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.
Hutter, Senta