Supported by grants from the Broad Medical Research Program (IBD-0253) and the National Institutes of Health (R56 AI089700) to B.J.C., and by an unrestricted educational grant from Wyeth Nutrition to L.W.
Version of Record online: 23 FEB 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 1, pages 112–119, January 2012
How to Cite
Wang, L., Trebicka, E., Fu, Y., Ellenbogen, S., Hong, C. C., Babitt, J. L., Lin, H. Y. and Cherayil, B. J. (2012), The bone morphogenetic protein–hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis, 18: 112–119. doi: 10.1002/ibd.21675
Conflicts of interest: H.Y.L. and J.L.B. have ownership interest in Ferrumax Pharmaceuticals, which has licensed technology from Massachusetts General Hospital based on their work. A patent application entitled “Methods and Composition to Regulate Iron Metabolism” has been submitted by Massachusetts General Hospital.
- Issue online: 11 DEC 2011
- Version of Record online: 23 FEB 2011
- Manuscript Accepted: 12 JAN 2011
- Manuscript Received: 5 JAN 2011
- bone morphogenetic protein;
A debilitating anemia associated with low serum iron often accompanies inflammatory bowel disease (IBD). Increased production of the iron regulatory hormone hepcidin is implicated in its pathogenesis and may also contribute to the inflammatory process itself. Hepcidin expression is dependent on bone morphogenetic proteins (BMPs) like BMP6, but the mechanisms that increase hepcidin levels during intestinal inflammation are not clear. Here we test the hypothesis that inhibiting hepcidin expression may have beneficial effects in IBD, and also shed light on the mechanism of colitis-induced hepcidin upregulation.
Mice with T cell transfer colitis were treated with vehicle or one of three anti-BMP reagents: HJV.Fc, a recombinant protein that prevents binding of BMPs to their receptor, LDN-193189, a small molecule inhibitor of BMP signal transduction, and an anti-BMP6 antibody. The effects of these reagents on colitis severity, liver hepcidin mRNA, and serum iron were determined. The mechanism of hepcidin upregulation was investigated by examining BMP6 expression and activity and the effects of IL-6 deficiency.
All the anti-BMP reagents inhibited hepcidin expression and increased serum iron levels in the colitic mice. They also produced modest reductions in colon inflammatory cytokine expression. Although hepcidin upregulation during colitis was dependent on BMP6, it was not associated with increased BMP6 expression or activity. IL-6 was required for increased hepcidin expression during colitis.
Inhibiting hepcidin expression may help to correct the anemia of IBD and may also attenuate intestinal inflammation. The mechanism of colitis-induced hepcidin upregulation involves both BMP6 and IL-6. (Inflamm Bowel Dis 2011)