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Inhibition of FGF23 is a therapeutic strategy to target hematopoietic stem cell niche defects in β-thalassemia
Science Translational Medicine ( IF 15.8 ) Pub Date : 2023-05-31 , DOI: 10.1126/scitranslmed.abq3679
Annamaria Aprile 1 , Laura Raggi 1, 2 , Simona Bolamperti 3, 4 , Isabella Villa 3, 4 , Mariangela Storto 1 , Gaia Morello 5 , Sarah Marktel 6 , Claudio Tripodo 5, 7 , Maria Domenica Cappellini 8, 9 , Irene Motta 8, 9 , Alessandro Rubinacci 3 , Giuliana Ferrari 1, 10
Affiliation  

Clinical evidence highlights a relationship between the blood and the bone, but the underlying mechanism linking these two tissues is not fully elucidated. Here, we used β-thalassemia as a model of congenital anemia with bone and bone marrow (BM) niche defects. We demonstrate that fibroblast growth factor 23 (FGF23) is increased in patients and mice with β-thalassemia because erythropoietin induces FGF23 overproduction in bone and BM erythroid cells via ERK1/2 and STAT5 pathways. We show that in vivo inhibition of FGF23 signaling by carboxyl-terminal FGF23 peptide is a safe and efficacious therapeutic strategy to rescue bone mineralization and deposition in mice with β-thalassemia, normalizing the expression of niche factors and restoring hematopoietic stem cell (HSC) function. FGF23 may thus represent a molecular link connecting anemia, bone, and the HSC niche. This study provides a translational approach to targeting bone defects and rescuing HSC niche interactions, with potential clinical relevance for improving HSC transplantation and gene therapy for hematopoietic disorders.

中文翻译:

抑制 FGF23 是针对 β-地中海贫血造血干细胞生态位缺陷的治疗策略

临床证据强调了血液和骨骼之间的关系,但连接这两种组织的潜在机制尚未完全阐明。在这里,我们使用 β-地中海贫血作为先天性贫血伴有骨和骨髓 (BM) 生态位缺陷的模型。我们证明成纤维细胞生长因子 23 (FGF23) 在患有 β-地中海贫血的患者和小鼠中增加,因为促红细胞生成素通过 ERK1/2 和 STAT5 途径诱导骨和 BM 红细胞中 FGF23 的过量产生。我们表明,羧基末端 FGF23 肽对 FGF23 信号的体内抑制是一种安全有效的治疗策略,可挽救 β-地中海贫血小鼠的骨矿化和沉积,使生态位因子的表达正常化并恢复造血干细胞 (HSC) 功能. 因此,FGF23 可能代表连接贫血、骨、和 HSC 利基市场。本研究提供了一种针对骨缺损和挽救 HSC 生态位相互作用的转化方法,具有改善 HSC 移植和造血障碍基因治疗的潜在临床相关性。
更新日期:2023-05-31
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