Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis.
OBJECTIVE
Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis. Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in hereditary hemochromatosis mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6-SMAD regulation of hepcidin expression.


METHODS
The BMP6-SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice.


RESULTS
Liver levels of Bmp6 messenger RNA (mRNA) were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes.


CONCLUSIONS
HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron.
Corradini
Elena
E
Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Garuti
Cinzia
C
Montosi
Giuliana
G
Ventura
Paolo
P
Andriopoulos
Billy
B
Lin
Herbert Y
HY
Pietrangelo
Antonello
A
Babitt
Jodie L
JL
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D019266:Iron, Dietary / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D019266:Iron, Dietary; D008565:Membrane Proteins; D012333:RNA, Messenger; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse