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

项目摘要 最近的出版物表明，骨髓分泌蛋白，erythroferrone（ERFE），是铁调素的负调节剂，铁调素反过来又是铁吸收和再循环的主要负调节剂。铁调素抑制能够在应激红细胞生成期间增加铁的可用性。因此，无效红细胞生成的疾病，如β-地中海贫血，伴随慢性红细胞扩增，与ERFE表达增加相关，最终导致全身性铁过载。此外，骨质减少、骨质疏松和全身性皮质骨变薄归因于无效的红细胞生成、红细胞扩张以及继发性铁过载引起的代谢和内分泌功能障碍。最近的证据表明，ERFE抑制hepcidin螯合骨形成蛋白，因为骨形成蛋白是至关重要的骨代谢，我们推测，ERFE可能参与协调铁代谢，红细胞生成和骨稳态。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，并且在th 3/+小鼠中ERFE损失通过增强破骨细胞生成导致骨矿物质密度进一步降低。此外，最近的数据提供证据表明，铁过载不是β地中海贫血中骨丢失的主要驱动因素。因此，我们拟在非输血依赖性中间型β地中海贫血（Hbbth 3/+（th 3/+））和输血依赖性重型β地中海贫血（Hbbth 3/th 3（th 3/th 3））小鼠模型中详细探讨ERFE的细胞特异性作用机制及其在骨代谢紊乱中的作用，并评价ERFE在协调铁代谢、红细胞生成和骨稳态中的作用。我们的最终目标是为红细胞生成失调疾病中铁代谢调节和骨稳态之间的复杂相互作用提供新的见解，并支持进一步探索ERFE治疗β-地中海贫血的治疗潜力的基本原理。

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.