• Endothelial Bmp6 conditional knockout mice exhibit hemochromatosis, whereas hepatocyte and macrophage Bmp6 conditional knockout mice do not.• Our data support a model in which EC Bmp6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin production.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. (Blood. 2017;129(4):405-414) IntroductionIron homeostasis is tightly controlled to ensure sufficient iron for erythropoiesis and other fundamental metabolic processes and to prevent the toxicity of excess iron.1 The peptide hormone hepcidin is a master regulator of systemic iron balance by mediating the degradation of the iron export protein ferroportin to limit dietary iron absorption and macrophage iron recycling.2 Hepcidin production in the liver is carefully titrated in response to changes in organismal iron content and iron utilization requirements.1 Failure to appropriately induce hepcidin in response to iron is a central feature of hereditary hemochromatosis, a genetic disorder characterized by excess iron deposits in the liver, heart, and endocrine glands, resulting in organ dysfunction. 3 The most severe juvenile-onset form of this disease is caused by mutations in the genes encoding hepcidin itself (HAMP) or hemojuvelin (HFE2, also known as HJV), which regulates hepcidin transcription in hepatocytes. 4,5 Mice with global or hepatocyte-specific deletion of these genes have a similar iron overload phenotype, 6-11 confirming the essential role of hepat...
Hepcidin is a key iron regulatory hormone that controls expression of the iron exporter ferroportin to increase the iron supply when needed to support erythropoiesis and other essential functions, but to prevent the toxicity of iron excess. The bone morphogenetic protein (BMP)-SMAD signaling pathway, through the ligand BMP6 and the co-receptor hemojuvelin, is a central regulator of hepcidin transcription in the liver in response to iron. Here, we show that dietary iron loading has a residual ability to induce Smad signaling and hepcidin expression in Bmp6−/− mice, effects that are blocked by a neutralizing BMP2/4 antibody. Moreover, BMP2/4 antibody inhibits hepcidin expression and induces iron loading in wildtype mice, whereas a BMP4 antibody has no effect. Bmp2 mRNA is predominantly expressed in endothelial cells of the liver, where its baseline expression is higher, but its induction by iron is less robust than Bmp6. Mice with a conditional ablation of Bmp2 in endothelial cells exhibit hepcidin deficiency, serum iron overload, and tissue iron loading in liver, pancreas and heart, with reduced spleen iron. Together, these data demonstrate that in addition to BMP6, endothelial cell BMP2 has a non-redundant role in hepcidin regulation by iron.
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