title: Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.
abstract: Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys.
  
  
  CONCLUSIONS
  These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice.
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Latour
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Besson-Fournier
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Meynard
authors.affiliation: San Raffaele Scientific Institute & Vita-Salute University, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Gourbeyre
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.|Laboratory of Haematology, CHRU de Montpellier, Hôpital Saint Eloi, Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Martinez
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Coppin
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007501:Iron; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011990:Receptors, Transferrin / Q000235:genetics*
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D007501:Iron