The Experts below are selected from a list of 1314 Experts worldwide ranked by ideXlab platform
Jodie L. Babitt - One of the best experts on this subject based on the ideXlab platform.
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endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
Blood, 2017Co-Authors: Susanna Canali, Kimberly B Zumbrennenbullough, Amanda B Core, Chiayu Wang, Manfred Nairz, Richard Bouley, Filip K Swirski, Jodie L. BabittAbstract: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.
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activin b induces noncanonical smad1 5 8 signaling via bmp type i receptors in hepatocytes evidence for a role in hepcidin induction by inflammation in male mice
Endocrinology, 2016Co-Authors: Susanna Canali, Alan L Schneyer, Antonello Pietrangelo, Kimberly B Zumbrennenbullough, Amanda B Core, Chiayu Wang, Maria Merkulova, Jodie L. BabittAbstract:Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor Hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by Hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.
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Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis.
Frontiers in Pharmacology, 2014Co-Authors: Amanda B Core, Susanna Canali, Jodie L. BabittAbstract:Mutations in Hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
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A novel validated enzyme-linked immunosorbent assay to quantify soluble Hemojuvelin in mouse serum
Haematologica, 2012Co-Authors: Wenjie Chen, Jodie L. Babitt, Chia Chi Sun, Shanzhuo Chen, Delphine Meynard, Herbert Y. LinAbstract:Hemojuvelin is a critical regulator of hepcidin expression and can be cleaved by proteases to form soluble Hemojuvelin. Soluble Hemojuvelin has been recently identified in human serum but the presence and quantity of soluble Hemojuvelin in mouse serum is unknown. We developed a two-site enzyme-linked immunosorbent assay using a monoclonal anti-Hemojuvelin as the capture antibody and a biotinylated polyclonal anti-Hemojuvelin as the detection antibody to quantify the levels of soluble Hemojuvelin in mouse serum. We validated this assay using cell-conditioned media and serum from Hemojuvelin-null and Bone morphogenetic protein 6-null mice. We also used this validated assay to measure serum soluble Hemojuvelin concentrations in mice receiving an acute low iron or high iron treatment. This two-site enzyme-linked immunosorbent assay was highly specific for mouse Hemojuvelin, with a lower limit of detection at 13.2-26.8 ng/mL of soluble Hemojuvelin in mouse serum. The median serum soluble Hemojuvelin concentration in wild-type C57BL/6J mice was 57.9±22 ng/mL, which is 4- to 20-fold less than that reported in healthy human volunteers. After acute low iron diet treatment in these mice, serum soluble Hemojuvelin levels were increased and correlated with lowered serum iron levels and decreased hepatic hepcidin expression. An acute high iron diet in wild-type mice or chronically iron-overloaded Bone morphogenetic protein 6-null mice did not significantly lower serum soluble Hemojuvelin concentrations. Here we report reliable quantitation of mouse serum soluble Hemojuvelin using a novel and validated enzyme-linked immunosorbent assay. This assay may provide a useful tool to elucidate the source and physiological role of serum soluble Hemojuvelin in hepcidin regulation and iron metabolism using well-established mouse models of iron-related disorders.
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Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
Journal of Clinical Investigation, 2007Co-Authors: Jodie L. Babitt, Yin Xia, Franklin W. Huang, Nancy C. Andrews, Yisrael Sidis, Herbert Y. LinAbstract:Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been implicated in the pathogenesis of anemia of chronic disease, while hepcidin deficiency has a key role in the pathogenesis of the iron overload disorder hemochromatosis. We have recently shown that Hemojuvelin is a coreceptor for bone morphogenetic protein (BMP) signaling and that BMP signaling positively regulates hepcidin expression in liver cells in vitro. Here we show that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. We also show that soluble Hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores, and increases serum iron levels in vivo. These data support a role for modulators of the BMP signaling pathway in treating diseases of iron overload and anemia of chronic disease.
Frank M. Torti - One of the best experts on this subject based on the ideXlab platform.
