Section A Project A01

Regulatory mechanisms linking chronic gut inflammation and bone loss

Intestinal inflammation triggers profound bone loss, suggesting that intestinal epithelial barrier and gut vascular barrier influences bone homeostasis (Wakkach, et al., 2015; Ciucci, et al., 2015). This project aims to elucidate how gut vascular barrier dysfunction affects bone. Our preliminary data suggest that erythropoietin (EPO)/EPO-R signaling in colonic endothelial cells determines vascular stability and intestinal barrier function and promotes intestinal inflammation. We hypothesize that the sensitized intestinal endothelium allows translocation of bacteria or bacterial products and drives diapedesis of primed T cells to support the secretion of osteoclast-promoting – microbiota-specific – Ig antibodies by intestinal B cells. We will therefore study bone loss in the context of intestinal inflammation induced by EPO exposure, as well as the impact of vascular dysfunction in the gut and the bones on bone loss in the context of inducible arthritis. In addition, we will study the effect of the (A>G) EPO SNP that determines EPO function on the human bone phenotype.