title: The mutual control of iron and erythropoiesis.
abstract: BACKGROUND
  Iron is essential for hemoglobin synthesis during terminal erythropoiesis. To supply adequate iron the carrier transferrin is required together with transferrin receptor endosomal cycle and normal mitochondrial iron utilization. Iron and iron protein deficiencies result in different types of anemia. Iron-deficiency anemia is the commonest anemia worldwide due to increased requirements, malnutrition, chronic blood losses and malabsorption. Mutations of transferrin, transferrin receptor cycle proteins, enzymes of the first step of heme synthesis and iron sulfur cluster biogenesis lead to rare anemias, usually accompanied by iron overload. Hepcidin plays an indirect role in erythropoiesis by controlling plasma iron. Inappropriately high hepcidin levels characterize the rare genetic iron-refractory iron-deficiency anemia (IRIDA) and the common anemia of chronic disease. Iron modulates both effective and ineffective erythropoiesis: iron restriction reduces heme and alpha-globin synthesis that may be of benefit in thalassemia.
  
  
  METHODS
  This review relies on the analysis of the most recent literature and personal data.
  
  
  RESULTS
  Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and EPO treatment. Erythroferrone, produced by EPO-stimulated erythropoiesis, inhibits hepcidin only when the activity of BMP/SMAD pathway is low, suggesting that EPO somehow modulates the latter signaling. Erythroblasts sense circulating iron through the second transferrin receptor (TFR2) that, in animal models, modulates the sensitivity of the erythroid cells to EPO.
  
  
  CONCLUSIONS
  The advanced knowledge of the regulation of systemic iron homeostasis and erythropoiesis-mediated hepcidin regulation is leading to the development of targeted therapies for anemias and iron disorders.
authors.affiliation: Vita Salute University and San Raffaele Scientific Institute, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Camaschella
authors.affiliation: Vita Salute University and San Raffaele Scientific Institute, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pagani
authors.affiliation: Vita Salute University and San Raffaele Scientific Institute, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Nai
authors.affiliation: Vita Salute University and San Raffaele Scientific Institute, Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Silvestri
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000209:etiology; D000818:Animals; D004920:Erythropoiesis / Q000502:physiology*; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000502:physiology; D000090463:Iron Deficiencies
chemical_list: D064451:Hepcidins; D007501:Iron
keywords: Anemia; erythropoiesis; erythropoietin; iron; transferrin