The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry

Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves...

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Bibliographic Details
Published in:	eLife 2021-05, Vol.10
Main Authors:	Castro-Mollo, Melanie, Gera, Sakshi, Ruiz-Martinez, Marc, Feola, Maria, Gumerova, Anisa, Planoutene, Marina, Clementelli, Cara, Sangkhae, Veena, Casu, Carla, Kim, Se-Min, Ostland, Vaughn, Han, Huiling, Nemeth, Elizabeta, Fleming, Robert, Rivella, Stefano, Lizneva, Daria, Yuen, Tony, Zaidi, Mone, Ginzburg, Yelena
Format:	Article
Language:	eng
Subjects:	Aging Analysis Anemia Animals beta-Thalassemia - genetics beta-Thalassemia - metabolism Blood diseases Bone and Bones - metabolism Bone Development - genetics Bone diseases bone formation Bone growth Bone loss Bone marrow Bone mass Bone morphogenetic proteins Bone Morphogenetic Proteins - metabolism Bone resorption Cells, Cultured Cytokines - genetics Cytokines - metabolism Diabetes mellitus Disease Models, Animal Erythroblasts erythroferrone Erythropoiesis Erythropoietin Hepcidin Hepcidins Homeostasis Iron Kidney diseases Laboratories Male Medical research Medicine Medicine, Experimental Metabolism Mice Mice, Inbred C57BL Mineralization Muscle Proteins - genetics Muscle Proteins - metabolism Mutation Osteoblasts Osteoblasts - metabolism Osteoclastogenesis Osteoclasts Osteogenesis Osteoporosis Phenotyping Phosphatase SOST protein Thalassemia TRANCE protein
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Summary:	Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the mouse model as well as β-thalassemic ( ) mice with systemic loss of ERFE expression. In additional, we employ comprehensive skeletal phenotyping analyses as well as functional assays in vitro to address mechanistically the function of ERFE in bone. We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. mice display low-bone-mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, osteoblasts exhibit enhanced mineralization, and expression, and BMP-mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in mice. Importantly, loss in mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss. Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in β-thalassemia. YZG acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to YZG and DK095112 to RF, SR, and YZG). MZ acknowledges the support of the National Institute on Aging (U19 AG60917) and NIDDK (R01 DK113627). TY acknowledges the support of the National Institute on Aging (R01 AG71870). SR acknowledges the support of NIDDK (R01 DK090554) and Commonwealth Universal Research Enhancement (CURE) Program Pennsylvania.
ISSN:	2050-084X 2050-084X