title: Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload.
abstract: The inhibitory Smad7 acts as a critical suppressor of hepcidin, the major regulator of systemic iron homeostasis. In this study we define the mRNA expression of the two functionally related Smad proteins, Smad6 and Smad7, within pathways known to regulate hepcidin levels. Using mouse models for hereditary hemochromatosis (Hfe-, TfR2-, Hfe/TfR2-, Hjv- and hepcidin1-deficient mice) we show that hepcidin, Smad6 and Smad7 mRNA expression is coordinated in such a way that it correlates with the activity of the Bmp/Smad signaling pathway rather than with liver iron levels. This regulatory circuitry is disconnected by iron treatment of Hfe-/- and Hfe/TfR2 mice that significantly increases hepatic iron levels as well as hepcidin, Smad6 and Smad7 mRNA expression but fails to augment pSmad1/5/8 levels. This suggests that additional pathways contribute to the regulation of hepcidin, Smad6 and Smad7 under these conditions which do not require Hfe.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Hospital of Heidelberg, Germany. vujic@embl.de
authors.forename: Maja
authors.initials: M
authors.lastname: Vujić Spasić
authors.forename: Richard
authors.initials: R
authors.lastname: Sparla
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mleczko-Sanecka
authors.forename: Mary C
authors.initials: MC
authors.lastname: Migas
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.forename: Robert E
authors.initials: RE
authors.lastname: Fleming
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011990:Receptors, Transferrin / Q000172:deficiency / Q000235:genetics; D051905:Smad6 Protein / Q000235:genetics* / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D051905:Smad6 Protein; D051906:Smad7 Protein; D007501:Iron