Thursday, May 29, 2025
5/29/2025
The Role of Erythroferrone in Regulating Bone Metabolism in Beta-Thalassemia - 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.
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