Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge: Combined BMP6/HJV deficiency, iron and inflammation

International audienceLack of either BMP6 or the BMP co-receptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a co-receptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed Hjv-/- and Bmp6-/- mice and compared the phenotype of animals of the F2 progeny. Loss of Bmp6 further repressed Smad signaling and hepcidin expression in the liver of Hjv-/- mice of both genders, and led to iron accumulation in the pancreas and the heart of females. These data suggest that, in Hjv-/- females, Bmp6 can provide a signal adequate to maintain hepcidin to a level sufficient to avoid extrahepatic iron loading. We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammation. Our data show that lack of one or both molecules does not prevent induction of hepcidin by LPS. However, BMP/Smad signaling in unchallenged animals is determinant for the level of hepcidin reached after stimulation, which is consistent with a synergy between IL6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation

Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis

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Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B Supplementary data

International audienceActivin B, which is strongly induced by inflammatory stimuli in the mouse liver, has recently appeared as a potent inductor of hepcidin in vitro, via the crossactivation of non-canonical SMAD1/5/8 signaling1,2. To confirm the cause and effect relationship between activin B, Smad1/5/8 phosphorylation, and hepcidin in vivo, we challenged Inhbb-/- mice (deficient in activin B) with LPS or infected them with a E. coli septicemic strain. Our data show that full induction of hepcidin expression by inflammatory stimuli requires a functional BMP6-activated signaling pathway in the hepatocyte but is independent of activin B and its activation of Smad1/5/8 signaling that likely occurs in other cells of the liver

Testosterone perturbs systemic iron balance through activation of EGFR signaling in the liver and repression of hepcidin.

International audienceGender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g. chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However their mechanisms remain poorly understood. In this study, we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We showed that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective Egfr inhibition by gefitinib (Iressa®) in males markedly increases hepcidin expression. In males where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart and kidneys. Conclusion: These data indicate that testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. They suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases. (Hepatology 2013;)

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

International audienceHepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested formatriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic down stream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the BMP-SMAD signaling