Abstract
Iron is crucial for many biological functions, but quantitatively the most important use of iron is in the production of hemoglobin in red blood cell precursors. The amount of iron in the plasma, and hence its availability for hemoglobin synthesis, is determined by the liver-derived iron regulatory hormone hepcidin. When the iron supply to erythroid precursors is limited, as often occurs during stimulated erythropoiesis, these cells produce signals to inhibit hepatic hepcidin production, thereby increasing the amount of iron that enters the plasma. How stimulated erythropoiesis suppresses hepcidin production is incompletely understood, but erythroferrone, Gdf15 and Twsg1 have emerged as candidate regulatory molecules. To further examine the relationship between erythropoiesis and the candidate erythroid regulators, we have studied five mouse models of anemia, including two models of β-thalassemia (Hbbth3/+ and RBC14), the hemoglobin deficit mouse (hbd), dietary iron deficient mice and mice treated with phenylhydrazine to induce acute hemolysis. Hematological parameters, iron status and the expression of Erfe (the gene encoding erythroferrone), Gdf15 and Twsg1 in the bone marrow and spleen were examined. Erfe expression was the most consistently upregulated of the candidate erythroid regulators in all of the mouse models examined. Gene expression was particularly high in the bone marrow and spleen of iron deficient animals, making erythroferrone an ideal candidate erythroid regulator, as its influence is strongest when iron supply to developing erythroid cells is limited. Gdf15 expression was also upregulated in most of the anemia models studied although the magnitude of the increase was generally less than that of Erfe. In contrast, very little regulation of Twsg1 was observed. These results support the prevailing hypothesis that erythroferrone is a promising erythroid regulator and demonstrate that Erfe expression is stimulated most strongly when the iron supply to developing erythroid cells is compromised.
Highlights
The peptide hormone hepcidin is often referred to as the master regulator of iron homeostasis because it regulates both the amount of iron absorbed from the diet and the release of iron from intracellular storage sites [1]
We have investigated the expression of the three candidate erythroid regulators in various mouse models of anemia
Hamp1 message levels were drastically decreased in the iron deficient group (>10,000-fold reduction) and the phenylhydrazine treated mice (6% of untreated mice) (Fig 1H). These results demonstrate that a range of Hamp1 expression responses can be obtained from the different models of anemia, making them useful tools with which to examine the expression of the putative erythroid regulators
Summary
The peptide hormone hepcidin is often referred to as the master regulator of iron homeostasis because it regulates both the amount of iron absorbed from the diet and the release of iron from intracellular storage sites (predominantly hepatocytes and macrophages) [1] Hepcidin achieves this by binding to and triggering the degradation of the cell surface iron export protein ferroportin, thereby inhibiting cellular iron release [2]. BMP6 binds to the BMP receptor complex on the surface of hepatocytes, resulting in activation of the SMAD pathway, which, in turn, directly stimulates the HAMP promoter and hepcidin production [6] This pathway allows the stores regulator to adjust circulating hepcidin levels to ensure that body iron levels
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
