The Role of Erythroferrone in Regulating Bone Metabolism in Beta-Thalassemia

赤铁酮在调节β-地中海贫血骨代谢中的作用

基本信息

批准号：
10560583
负责人：
Yelena Ginzburg
金额：
$ 58.79万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560583
关键词：
American Society of Hematology BMP15 gene BMP2 gene Bone Density Bone Diseases Bone Formation Stimulation Bone Marrow Bone Morphogenetic Proteins Bone Resorption Bone remodeling Cell Culture Techniques Cells Chronic Complex Cooley&apos s anemia Data Dependence Disease Endocrine Erythroblasts Erythroid Erythropoiesis Evaluation Exhibits Femur Fracture Functional disorder Genes Goals Hemoglobin Homeostasis Human Iron Iron Overload Knock-out Lead Literature Messenger RNA Metabolic Metabolic Bone Diseases Modeling Mus Osteoblasts Osteoclasts Osteopenia Osteoporosis Pathway interactions Patients Pelvis Phenotype Play Process Protein Secretion Proteins Publications Recombinants Recycling Regulation Risk Role Signal Pathway Signaling Protein Stress Thalassemia Therapeutic Thinness Tissues Transfusion beta Thalassemia bone bone cell bone health bone loss bone mass bone metabolism cortical bone hepcidin improved in vitro Assay inhibitor insight iron absorption iron metabolism mimetics mineralization mouse model novel novel therapeutics osteoclastogenesis osteoprotective programs protein function response skeletal stress state thalassemia intermedia translational potential treatment optimization

项目摘要

PROJECT SUMMARY Recent publications demonstrate that a bone marrow secreted protein, erythroferrone (ERFE), is a negative regulator of hepcidin, which in turn is the main negative regulator of iron absorption and recycling. Hepcidin suppression enables an increase in iron availability during stress erythropoiesis. Thus, diseases of ineffective erythropoiesis, such as β-thalassemia, with chronic erythroid expansion, are associated with increased ERFE expression ultimately causing systemic iron overload. In addition, osteopenia, osteoporosis, and generalized cortical bone thinning have been attributed to ineffective erythropoiesis, erythroid expansion, and the metabolic and endocrine dysfunction caused by secondary iron overload in this disease. Very recent evidence reveals that ERFE suppresses hepcidin by sequestering BMPs, and because BMPs are crucially important for bone metabolism, we hypothesize that ERFE may be involved in coordinating iron metabolism, erythropoiesis, and bone homeostasis. Our preliminary data demonstrates that ERFE is expressed at many fold higher levels in osteoblasts and osteoclasts relative to erythroblasts, ERFE knockout osteoblasts exhibit enhanced mineralization, and ERFE loss in th3/+ mice leads to further decreased bone mineral density by enhancing osteoclastogenesis. Furthermore, recent data provides evidence that iron overload is not a primary driver of bone loss in β-thalassemia. We thus propose to explore in detail the cell specific mechanism of action of ERFE and its role in disordered bone metabolism in mouse models of non-transfusion dependent β-thalassemia intermedia (Hbbth3/+ (th3/+)) and transfusion-dependent β-thalassemia major (Hbbth3/th3 (th3/th3)) and evaluate the function of ERFE in coordinating iron metabolism, erythropoiesis, and bone homeostasis. Our ultimate goal is to provide novel insights into the complex interplay between regulation of iron metabolism and bone homeostasis in disease of dysregulated erythropoiesis and support the rationale to further explore the therapeutic potential of ERFE for β-thalassemia.

项目概要最近的出版物表明，骨髓分泌蛋白赤铁酮 (ERFE) 是铁调素的负调节剂，而铁调素又是铁吸收和再循环的主要负调节剂，可以增加应激性红细胞生成过程中铁的利用率。红细胞生成无效的疾病，例如伴有慢性红细胞扩张的β-地中海贫血，与ERFE表达增加有关，最终导致全身铁超负荷。骨质减少、骨质疏松和全身骨皮质变薄是由于红细胞生成无效、红细胞扩张以及继发性铁超负荷引起的代谢和内分泌功能障碍所致。最近的证据表明，ERFE 通过隔离 BMP 来抑制铁调素，因为 BMP 是铁调素的主要来源。对于骨代谢至关重要，我们发现 ERFE 可能参与协调铁代谢、红细胞生成和骨代谢我们的初步数据表明，相对于成红细胞，ERFE 在成骨细胞和破骨细胞中的表达水平高出许多倍，ERFE 敲除的成骨细胞表现出增强的矿化作用，并且 th3/+ 小鼠中 ERFE 的损失通过增强破骨细胞生成导致骨密度进一步降低。最近的数据证明铁过载并不是β-地中海贫血骨质流失的主要驱动因素，因此我们建议详细探索其细胞特异性作用机制。 ERFE 及其在非输血依赖性中间型 β-地中海贫血 (Hbbth3/+ (th3/+)) 和输血依赖性重型 β-地中海贫血 (Hbbth3/th3 (th3/th3)) 小鼠模型骨代谢紊乱中的作用并评估ERFE 在协调铁代谢、红细胞生成和骨稳态中的功能我们的最终目标是为铁代谢调节和骨之间的复杂相互作用提供新的见解。红细胞生成失调疾病中的稳态，并支持进一步探索 ERFE 对 β-地中海贫血的治疗潜力的基本原理。