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：
10366984
负责人：
Yelena Ginzburg
金额：
$ 59.83万
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/10366984
关键词：
American Society of Hematology BMP15 gene BMP2 gene Bone Density Bone Diseases 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 Osteogenesis Osteopenia Osteoporosis Pathway interactions Patients Pelvis Phenotype Play Process Protein Biosynthesis Proteins Publications Recombinants Recycling Regulation Risk Role Signal Pathway Signaling Protein Stress Thalassemia Therapeutic Thinness Tissues Transfusion base beta Thalassemia bone bone cell bone health bone loss bone mass bone metabolism cortical bone hepcidin in vitro Assay inhibitor insight iron absorption iron metabolism mimetics mineralization mouse model novel novel therapeutics osteoclastogenesis 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.

项目摘要最近的出版物表明，骨髓分泌的蛋白Erythroferrone（ERFE）是肝素的负调节剂，而肝蛋白的负调节剂反过来又是铁浮雕和回收利用的主要负调节剂。肝素抑制可在压力红细胞生成期间增加铁的可用性。那是无效性红细胞生成的疾病，例如具有慢性红细胞增生的β-thal症，与ERFE表达增加有关，最终导致全身铁超载。此外，骨质减少症，骨质疏松症和普遍的皮质骨稀疏归因于无效的红细胞生成，红细胞膨胀以及该疾病中次生铁超载引起的代谢和内分泌功能障碍。最近的证据表明，ERFE通过隔离BMP抑制肝素素，并且由于BMP对骨代谢至关重要，我们假设ERFE可能是ERFE敲除成骨成骨细胞增强的矿化，而ERFE的矿物质损失可能会通过进一步降低骨骼矿物质矿物质密度降低，从而增强了骨骼矿物质的损失。此外，最近的数据提供了证据，表明铁超载不是β-丘脑贫血中骨质流失的主要驱动力。因此，我们建议详细探讨ERFE的作用细胞特异性机制及其在无序的骨代谢中的作用，在非转输血依赖性β-thalassymia Intermedia（HBBTH3/+（TH3/+））和依赖性β-thalassemia Major（HBBTH3/TH3/TH3 33/TH3（TH3 33/TH3（TH3 33/TH3））中，均和依赖于TH33/TH3 33（TH3/TH3 33/TH3 33（TH3/TH3 33/TH3））的作用和代谢，红细胞生成和骨稳态。我们的最终目标是提供有关铁代谢的调节与骨体内平衡之间复杂相互作用的新颖见解，这些疾病在失调的红细胞生成疾病中，并支持基本原理，以进一步探索ERFE对β-丘脑中性疾病的治疗潜力。