Session: 112. Thalassemia and Globin Gene Regulation
Hematology Disease Topics & Pathways:
Biological, Diseases, Therapies, thalassemia, Hemoglobinopathies, Biological Processes, erythropoiesis, hematopoiesis, transplantation, microenvironment
Consistently with the common finding of osteoporosis in BT patients, we found reduced bone deposition and low levels of PTH also in the murine model. We investigated the potential mechanisms underlying the decreased PTH and bone defect and we focused on the role of fibroblast growth factor-23 (FGF-23). FGF-23 is a systemic hormone mainly secreted by osteocytes, which acts as negative regulator of bone metabolism by inhibiting bone mineralization and PTH production by parathyroid glands. Since FGF-23 is positively modulated by the anemia-related factor erythropoietin (EPO), we hypothesized that the high EPO levels in BT, subsequent to ineffective erythropoiesis, might contribute to increase FGF-23.
We measured high levels of circulating FGF-23 in th3 mice (wt vs. th3: 399.7±69.77 vs. 1975±209.3 pg/ml, p<0.01) and also in BT patients (HD vs. THAL: 94.2±3.8 vs. 125.8±9.2 RU/ml, p<0.05). To provide proof of concept data of the causative role of FGF-23 on BT bone and stromal niche defects, we inhibited FGF-23 signaling. FGF-23 inhibition by in vivo administration of FGF-23 blocking peptide rescued the bone defect in th3 mice, by increasing trabecular bone mineral density (th3 vs. th3+FGF23inh: 117.7±3.3 vs. 181.1±6.9 mg/cm3, p<0.0001). Importantly, the treatment restored the frequency of HSC to levels comparable to wild-type controls by expanding the pool of quiescent cells (th3 vs. th3+FGF23inh: 0.03±0.002 vs. 0.07±0.0% on Linneg BM cells, p<0.0001). Consistently, we found increased the expression of key molecules by bone cells, such as Jagged-1 and osteopontin, involved in the functional crosstalk between HSC and the stromal niche. Interestingly, FGF-23 inhibition had also a positive anti-apoptotic effect on the expanded BM erythroid compartment, promoting the maturation of erythroid precursors, as already shown in models of secondary anemias. Preliminary evidence in BT patients showed negative correlations between FGF-23 levels and markers of bone homeostasis (e.g. osteocalcin and vitamin D) and positive correlations with makers of ineffective erythropoiesis (e.g. reticulocytes), thus proposing FGF-23 as the molecule at the crossroads of erythropoiesis and bone metabolism in BT. In vivo studies and molecular analysis in th3 mice and patients’ samples will better unravel the causative role of EPO on FGF-23 levels in BT and the negative impact of high FGF-23 on bone mineralization and BM stromal niche-HSC interactions.
Our findings uncover an underexplored role of FGF-23 in bone and BM niche defects in BT, as a condition of severe anemia and chronic EPO stimulation. The inhibition of FGF-23 signaling might provide a novel strategy to ameliorate bone compartment and restore HSC-BM niche interactions in BT, with a potential translational relevance in improving HSC transplantation approaches.
Disclosures: Motta: Sanofi Genzyme: Honoraria. Cappellini: Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees.
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