Abstract
BackgroundMacrophage stimulating protein (MSP) is a serum growth factor that binds to and activates the receptor tyrosine kinase, Recepteur d'Origine Nantais (RON). A non-synonymous coding variant in MSP (689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD) characterized by chronic inflammation of the digestive tract. We investigated the consequences of this polymorphism for MSP-RON pathway activity and IBD pathogenesis.MethodsRON expression patterns were examined on mouse and human cells and tissues under normal and disease conditions to identify cell types regulated by MSP-RON. Recombinant MSP variants were tested for their ability to bind and stimulate RON and undergo proteolytic activation. MSP concentrations were quantified in the serum of individuals carrying the MSP 689R and 689C alleles.ResultsIn intestinal tissue, RON was primarily expressed by epithelial cells under normal and disease conditions. The 689C polymorphism had no impact on the ability of MSP to bind to or signal through RON. In a cohort of normal individuals and IBD patients, carriers of the 689C polymorphism had lower concentrations of MSP in their serum.ConclusionsBy reducing the quantities of circulating MSP, the 689C polymorphism, or a variant in linkage disequilibrium with this polymorphism, may impact RON ligand availability and thus receptor activity. Given the known functions of RON in regulating wound healing and our analysis of RON expression patterns in human intestinal tissue, these data suggest that decreased RON activity may impact the efficiency of epithelial repair and thus underlie the increased IBD susceptibility associated with the MSP 689C allele.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC) are two clinically distinct forms of inflammatory bowel disease (IBD) characterized by chronic inflammatory responses within the intestinal tract
Proteolytic cleavage of pro-Macrophage stimulating protein (MSP) between R483 and V484 converts it into an active, two-chain disulfide-linked a/b heterodimer able to bind Recepteur d’Origine Nantais (RON) with high affinity and induce receptor signaling [9,10,11]. pro-MSP can be proteolytically activated by a number of different serine proteases, including those involved in the coagulation cascade and induced during inflammatory responses [12,13,14,15]
In order to identify cell types likely to be affected by alterations in MSP activity stemming from the 689C polymorphism, we sought to characterize RON expression in a variety of murine and human cell types
Summary
Crohn’s disease (CD) and ulcerative colitis (UC) are two clinically distinct forms of inflammatory bowel disease (IBD) characterized by chronic inflammatory responses within the intestinal tract. A major difficulty in using GWAS data to infer disease-relevant biology and/or identify therapeutic targets is the lack of information on the identity of causative alleles associated with susceptibility loci and the effect that these genetic variations have on specific biological processes. Using both GWAS and candidate gene approaches, several groups have identified polymorphisms in macrophage stimulating protein (MSP, known as hepatocyte growth factor-like (HGFL) and MST1) that are associated with susceptibility to both CD and UC [2,3,4,5,6,7,8]. We investigated the consequences of this polymorphism for MSP-RON pathway activity and IBD pathogenesis
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