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The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry

  1. Melanie Castro-Mollo
  2. Sakshi Gera
  3. Marc Ruiz Martinez
  4. Maria Feola
  5. Anisa Gumerova
  6. Marina Planoutene
  7. Cara Clementelli
  8. Veena Sangkhae
  9. Carla Casu
  10. Se-Min Kim
  11. Vaughn Ostland
  12. Huiling Han
  13. Elizabeta Nemeth
  14. Robert Fleming
  15. Stefano Rivella
  16. Daria Lizneva
  17. Tony Yuen
  18. Mone Zaidi
  19. Yelena Ginzburg  Is a corresponding author
  1. Icahn School of Medicine at Mount Sinai, United States
  2. UCLA, United States
  3. Childrens Hospital of Philadelphia, United States
  4. Intrinsic Lifesciences, LLC, United States
  5. Saint Louis University, United States
Research Article
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Cite this article as: eLife 2021;10:e68217 doi: 10.7554/eLife.68217

Abstract

Background: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis.

Methods: To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe-/- mouse model as well as β–thalassemic (Hbbth3/+) mice with systemic loss of ERFE expression. In additional, we employ comprehensive skeletal phenotyping analyses as well as functional assays in vitro to address mechanistically the function of ERFE in bone.

Results: We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe-/- mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe loss in Hbbth3/+ mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss.

Conclusions: Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in β–thalassemia.

Funding: Y.Z.G. acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to Y.Z.G. and DK095112 to R.F., S.R., and Y.Z.G.). M.Z. acknowledges the support of the National Institute on Aging (U19 AG60917) and NIDDK (R01 DK113627). T.Y. acknowledges the support of the National Institute on Aging (R01 AG71870). S.R. acknowledges the support of NIDDK (R01 DK090554) and Commonwealth Universal Research Enhancement (C.U.R.E.) Program Pennsylvania.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Melanie Castro-Mollo

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  2. Sakshi Gera

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1615-6259
  3. Marc Ruiz Martinez

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  4. Maria Feola

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  5. Anisa Gumerova

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  6. Marina Planoutene

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  7. Cara Clementelli

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  8. Veena Sangkhae

    Pulmonary and Critical Care, UCLA, Los Angeles, United States
    Competing interests
    No competing interests declared.
  9. Carla Casu

    Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  10. Se-Min Kim

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  11. Vaughn Ostland

    Intrinsic Lifesciences, LLC, Intrinsic Lifesciences, LLC, La Jolla, United States
    Competing interests
    Vaughn Ostland, employment and stock options - Vaugh Ostland is affiliated with Intrinsic Lifesciences, LLC. The author has no other competing interests to declare..
  12. Huiling Han

    Intrinsic Lifesciences, LLC, Intrinsic Lifesciences, LLC, La Jolla, United States
    Competing interests
    Huiling Han, employment and stock options - Huiling Han is affiliated with Intrinsic Lifesciences, LLC. The author has no other competing interests to declare..
  13. Elizabeta Nemeth

    Pulmonary and Critical Care, UCLA, Los Angeles, United States
    Competing interests
    No competing interests declared.
  14. Robert Fleming

    Pediatrics, Saint Louis University, Saint Louis, United States
    Competing interests
    No competing interests declared.
  15. Stefano Rivella

    Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  16. Daria Lizneva

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  17. Tony Yuen

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  18. Mone Zaidi

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Mone Zaidi, Deputy editor, eLife.
  19. Yelena Ginzburg

    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    yelena.ginzburg@mssm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3496-3783

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK107670)

  • Yelena Ginzburg

National Institute of Diabetes and Digestive and Kidney Diseases (DK095112)

  • Robert Fleming
  • Stefano Rivella
  • Yelena Ginzburg

National Institute of Diabetes and Digestive and Kidney Diseases (DK113627)

  • Mone Zaidi

National Institute on Aging (AG60917)

  • Mone Zaidi

National Institute of Diabetes and Digestive and Kidney Diseases (DK09055)

  • Stefano Rivella

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#16-0143) of the Icahn School of Medicine.

Reviewing Editor

  1. Subburaman Mohan, Loma Linda University, United States

Publication history

  1. Received: March 8, 2021
  2. Accepted: May 17, 2021
  3. Accepted Manuscript published: May 18, 2021 (version 1)

Copyright

© 2021, Castro-Mollo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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