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

项目总结 最近的研究表明，一种骨髓分泌蛋白--红细胞铁蛋白(ERFe)是海普西丁的负性调节因子，而海普西丁又是铁吸收和循环的主要负性调节因子。在应激性红血球生成过程中，抑制海普西丁可增加铁的利用率。因此，红细胞生成无效的疾病，如β-地中海贫血，伴随着慢性红系扩张，与ERFe表达增加有关，最终导致全身铁超载。此外，骨量减少、骨质疏松症和全身性皮质骨变薄被归因于本病中无效的红细胞生成、红系扩张以及继发性铁负荷引起的代谢和内分泌功能障碍。最近的证据显示，ERFe通过隔离BMPs抑制海普西丁，由于BMPs对骨代谢至关重要，我们推测ERFe可能参与协调铁代谢、红血球生成和骨稳态。我们的初步数据表明，Erfe在成骨细胞和破骨细胞中的表达水平是红细胞的数倍，Erfe基因敲除的成骨细胞显示出增强的矿化作用，而Erfe基因的缺失通过促进破骨细胞的形成而导致骨密度的进一步降低。此外，最近的数据提供了证据表明，铁超载不是β地中海贫血患者骨丢失的主要驱动因素。因此，我们建议在非输血依赖型β-地中海贫血(Hbbth3/(Th3/))和输血依赖型β-地中海贫血(Hbbth3/Th3/Th3)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铁代谢调节和骨稳态在红细胞生成失调疾病中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-地中海贫血的潜力的理论基础。

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.