FGF-23 as a novel mediator in osteohematology

骨髓增生异常综合征（MDS）的特点是有缺陷的造血干细胞不能产生足够的血细胞，导致各种谱系的细胞减少。新出现的证据表明，骨微环境控制疾病的进展。然而，潜在的机制尚不完全清楚，同样，尚不清楚有缺陷的造血室如何影响骨稳态。使用超过90万的参保人群，我们现在可以显示MDS患者有患骨质疏松症的双重风险。此外，我们实验室使用NUP98-HOXD13 （NHD13）小鼠（一种完善的MDS小鼠模型）的初步数据表明，MDS的骨微结构发生了改变，其特征是骨矿化低，成纤维细胞生长因子-23 （FGF-23）水平高。此外，据报道FGF-23对红细胞生成有负面影响。在这个项目中，我们将检验MDS中有缺陷的造血干细胞增加成骨细胞中FGF-23的产生，从而导致红细胞生成缺陷和骨矿化缺乏的假设。通过纠正FGF-23水平，我们假设骨矿化和红细胞生成将得到改善，从而导致MDS的延迟发病。在本研究中，我们将详细表征NHD13转基因小鼠的骨和血液表型，确定MDS对体内和体外FGF-23调控轴的影响，并探讨中和FGF-23如何影响骨矿化和MDS的进展。为此，将进行各种体内和体外测定。主要研究结果将在德累斯顿大型MDS注册中心的患者中得到验证。该项目将为MDS对骨稳态的影响及其与造血细胞的相互作用提供新颖而详细的见解，并确定FGF-23在其中的作用。此外，将评估FGF-23中和抗体作为MDS新治疗策略的潜力。

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.