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Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression

Abstract

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2−/− hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.

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Figure 1: Hemojuvelin signals via the BMP, but not the TGF-β, pathway.
Figure 2: Hjv.Fc forms a complex with 125I-BMP-2 in solution.
Figure 3: Hemojuvelin mutants associated with hemochromatosis show impaired BMP signaling ability.
Figure 4: Hfe2−/− livers show decreased basal BMP signaling compared with wild-type livers.
Figure 5: Hemojuvelin positively regulates hepcidin mRNA expression.
Figure 6: BMP-2 positively regulates hepcidin mRNA expression.
Figure 7: Hepcidin induction by BMP-2 is enhanced by hemojuvelin and blunted in Hfe2−/− hepatocytes.
Figure 8: Schematic diagram depicting the role of hemojuvelin (HJV) in the BMP signaling pathway and hepcidin regulation.

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Acknowledgements

We thank S. Breton and N. Da Silva for technical assistance with quantitative real-time PCR. We thank Y. Kamegaya for assistance with the initial characterization of the α-HJV antibody. We thank D.K. Podolsky, D. Brown and W.F. Crowley for critical discussions. J.L.B. was supported in part by US National Institutes of Health (NIH) grant F32 DK-068997. H.Y.L. was supported in part by NIH grants DK-69533 and DK-71837. F.W.H. and D.M.W. were supported in part by NIH Grant T32 HL07623. N.C.A. was supported in part by a research grant from Roche Foundation for Anemia Research and is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Herbert Y Lin.

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A patent application entitled “Methods and composition to regulate iron metabolism” has been submitted to the US Patent Office.

Supplementary information

Supplementary Fig. 1

Hemojuvelin-mediated BMP signaling is ligand dependent. (PDF 446 kb)

Supplementary Fig. 2

Hjv.Fc binds 125I-BMP-2 and 125I-BMP-4 in solution. (PDF 650 kb)

Supplementary Fig. 3

Hemojuvelin mediates BMP signaling via BMP type I receptors ALK3 and ALK6 and can be cross-linked with ALK6 at the cell surface in the presence of BMP-2. (PDF 1108 kb)

Supplementary Fig. 4

Hemojuvelin mediates BMP signaling via BMP receptor–activated Smad1. (PDF 176 kb)

Supplementary Fig. 5

The proximal hepcidin promoter is conserved among mammals and contains putative BMP-responsive elements. (PDF 172 kb)

Supplementary Fig. 6

BMP-2 regulation of hepcidin expression is not affected by cycloheximide. (PDF 156 kb)

Supplementary Table 1

Primer sequences. (PDF 28 kb)

Supplementary Methods (PDF 48 kb)

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Babitt, J., Huang, F., Wrighting, D. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38, 531–539 (2006). https://doi.org/10.1038/ng1777

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