Developmental changes in iron metabolism and erythropoiesis in mice with human gain‐of‐function erythropoietin receptor

Abstract

Iron availability for erythropoiesis is controlled by the iron‐regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain‐of‐function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3–6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age‐related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive‐mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose‐dependent alterations of downstream EPOR stimulation.

Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen‐sensing pathway from primary familial and congenital polycythaemia

“…56,57 In PFCP mouse model, these features were observed only in the prenatal/perinatal period but not in later stages of postanal life. 46 Here, we confirm that only patients with molecular defects in the oxygen-sensing pathway display elevated ERFE contributing to hepcidin suppression. Although we cannot fully exclude that intermittent erythrocytapheresis/phlebotomies may have influenced (to some extent) the levels of measured parameters of iron metabolism, elevated ERFE in untreated HIF2A-mutant patients and one VHL-mutant child who had the last phlebotomy 20 months prior to the measurements strongly supports the idea that ERFE induction is an intrinsic characteristic of congenital erythrocytosis with inherited defects in oxygen-sensing pathway.…”

“…There is limited knowledge on the interconnection of crucial regulators of iron homoeostasis in congenital erythrocytosis. We recently demonstrated ontogenesis‐related changes in iron homoeostasis in a mouse model of PFCP 45 which neither presented postnatal iron deficiency, nor hepcidin suppression and ERFE overproduction 46 as one would expect. Assessment of two EPOR ‐mutant patients confirmed normal hepcidin and the absence of ERFE upregulation, in contrast to the paediatric patients with HIF2A G537R ‐mutant erythrocytosis 46 .…”

“…We recently demonstrated ontogenesis‐related changes in iron homoeostasis in a mouse model of PFCP 45 which neither presented postnatal iron deficiency, nor hepcidin suppression and ERFE overproduction 46 as one would expect. Assessment of two EPOR ‐mutant patients confirmed normal hepcidin and the absence of ERFE upregulation, in contrast to the paediatric patients with HIF2A G537R ‐mutant erythrocytosis 46 . Here, we expanded the group to include another PFCP patient with a different EPOR mutation and three patients with the c.340+770T>C VHL mutation, and provide additional measurements and parameters.…”

“…Assessment of two EPOR-mutant patients confirmed normal hepcidin and the absence of ERFE upregulation, in contrast to the paediatric patients with HIF2A G537R -mutant erythrocytosis. 46 Here, we expanded the group to include another PFCP patient with a different EPOR mutation and three patients with the c.340+770T>C VHL mutation, and provide additional measurements and parameters. The patients with VHL mutation, one adult and both adolescents, had lowest transferrin saturation (TSAT), ferritin and serum iron (sFe), supressed hepcidin and markedly elevated ERFE (Table 3).…”

Excessive Erythrocytosis Is Not Associated With Altered Iron Homeostasis in Men From the World’s Highest City

“…In healthy people ascending to high altitude, increased erythropoiesis is accompanied by massive mobilization of iron stores. 2 , 3 , 7 Similarly, in erythrocytic mice constitutively overexpressing EPO systemically, 11 or with gain-of-function mutation of EPO receptor, 12 low hepcidin levels are associated with reduced transferrin saturation and low iron stores. Conversely, normal ferritin and transferrin levels are found in Puno residents 6 ; similarly, Ethiopian highlanders do not show decreased body iron stores despite high hemoglobin concentration.…”