title: Altered hepatic BMP signaling pathway in human HFE hemochromatosis.
abstract: Human hemochromatosis (HC) has been associated with the common C282Y polymorphism of HFE or rare pathogenic mutations of TfR2, HJV, FPN and HAMP. All forms of human HC seem to be caused by low or inadequate levels of hepcidin, the iron hormone. We and others have recently shown that Hfe(-/-) mice exhibit an impairment in the bone morphogenetic protein (BMP) signaling pathway controlling hepcidin. However, all data indicating the central role of BMPs in hepcidin regulation and an impaired BMP/SMAD signaling in HC have been collected in mice. In this study we investigated whether also in humans the expression of BMP signaling targets, SMAD7 and Id1, are associated with liver iron concentration (LIC) and whether such regulation is disrupted in HFE-HC. We correlated the mRNA expression, assessed by RT-PCR, of HAMP, SMAD7 and Id1 with LIC in liver biopsies from patients with normal iron status, HFE-HC or non-HC hepatic iron overload. We found that in human liver, not only HAMP, but also SMAD7 and Id1 mRNA significantly correlate with the extent of hepatic iron burden. However, this correlation is lost in patients with HFE-HC, but maintained in subjects with non-hemochromatotic iron overload. These data indicate that in human HFE-HC a disrupted BMP/SMAD signaling in the liver is key in the pathogenesis of the disease.
authors.affiliation: Center for Hemochromatosis, University Hospital of Modena, Modena, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Bolondi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Garuti
authors.forename: Elena
authors.initials: E
authors.lastname: Corradini
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Vogel
authors.forename: Armin
authors.initials: A
authors.lastname: Finkenstedt
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Antonello
authors.initials: A
authors.lastname: Pietrangelo
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D019190:Iron Overload / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D008565:Membrane Proteins; D012333:RNA, Messenger; C497806:SMAD7 protein, human; D051906:Smad7 Protein