Inhibition of FGF23 is a therapeutic strategy to target hematopoietic stem cell niche defects in β-thalassemia.

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. Editor's summary: Why β-thalassemia results in bone defects in some patients is unclear. Aprile et al. show that the elevated erythropoietin seen in β-thalassemia results in increased fibroblast growth factor 23 (FGF23) in the bone and bone marrow, which can produce bone defects. A small peptide inhibiting FGF23 both restored the bone marrow hematopoietic stem cell niche and rescued bone defects in a mouse model. This study thus ties the blood and bone together in β-thalassemia and demonstrates an avenue to target their pathological interaction. —Catherine A. Charneski [ABSTRACT FROM AUTHOR]