The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry.
The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry.
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DOI：
10.7554/elife.68217
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发表时间：
2021-05-18
期刊：
影响因子：
7.7
通讯作者：
Ginzburg Y
中科院分区：
文献类型：
--
作者：
Castro-Mollo M;Gera S;Ruiz-Martinez M;Feola M;Gumerova A;Planoutene M;Clementelli C;Sangkhae V;Casu C;Kim SM;Ostland V;Han H;Nemeth E;Fleming R;Rivella S;Lizneva D;Yuen T;Zaidi M;Ginzburg Y
红细胞红细胞素(ERFe)的分泌通过隔离几个骨形态发生蛋白(BMP)家族成员来抑制海普西丁的表达，从而增加红细胞生成所需的铁的利用率。为了解决Erfe是否也在骨骼中发挥作用，以及Erfe在骨骼中的作用机制是否涉及BMP，我们利用了Erfe-/-小鼠模型和系统性缺失Erfe表达的β-地中海贫血(Hbbth3/+)小鼠。此外，我们使用全面的骨骼表型分析以及体外功能分析来从机制上解决Erfe在骨骼中的功能。我们报道，ERFe在成骨细胞中的表达高于红细胞，不依赖于促红细胞生成素，并且具有抑制肝细胞海普西丁表达的功能。ERFe-/-小鼠表现出由于骨吸收增加而产生的低骨量，尽管伴随着骨形成的增加。ERFe-/-成骨细胞在体外表现出矿化增强、SOST和RANKL表达增强以及BMP介导的信号转导。ERFe对破骨细胞的作用是通过增加成骨细胞RANKL和硬化素的表达，增加ERFe-/-小鼠破骨细胞的生成来实现的。重要的是，在Hbbth3/+小鼠中，Erfe的丢失是一种增加Erfe表达的疾病模型，它会引发严重的破骨细胞性骨吸收和骨丢失。总之，ERFe通过调节成骨细胞中的骨形态发生蛋白信号，减少RANKL的产生来限制破骨细胞的生成，并防止β地中海贫血患者在扩大红细胞生成过程中过度的骨丢失，从而发挥骨保护作用。YZG感谢国家糖尿病、消化和肾脏疾病研究所(NIDDK)的支持(R01 DK107670到YZG，DK095112到RF，SR和YZG)。MZ感谢国家老龄研究所(U19 AG60917)和NIDDK(R01 DK113627)的支持。TY感谢国家老龄研究所(R01 AG71870)的支持。SR感谢NIDDK(R01 DK090554)和宾夕法尼亚州联邦普遍研究增强(CURE)计划的支持。
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 Erfe-/- mouse model as well as β–thalassemic (Hbbth3/+) 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. 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 Hbbth3/+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.