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 [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. 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 ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. 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 in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with 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 with grafts from wild-type mice.

CONCLUSIONS:

OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.

• Authors: Senta Hutter, Wouter T van Haaften, Anouk Hünerwadel, Katharina Baebler, Neel Herfarth, Tina Raselli, Céline Mamie, Benjamin Misselwitz, Gerhard Rogler, Bruce Weder, Gerard Dijkstra, Chantal Florence Meier, Cheryl de Vallière, Achim Weber, Pedro H Imenez Silva, Carsten A Wagner, Isabelle Frey-Wagner, Pedro A Ruiz, Martin Hausmann
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 12 Issue 11 Pg. 1348-1358 (Nov 15 2018) ISSN: 1876-4479 [Electronic] England
• PMID: 30165600 (Publication Type: Journal Article)

Chemical References

• ACTA2 protein, human
• Actins
• Biomarkers
• CCN2 protein, mouse
• COL3A1 protein, human
• COL3A1 protein, mouse
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Collagen Type III
• GPR68 protein, human
• GPR68 protein, mouse
• RNA, Messenger
• Receptors, G-Protein-Coupled
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• Vim protein, mouse
• Vimentin
• Connective Tissue Growth Factor
• Collagen
• Dextran Sulfate

Topics

• Actins (genetics)
• Animals
• Biomarkers
• Colitis (chemically induced, genetics)
• Collagen (genetics, metabolism)
• Collagen Type I (genetics)
• Collagen Type I, alpha 1 Chain
• Collagen Type III (genetics)
• Connective Tissue Growth Factor (genetics)
• Crohn Disease (genetics, pathology)
• Dextran Sulfate
• Female
• Fibrosis
• Gene Expression
• Humans
• Ileum (metabolism, pathology, transplantation)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• RNA, Messenger (metabolism)
• Receptors, G-Protein-Coupled (genetics)
• Transforming Growth Factor beta1 (genetics)
• Transplantation, Heterotopic
• Vimentin (genetics)