesis. Methods Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analyzed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate (DSS)-induced chronic colitis and the heterotopic intestinal transplantation model were used. Results Increased expression of fibrosis markers was accompanied by an increase of OGR1 (2.71±0.69 vs. 1.18±0.03,P=0.016) in fibrosis-affected human terminal ileum, compared to the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines (TGFB1 and CTGF) and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared to grafts from wildtype mice. Conclusions OGR1 expression correlates with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency is associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.

Abstract

Background and aims pH-sensing ovarian cancer G-protein coupled receptor-1 (OGR1/GPR68) is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases (IBD) express increased mucosal levels of OGR1 compared to non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extra-cellular acidification leads to fibroblast activation and extracellular matrix remodeling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease (CD) patients, and the effect of Ogr1 deficiency in fibrogenesis. Methods Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analyzed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate (DSS)-induced chronic colitis and the heterotopic intestinal transplantation model were used. Results Increased expression of fibrosis markers was accompanied by an increase of OGR1 (2.71±0.69 vs. 1.18±0.03,P=0.016) in fibrosis-affected human terminal ileum, compared to the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines (TGFB1 and CTGF) and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared to grafts from wildtype mice. Conclusions OGR1 expression correlates with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency is associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

2 downloads since deposited on 01 Nov 2018
2 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 November 2018
Deposited On:01 Nov 2018 12:34
Last Modified:17 Nov 2018 02:05
Publisher:Oxford University Press
ISSN:1873-9946
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Journal of Crohn's & Colitis following peer review. The definitive publisher-authenticated version Intestinal activation of pH-sensing receptor OGR1 (GPR68) contributes to fibrogenesis is available online at: https://doi.org/10.1093/ecco-jcc/jjy118
OA Status:Green
Publisher DOI:https://doi.org/10.1093/ecco-jcc/jjy118
PubMed ID:30165600

Download

Download PDF  'Intestinal activation of pH-sensing receptor OGR1 (GPR68) contributes to fibrogenesis'.
Preview
Content: Accepted Version
Filetype: PDF
Size: 1MB