Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice

FGF23 在镰状细胞病小鼠骨、肾、血液和串扰中的作用

基本信息

批准号：
10597099
负责人：
Marja Marie Hurley
金额：
$ 55.43万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597099
关键词：
Adult Affect Age Anemia Apoptosis BFU-E Biochemical Blocking Antibodies Blood Bone Density Bone Diseases Bone Infarction Bone Marrow Bone Marrow Involvement Cell Cycle Chronic Data Diphosphates Dual-Energy X-Ray Absorptiometry Erythrocytes Erythroid Erythroid Cells Erythroid Progenitor Cells Erythropoiesis Erythropoietin Etiology FDA approved Familial hypophosphatemic bone disease Fibroblast Growth Factor Receptors Future Gender General Population Hematopoietic stem cells Hemoglobinopathies Hip region structure Histologic Homeostasis Hormonal Hormones Human Hypophosphatemia Immunoglobulin G Impairment In Vitro Inflammation Inorganic Phosphate Transporter Ischemia Kidney Kidney Failure Mechanics Menopausal Status Messenger RNA Mitogen-Activated Protein Kinases Molecular Molecular Analysis Mus Necrosis Osteoblasts Osteomalacia Osteoporosis Pathogenesis Pathology Patients Phenotype Physiologic calcification Process Production Proteins RNA analysis Reporting Risk Factors Role Secondary to Serum Serum Markers Sickle Cell Sickle Cell Anemia Signal Pathway Signal Transduction Sodium Stromal Cells Testing Therapeutic Urine Vitamin D Deficiency absorption bone bone loss bone marrow hyperplasia bone strength bone turnover effective therapy fibroblast growth factor 23 improved in vivo inorganic phosphate iron deficiency microCT mineralization mouse model neutralizing antibody novel osteoblast differentiation prevent progenitor response sodium-phosphate cotransporter proteins targeted treatment wasting

项目摘要

Summary Sickle cell disease (SCD) is a hemoglobinopathy associated with severe bone abnormalities including osteoporosis. Eighty percent of SCD adults have low bone mineral density (BMD) that is independent of risk factors such as age, gender, and menopausal status, suggesting the etiology of osteoporosis in SCD differs from the general population. Proposed contributing factors to bone loss in SCD include marrow hyperplasia secondary to chronic anemia, inflammation, ischemia, and vitamin D deficiency. However, the mechanisms of bone loss in SCD subjects has not been fully investigated, and there are no targeted therapies. Hormonal fibroblast growth factor 23 (FGF23), which controls phosphate homeostasis and has direct and indirect effects on bone mineralization, is reported to be increased in human anemia. Based on our exciting preliminary data showing that increased serum FGF23 and hypophosphatemia in humanized Townes SCD mice, which are anemic but not in renal failure, and that in vitro and in vivo FGF23 blockade partially rescues impaired mineralization and improved reduced BMD in SCD mice, we posit that cross-talk involving bone marrow erythropoiesis, kidney, and bone contributes to osteoporosis in SCD mice. Specifically, we posit that 1) sickling of red blood cells and the resulting anemia causes increased erythropoietin production by the kidney, which increases bone FGF23 production that impairs phosphate reabsorption; and 2) anemia-induced FGF23 results in impaired osteoblast differentiation, mineralization, and bone strength in SCD mice due to hypophosphatemia and pyrophosphate abnormalities via impaired sodium phosphate transporters PIT1 and PIT2 signaling in bone. Furthermore, increased FGF23 reduces PIT1 signaling that can interfere with erythrocyte differentiation, further perpetuating the anemic state. To test our hypotheses, we propose the following Specific Aims: Aim 1: Examine the molecular mechanisms by which FGF23 contributes to phosphate wasting in SCD Mice; Aim 2: Assess the molecular mechanism by which FGF23 contributes to impaired bone mineralization in SCD mice; and Aim 3: Determine whether FGF23 neutralizing antibody modulates the anemia phenotype of SCD mice. Our proposed studies may identify FGF23 as a novel contributor to the pathogenesis of bone loss and anemia in SCD mice. Since the FGF23Ab is now FDA approved for the treatment of X-linked hypophosphatemia, it may also be a useful therapy to prevent bone loss and improve anemia in human SCD in the future.

概括镰状细胞病（SCD）是与严重骨异常有关的血红蛋白病骨质疏松症。 80％的SCD成年人具有低骨矿物质密度（BMD），与风险无关年龄，性别和绝经状态等因素，表明SCD中骨质疏松的病因与普通人群。提出的促成SCD骨质流失的因素包括骨髓增生次级慢性贫血，炎症，缺血和维生素D缺乏症。但是，骨质流失的机制 SCD受试者尚未得到充分研究，也没有针对性的疗法。激素成纤维细胞生长因子23（FGF23），控制磷酸盐稳态，对骨骼有直接和间接的影响据报道，人类贫血增加了矿化。根据我们令人兴奋的初步数据增加了人源化城镇中的血清FGF23和下磷酸化的SCD小鼠，这是贫血的但没有肾功能衰竭，并且体外和体内FGF23封锁部分挽救了受损矿化并改善了SCD小鼠的BMD降低，我们认为涉及骨髓的串扰促红细胞，肾脏和骨骼会导致SCD小鼠的骨质疏松症。具体来说，我们认为1）红细胞和由此产生的贫血导致肾脏产生红细胞生成素的增加，这是增加骨FGF23的产生，损害磷酸盐的吸收； 2）贫血引起的FGF23结果由于低磷酸血症，SCD小鼠的成骨细胞分化，矿化和骨强度受损通过磷酸钠转运蛋白pIT1和骨中的pIT2信号传导，和焦磷酸异常。此外，增加的FGF23降低了可能干扰红细胞分化的PIT1信号传导，进一步使贫血状态永存。为了检验我们的假设，我们提出以下特定目的：目标1：检查 FGF23在SCD小鼠中促进磷酸盐的分子机制；目标2：评估 FGF23有助于SCD小鼠骨矿化受损的分子机制；和目标3：确定FGF23中和抗体是否调节SCD小鼠的贫血表型。我们提出的研究可以将FGF23识别为SCD小鼠骨质流失和贫血发病机理的新贡献者。由于FGF23AB现在已被FDA批准用于治疗X连锁低磷酸血症，因此它也可能是有用的疗法可预防骨质流失并改善未来人类SCD的贫血。