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The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry
BACKGROUND: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. METHODS: To address whether ERFE functions also in bone and whether the mechanism of ERFE ac...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205482/ https://www.ncbi.nlm.nih.gov/pubmed/34002695 http://dx.doi.org/10.7554/eLife.68217 |
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author | 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 |
author_facet | 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 |
author_sort | Castro-Mollo, Melanie |
collection | PubMed |
description | BACKGROUND: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. METHODS: To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe(-/-) mouse model as well as β–thalassemic (Hbb(th3/+)) 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. RESULTS: We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe(-/-) mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe(-/-) osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe(-/-) mice. Importantly, Erfe loss in Hbb(th3/+)mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss. CONCLUSIONS: 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. FUNDING: 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. |
format | Online Article Text |
id | pubmed-8205482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-82054822021-06-16 The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry 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 eLife Medicine BACKGROUND: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. METHODS: To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe(-/-) mouse model as well as β–thalassemic (Hbb(th3/+)) 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. RESULTS: We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe(-/-) mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe(-/-) osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe(-/-) mice. Importantly, Erfe loss in Hbb(th3/+)mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss. CONCLUSIONS: 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. FUNDING: 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. eLife Sciences Publications, Ltd 2021-05-18 /pmc/articles/PMC8205482/ /pubmed/34002695 http://dx.doi.org/10.7554/eLife.68217 Text en © 2021, Castro-Mollo et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Medicine 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 The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title | The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title_full | The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title_fullStr | The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title_full_unstemmed | The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title_short | The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
title_sort | hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205482/ https://www.ncbi.nlm.nih.gov/pubmed/34002695 http://dx.doi.org/10.7554/eLife.68217 |
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