β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for β-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor β pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb^th3/+ thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb^th3/+ mice with or without hematopoietic Tfr2 (Tfr2^BMKO/Hbb^th3/+) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb^th3/+ and Tfr2^BMKO/Hbb^th3/+ animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps.

中文翻译：

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骨髓 Tfr2 缺失提高了激活素受体配体陷阱 RAP-536 对 β 地中海贫血小鼠的治疗效果

β-地中海贫血是一种以贫血、无效红细胞生成（IE）和铁超负荷为特征的疾病，其治疗仍需改进。激活素受体-配体陷阱 Luspatercept 是一种治疗 β 地中海贫血的新选择，可刺激红细胞分化，抑制转化生长因子 β 途径。然而，其确切的作用机制以及与促红细胞生成素（Epo）（红细胞生成控制细胞因子）的可能联系仍有待阐明。此外，Luspatercept 并不能纠正该疾病的所有特征，因此需要确定增强其疗效的策略。转铁蛋白受体 2 (TFR2) 调节肝脏中的全身铁稳态，并调节红细胞对Epo的反应，从而平衡红细胞生成与铁可用性。刺激Epo信号传导、造血Tfr2缺失可改善Hbb ^{th3 / +}地中海贫血小鼠的贫血和 IE 。为了研究造血Tfr2失活是否会提高 Luspatercept 的疗效，我们用Luspatercept 的小鼠类似物 RAP-536治疗有或没有造血Tfr2 ( Tfr2 ^BMKO /Hbb ^{th3 / +} ) 的Hbb ^{th3 / +}小鼠。正如预期的那样，造血Tfr2缺失和 RAP-536 均能显着改善 IE 和贫血，并且组合方法具有相加效应。由于 RAP-536 在Hbb ^th3/+和Tfr2 ^BMKO /Hbb ^th3/+动物中具有相当的功效，因此我们建议该药物独立于 TFR2 和 EPO 刺激而促进红细胞分化。值得注意的是，缺乏Tfr2（而非 RAP-536）也可以减轻铁过载和相关并发症。总体而言，我们的结果进一步阐明了 Luspatercept 的作用机制，并表明旨在抑制造血 TFR2 的策略可能会提高激活素受体配体陷阱的治疗效果。