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effects of anti repulsive guidance molecule c rgmc Hemojuvelin antibody on hepcidin and iron in mouse liver and tumor xenografts
Clinical and Experimental Pharmacology, 2016Co-Authors: Suzy V. Torti, E Lemler, B K Mueller, A Popp, Frank M. TortiAbstract:Objective: Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. Methods: Effects of anti-Hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. Results: In tissue culture, the anti-Hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. Conclusion: Anti-Hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.
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Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts.
Clinical and Experimental Pharmacology, 2016Co-Authors: Suzy V. Torti, Lemler E, Popp A, Frank M. TortiAbstract:Objective: Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. Methods: Effects of anti-Hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. Results: In tissue culture, the anti-Hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. Conclusion: Anti-Hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.
Suzy V. Torti - One of the best experts on this subject based on the ideXlab platform.
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effects of anti repulsive guidance molecule c rgmc Hemojuvelin antibody on hepcidin and iron in mouse liver and tumor xenografts
Clinical and Experimental Pharmacology, 2016Co-Authors: Suzy V. Torti, E Lemler, B K Mueller, A Popp, Frank M. TortiAbstract:Objective: Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. Methods: Effects of anti-Hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. Results: In tissue culture, the anti-Hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. Conclusion: Anti-Hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.
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Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts.
Clinical and Experimental Pharmacology, 2016Co-Authors: Suzy V. Torti, Lemler E, Popp A, Frank M. TortiAbstract:Objective: Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. Methods: Effects of anti-Hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. Results: In tissue culture, the anti-Hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. Conclusion: Anti-Hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.
Tomas Ganz - One of the best experts on this subject based on the ideXlab platform.
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Soluble Hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site.
Blood Cells Molecules and Diseases, 2008Co-Authors: Lan Lin, Elizabeta Nemeth, Julia B. Goodnough, Dharma R. Thapa, Victoria Gabayan, Tomas GanzAbstract:As the principal iron-regulatory hormone, hepcidin plays an important role in systemic iron homeostasis. The regulation of hepcidin expression by iron loading appears to be unexpectedly complex and has attracted much interest. The GPI-linked membrane protein Hemojuvelin (GPI-Hemojuvelin) is an essential upstream regulator of hepcidin expression. A soluble form of Hemojuvelin (s-Hemojuvelin) exists in blood and acts as antagonist of GPI-Hemojuvelin to downregulate hepcidin expression. The release of s-Hemojuvelin is negatively regulated by both transferrin-bound iron (holo-Tf) and non-transferrin-bound iron (FAC), indicating s-Hemojuvelin could be one of the mediators of hepcidin regulation by iron. In this report, we investigate the proteinase involved in the release of s-Hemojuvelin and show that s-Hemojuvelin is released by a proprotein convertase through the cleavage at a conserved polybasic RNRR site.
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Iron-transferrin regulates hepcidin synthesis in primary hepatocyte culture through Hemojuvelin and BMP2/4
Blood, 2007Co-Authors: Lan Lin, Elizabeta Nemeth, Julia B. Goodnough, Victoria Gabayan, Erika V. Valore, Tomas GanzAbstract:The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin response to iron or iron transferrin was not observed. We now report that freshly isolated murine primary hepatocytes responded to holotransferrin but not apotransferrin by increasing hepcidin mRNA. Hepcidin increase was not due to contamination of the transferrin preparations by endotoxin, a potent pathologic stimulus of hepcidin synthesis. Using this culture system, we showed that holotransferrin concentrations regulate hepcidin mRNA concentrations through a Hemojuvelin/BMP2/4–dependent pathway. Although BMP9 is known to be expressed in the liver and potently increased the basal concentrations of hepcidin mRNA, it did not interact with Hemojuvelin, and interference with its signaling pathway did not affect iron regulation. Fresh primary hepatocytes constitute a sufficient system for the regulation of hepcidin by physiologic iron stimuli and will greatly facilitate studies of major disorders of iron homeostasis.
