Project Details
Projekt
FGF-23 as a novel mediator in osteohematology
Subject Area
Hematology, Oncology
Orthopaedics, Traumatology, Reconstructive Surgery
Orthopaedics, Traumatology, Reconstructive Surgery
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 395823501
Myelodysplastic syndromes (MDS) are characterized by defective hematopoietic stem cells that insufficiently produce blood cells, leading to cytopenias of various lineages. Emerging evidence indicates that the bone microenvironment controls disease progression. However, the underlying mechanisms are not fully understood and likewise, it is unclear how the defective hematopoietic compartment influences bone homeostasis. Using a large insurance-based population of over 900,000 participants, we could now show that patients with MDS have a two-fold risk for osteoporosis. Moreover, preliminary data from our lab using the NUP98-HOXD13 (NHD13) mouse, a well-established mouse model of MDS, suggest that the bone microarchitecture is altered in MDS and is characterized by low bone mineralization and high levels of fibroblast-growth factor-23 (FGF-23). Additionally, FGF-23 was reported to negatively impact on erythropoiesis. In this project, we will test the hypothesis that defective hematopoietic stem cells in MDS increase the production of FGF-23 in osteogenic cells, which causes a defect in erythropoiesis and a lack of bone mineralization. By correcting FGF-23 levels, we hypothesize that bone mineralization and erythropoiesis will improve, leading to a delayed onset of MDS. In this study, we will characterize the bone and blood phenotype of NHD13 transgenic mice in detail, determine the impact of MDS on the FGF-23 regulatory axis in vivo and in vitro, and address how neutralizing FGF-23 affects bone mineralization and MDS progression. To that end, various in vivo and in vitro assays will be performed. Key findings will be validated in patients using the large MDS registry in Dresden. This project will provide novel and detailed insights into the impact of MDS on bone homeostasis and the resulting interactions with hematopoietic cells, and define the role of FGF-23 therein. Moreover, the potential of FGF-23 neutralizing antibodies as a novel treatment strategy in MDS will be evaluated.
DFG Programme
Research Grants
