Contributions
Abstract: S268
Type: Oral Presentation
Session title: Changing the scene on thalassemias
Background
Over decades the research on beta-thalassemia (BT) has been mostly focused on erythropoiesis, leaving the study of the bone marrow (BM) environment and hematopoietic stem cells (HSC) underexplored. We have recently demonstrated that HSC function in BT is negatively affected by an altered BM microenvironment and that targeting of the defective HSC-BM stromal niche crosstalk rescues the impaired quiescence and self-renewal of HSC (Aprile et al., Blood 2020). BT can be cured by HSC transplantation from healthy donors or autologous HSC upon gene therapy. Since the quality of HSC and the conditions for engraftment depend on the presence of a healthy BM microenvironment, niche-HSC crosstalk plays a crucial role for post-transplant outcome.
Consistently with the common finding of osteoporosis in BT patients, we found in Hbbth3/+ (th3) BT mice reduced bone deposition and low levels of parathyroid hormone (PTH), negatively affecting stem cell number, quiescence and self-renewal. Fibroblast growth factor-23 (FGF-23) is a hormone mainly secreted by osteocytes, which acts as negative regulator of bone metabolism and PTH production. 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 FGF-23 increase, thus affecting bone and BM niche homeostasis.
Aims
We investigated the mechanisms underlying bone and HSC niche defects in BT and we focused on FGF-23. We also explored the role of EPO on enhancing FGF-23 levels.
Methods
We measured levels of FGF-23 in th3 mice and BT patients by ELISA. We inhibited FGF-23 signaling in th3 mice by in vivo administration of FGF-23 blocking peptide and we analyzed bone density by pQCT, HSC and erythroid populations upon treatment. We neutralized in vivo the EPO axis and analyzed FGF-23 levels.
Results
We measured high levels of circulating FGF-23 in BT mice (n=10) and patients (n=17). 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 rescued the bone defect in th3 mice, by increasing trabecular bone mineral density. Importantly, the treatment restored the frequency of HSC to levels comparable to wild-type controls by expanding the pool of quiescent cells. FGF-23 inhibition had also a positive anti-apoptotic effect on the expanded BM erythroid compartment, promoting the maturation of erythroid precursors, confirming results obtained in models of secondary anemias. In vivo neutralization of EPO axis demonstrated the causative role of EPO on enhancing FGF-23 levels in BT.
Preliminary evidence in BT patients showed negative correlations between FGF-23 and markers of bone homeostasis (e.g. osteocalcin and VitD), whereas positive correlations with ineffective erythropoiesis (e.g. reticulocytes).
Further analysis will unravel the negative impact of high FGF-23 on bone mineralization and BM stromal niche-HSC interactions in BT.
Conclusion
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, thus proposing FGF-23 as the molecule at the crossroads of erythropoiesis and bone metabolism. 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 and gene therapy/editing approaches.
Keyword(s): Beta thalassemia, Bone microenvironment, FGF, Hematopoietic stem cell
Abstract: S268
Type: Oral Presentation
Session title: Changing the scene on thalassemias
Background
Over decades the research on beta-thalassemia (BT) has been mostly focused on erythropoiesis, leaving the study of the bone marrow (BM) environment and hematopoietic stem cells (HSC) underexplored. We have recently demonstrated that HSC function in BT is negatively affected by an altered BM microenvironment and that targeting of the defective HSC-BM stromal niche crosstalk rescues the impaired quiescence and self-renewal of HSC (Aprile et al., Blood 2020). BT can be cured by HSC transplantation from healthy donors or autologous HSC upon gene therapy. Since the quality of HSC and the conditions for engraftment depend on the presence of a healthy BM microenvironment, niche-HSC crosstalk plays a crucial role for post-transplant outcome.
Consistently with the common finding of osteoporosis in BT patients, we found in Hbbth3/+ (th3) BT mice reduced bone deposition and low levels of parathyroid hormone (PTH), negatively affecting stem cell number, quiescence and self-renewal. Fibroblast growth factor-23 (FGF-23) is a hormone mainly secreted by osteocytes, which acts as negative regulator of bone metabolism and PTH production. 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 FGF-23 increase, thus affecting bone and BM niche homeostasis.
Aims
We investigated the mechanisms underlying bone and HSC niche defects in BT and we focused on FGF-23. We also explored the role of EPO on enhancing FGF-23 levels.
Methods
We measured levels of FGF-23 in th3 mice and BT patients by ELISA. We inhibited FGF-23 signaling in th3 mice by in vivo administration of FGF-23 blocking peptide and we analyzed bone density by pQCT, HSC and erythroid populations upon treatment. We neutralized in vivo the EPO axis and analyzed FGF-23 levels.
Results
We measured high levels of circulating FGF-23 in BT mice (n=10) and patients (n=17). 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 rescued the bone defect in th3 mice, by increasing trabecular bone mineral density. Importantly, the treatment restored the frequency of HSC to levels comparable to wild-type controls by expanding the pool of quiescent cells. FGF-23 inhibition had also a positive anti-apoptotic effect on the expanded BM erythroid compartment, promoting the maturation of erythroid precursors, confirming results obtained in models of secondary anemias. In vivo neutralization of EPO axis demonstrated the causative role of EPO on enhancing FGF-23 levels in BT.
Preliminary evidence in BT patients showed negative correlations between FGF-23 and markers of bone homeostasis (e.g. osteocalcin and VitD), whereas positive correlations with ineffective erythropoiesis (e.g. reticulocytes).
Further analysis will unravel the negative impact of high FGF-23 on bone mineralization and BM stromal niche-HSC interactions in BT.
Conclusion
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, thus proposing FGF-23 as the molecule at the crossroads of erythropoiesis and bone metabolism. 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 and gene therapy/editing approaches.
Keyword(s): Beta thalassemia, Bone microenvironment, FGF, Hematopoietic stem cell