Erythroferrone inhibits the induction of hepcidin by BMP6

  • Blood. 2018 Oct 4;132(14):1473-1477. doi: 10.1182/blood-2018-06-857995.
João Arezes  1 ,  Niall Foy  2 ,  Kirsty McHugh  3 ,  Anagha Sawant  4 ,  Doris Quinkert  3 ,  Virginie Terraube  2 ,  Alette Brinth  2 ,  May Tam  5  6 ,  Edward R LaVallie  5 ,  Stephen Taylor  7 ,  Andrew E Armitage  1 ,  Sant-Rayn Pasricha  1  8  9 ,  Orla Cunningham  2 ,  Matthew Lambert  2 ,  Simon J Draper  3 ,  Reema Jasuja  4 ,  Hal Drakesmith  1  10
Affiliations
  • 1. Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
  • 2. BioMedicine Design, Pfizer Biotherapeutics Research and Development (R&D), Dublin, Ireland.
  • 3. The Jenner Institute, University of Oxford, Oxford, United Kingdom.
  • 4. Rare Disease Research Unit, Pfizer Inc., Cambridge, MA.
  • 5. BioMedicine Design, Pfizer Biotherapeutics R&D, Cambridge, MA.
  • 6. Pharmacokinetics, Dynamics and Metabolism, Pfizer Biotherapeutics R&D, Andover, MA.
  • 7. Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
  • 8. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • 9. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia; and.
  • 10. Haematology Theme Oxford Biomedical Research Centre, Oxford, United Kingdom.
PMID: 30097509 DOI: 10.1182/blood-2018-06-857995
Abstract

Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in β-thalassemia. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for hepcidin control, and we show that EPO suppressed hepcidin and Other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron. In vitro, ERFE decreased SMAD1, SMAD5, and SMAD8 phosphorylation and inhibited expression of BMP target genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or Activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand trap generated by stimulated erythropoiesis to regulate the availability of iron.