title: The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease.
abstract: 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.
authors.affiliation: Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Wang
authors.forename: Estela
authors.initials: E
authors.lastname: Trebicka
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.forename: Shiri
authors.initials: S
authors.lastname: Ellenbogen
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Cherayil
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D064451:Hepcidins; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000637:transplantation
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D007501:Iron