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Pathophysiology of Rare Hemolytic Anemias

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Front. Physiol. | doi: 10.3389/fphys.2019.00304

The EPO-FGF23 signaling pathway in erythroid progenitor cells: opening a new area of research.

  • 1Van Creveldkliniek, Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Netherlands
  • 2Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Netherlands
  • 3Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Netherlands
  • 4Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Netherlands

We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias.
FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production.
Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.

Keywords: FGF23 = fibroblast growth factor 23, Osteoporosis, Erythropoetin, Anemia, Red Blood Cell (RBC)

Received: 10 Dec 2018; Accepted: 07 Mar 2019.

Edited by:

Lesley J. Bruce, NHS Blood and Transplant, United Kingdom

Reviewed by:

Anna Rita Migliaccio, Icahn School of Medicine at Mount Sinai, United States
Angela Risso, University of Udine, Italy  

Copyright: © 2019 Van Vuren, Gaillard, Eisenga, van Wijk and Van Beers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD. A.J. (Annelies) Van Vuren, University Medical Center Utrecht, Van Creveldkliniek, Department of Internal Medicine and Dermatology, Utrecht, Netherlands, A.J.vanVuren@umcutrecht.nl