9th Annual BMRP Investigator Meeting - Abstract
Targeting the Bone Morphogenetic Protein-Hepcidin Axis in Intestinal Inflammation
Lijian Wang1, Estela Trebicka1, Ying Fu1, Shiri Ellenbogen1, Herbert Y. Lin2, Jodie L. Babitt2 and Bobby J. Cherayil1,a
1Mucosal Immunology Laboratory and 2Program in Membrane Biology, Massachusetts General Hospital (Boston, Massachusetts, U.S.A.)
The secreted, hepatocyte-derived peptide hepcidin is the central regulator of iron homeostasis. Hepcidin levels are elevated in chronic inflammatory conditions, leading to intracellular iron sequestration and a refractory iron deficiency anemia. Our preliminary studies showed that hepcidin expression is increased in murine colitis and contributes to the inflammatory process itself as well as to the associated dysregulation of iron metabolism. Therefore, we carried out investigations to determine if inhibiting hepcidin production would have beneficial effects in the T cell transfer colitis model of IBD. Our strategy was based on using broad-spectrum and selective inhibitors of bone morphogenetic proteins (BMPs) that are required for hepcidin expression. We found that 3 structurally and mechanistically distinct BMP inhibitors, including one that selectively blocked BMP6, significantly reduced hepcidin expression and increased serum iron concentrations in the colitic mice. A modest reduction in the severity of colitis was also seen. Our results suggest that reagents that block hepcidin expression could have clinical benefits in IBD by virtue of their ability to correct abnormal iron metabolism and prevent or treat the associated anemia. They may also help to attenuate the intestinal inflammation.