title: Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis.
abstract: Hereditary hemochromatosis (HH) is a common inherited iron overload disorder. The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively).
  
  
  CONCLUSIONS
  New data arising from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease.
authors.affiliation: Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland. jdpryan@yahoo.co.uk
authors.forename: John D
authors.initials: JD
authors.lastname: Ryan
authors.forename: Eleanor
authors.initials: E
authors.lastname: Ryan
authors.forename: Aurelie
authors.initials: A
authors.lastname: Fabre
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Lawless
authors.forename: John
authors.initials: J
authors.lastname: Crowe
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000172:deficiency*; D055418:Bone Morphogenetic Protein 6 / Q000502:physiology*; D006432:Hemochromatosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D019190:Iron Overload / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology*; D051905:Smad6 Protein / Q000096:biosynthesis*; D051906:Smad7 Protein / Q000096:biosynthesis*; D051904:Smad8 Protein / Q000235:genetics; D015854:Up-Regulation
chemical_list: D023181:Antimicrobial Cationic Peptides; D055418:Bone Morphogenetic Protein 6; C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051905:Smad6 Protein; D051906:Smad7 Protein; D051904:Smad8 Protein