The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease.

Wang L, Trebicka E, Fu Y, Ellenbogen S, Hong CC, Babitt JL, Lin HY, Cherayil BJ
Inflamm Bowel Dis. 2012 18 (1): 112-9

PMID: 21351217 · PMCID: PMC3139830 · DOI:10.1002/ibd.21675

BACKGROUND - 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.

METHODS - 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.

RESULTS - 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.

CONCLUSIONS - 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.

Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

MeSH Terms (19)

Animals Anti-Bacterial Agents Antimicrobial Cationic Peptides Blotting, Western Bone Morphogenetic Protein 6 Colitis Hepcidins Inflammatory Bowel Diseases Interleukin-6 Iron Male Mice Mice, Inbred C57BL Pyrazoles Pyrimidines Real-Time Polymerase Chain Reaction RNA, Messenger Signal Transduction T-Lymphocytes

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