title: Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice.
abstract: Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. How iron levels are sensed to regulate hepcidin production is not known, but local induction of liver BMP6 expression by iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and iron homeostasis regulation, we generated mice with tissue-specific ablation of Bmp6 in different liver cell populations and evaluated their iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidal membrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominant source of BMP6 in the liver and support a model in which EC BMP6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin transcription and maintain systemic iron homeostasis.
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Canali
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen-Bullough
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Core
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bouley
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, and.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000172:deficiency / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D016130:Immunophenotyping; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012333:RNA, Messenger; D007501:Iron; C045073:Cre recombinase; D019426:Integrases