Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

• Published in: Blood Vol. 139; no. 3; pp. 439 - 451
• Main Authors: Coffey, Richard, Jung, Grace, Olivera, Joseph D., Karin, Gabriel, Pereira, Renata C., Nemeth, Elizabeta, Ganz, Tomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2022; American Society of Hematology
• Subjects: Animals; Bone Morphogenetic Proteins - metabolism; Cytokines - genetics; Cytokines - metabolism; Developmental Disabilities - etiology; Developmental Disabilities - genetics; Developmental Disabilities - metabolism; Erythroid Cells - cytology; Erythroid Cells - metabolism; Female; Hepcidins - metabolism; Iron Overload - etiology; Iron Overload - genetics; Iron Overload - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle Proteins - genetics; Muscle Proteins - metabolism; Red Cells, Iron, and Erythropoiesis; Signal Transduction; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021014054

The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia, or other erythropoietic stimuli, and it suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is believed to be mediated by interference with paracrine bone morphogenetic protein (BMP) signaling that regulates hepcidin transcription in hepatocytes. In anemias with ineffective erythropoiesis, ERFE is pathologically overproduced, but its contribution to the clinical manifestations of these anemias is not well understood. We generated 3 lines of transgenic mice with graded erythroid overexpression of ERFE and found that they developed dose-dependent iron overload, impaired hepatic BMP signaling, and relative hepcidin deficiency. These findings add to the evidence that ERFE is a mediator of iron overload in conditions in which ERFE is overproduced, including anemias with ineffective erythropoiesis. At the highest levels of ERFE overexpression, the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots, and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive ERFE in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development. •ERFE excess causes iron overload even in the absence of other pathology.•High concentrations of ERFE cause growth delay and hypoplastic kidneys. [Display omitted]