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iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through Hemojuvelin and bmp2 4
Blood, 2007Co-Authors: Lan Lin, Elizabeta Nemeth, Julia B. Goodnough, Victoria Gabayan, Erika V. Valore, Tomas GanzAbstract:The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin response to iron or iron transferrin was not observed. We now report that freshly isolated murine primary hepatocytes responded to holotransferrin but not apotransferrin by increasing hepcidin mRNA. Hepcidin increase was not due to contamination of the transferrin preparations by endotoxin, a potent pathologic stimulus of hepcidin synthesis. Using this culture system, we showed that holotransferrin concentrations regulate hepcidin mRNA concentrations through a Hemojuvelin/BMP2/4–dependent pathway. Although BMP9 is known to be expressed in the liver and potently increased the basal concentrations of hepcidin mRNA, it did not interact with Hemojuvelin, and interference with its signaling pathway did not affect iron regulation. Fresh primary hepatocytes constitute a sufficient system for the regulation of hepcidin by physiologic iron stimuli and will greatly facilitate studies of major disorders of iron homeostasis.
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Sensing Iron: Reciprocal Regulation of Hepcidin mRNA by Soluble and Cell-Associated Hemojuvelin.
Blood, 2005Co-Authors: Lan Lin, Y Paul Goldberg, Tomas GanzAbstract:Human genetic studies identified HJV (also called HFE2 ) as the major cause for juvenile hemochromatosis (JH). Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. We attempted to establish the specific roles of HJV in iron metabolism, especially its relationship with hepcidin. Translation of the genomic sequence indicated a C-terminal GPI anchor for the protein product of HJV , Hemojuvelin. This suggested that Hemojuvelin may have either a soluble or a cell-associated form. In human hepatoma cell line Hep3B, knockdown of cellular HJV by siRNA decreased hepcidin expression, independently of the IL-6 pathway. Intriguingly, the addition of recombinant soluble Hemojuvelin (rs-Hemojuvelin) also suppressed hepcidin expression in primary human hepatocytes, in a log-linear dose-dependent manner, suggesting competition between soluble and cell-associated forms of Hemojuvelin. Soluble Hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro . In cells engineered to express Hemojuvelin, soluble Hemojuvelin release was progressively inhibited by increasing iron or holotransferrin concentrations. Our study suggests that soluble and cell-associated Hemojuvelin reciprocally regulate hepcidin mRNA levels, and that Hemojuvelin may serve as a molecular messenger for iron homeostasis. Even in hepatocytes stimulated with IL-6, we observed strong suppression of hepcidin mRNA by rs-Hemojuvelin. If rs-Hemojuvelin or its active fragments also suppress hepcidin production in vivo , they could be used to alleviate anemia of inflammation.
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Competitive regulation of hepcidin mRNA by soluble and cell-associated Hemojuvelin.
Blood, 2005Co-Authors: Lan Lin, Y Paul Goldberg, Tomas GanzAbstract:Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, Hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. However, neither the specific role of Hemojuvelin in maintaining iron homeostasis nor its relationship to hepcidin has been experimentally established. In this study we used Hemojuvelin-specific siRNAs to vary Hemojuvelin mRNA concentration and showed that cellular Hemojuvelin positively regulated hepcidin mRNA expression, independently of the interleukin 6 pathway. We also showed that recombinant soluble Hemojuvelin (rs-Hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dose-dependent manner, suggesting binding competition between soluble and cell-associated Hemojuvelin. Soluble Hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express Hemojuvelin, soluble Hemojuvelin release was progressively inhibited by increasing iron concentrations. We propose that soluble and cell-associated Hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration.
Susanna Canali - One of the best experts on this subject based on the ideXlab platform.
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endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
Blood, 2017Co-Authors: Susanna Canali, Kimberly B Zumbrennenbullough, Amanda B Core, Chiayu Wang, Manfred Nairz, Richard Bouley, Filip K Swirski, Jodie L. BabittAbstract: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.
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activin b induces noncanonical smad1 5 8 signaling via bmp type i receptors in hepatocytes evidence for a role in hepcidin induction by inflammation in male mice
Endocrinology, 2016Co-Authors: Susanna Canali, Alan L Schneyer, Antonello Pietrangelo, Kimberly B Zumbrennenbullough, Amanda B Core, Chiayu Wang, Maria Merkulova, Jodie L. BabittAbstract:Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor Hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by Hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.
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Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis.
Frontiers in Pharmacology, 2014Co-Authors: Amanda B Core, Susanna Canali, Jodie L. BabittAbstract:Mutations in Hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.