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

• 批准号: 10437233
• 负责人: Marja Marie Hurley
• 金额: $ 54.85万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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/10437233
• 关键词: Adult; Affect; Age; Anemia; Anemia due to Chronic Disorder; 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; 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; base; 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

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) 是一种与严重骨异常相关的血红蛋白病，包括 骨质疏松症。 80% 的 SCD 成人骨矿物质密度 (BMD) 较低，且与风险无关 年龄、性别和绝经状况等因素，表明 SCD 骨质疏松症的病因不同于 普通民众。所提出的导致 SCD 骨质流失的因素包括继发性骨髓增生 慢性贫血、炎症、缺血和维生素 D 缺乏。然而，骨质流失的机制 SCD 受试者尚未得到充分研究，也没有靶向治疗。激素成纤维细胞生长 因子 23 (FGF23)，控制磷酸盐稳态并对骨有直接和间接影响 据报道，矿化作用在人类贫血症中增加。根据我们令人兴奋的初步数据显示 增加了贫血性 Townes SCD 小鼠的血清 FGF23 和低磷血症 但在肾功能衰竭中则不然，体外和体内 FGF23 阻断可部分挽救肾功能衰竭 SCD 小鼠的矿化和 BMD 的改善，我们认为涉及骨髓的串扰 红细胞生成、肾脏和骨骼导致 SCD 小鼠骨质疏松。具体来说，我们假设 1) 镰状 红细胞的减少和由此产生的贫血会导致肾脏产生促红细胞生成素增加，从而 增加骨 FGF23 的产生，从而损害磷酸盐的重吸收； 2) 贫血引起的 FGF23 结果 低磷血症导致 SCD 小鼠成骨细胞分化、矿化和骨强度受损 骨骼中钠磷酸盐转运蛋白 PIT1 和 PIT2 信号传导受损导致焦磷酸盐异常。 此外，FGF23 增加会减少 PIT1 信号传导，从而干扰红细胞分化，进一步 使贫血状态永久化。为了检验我们的假设，我们提出以下具体目标： 目标 1：检查 FGF23 导致 SCD 小鼠磷酸盐消耗的分子机制；目标 2：评估 FGF23 导致 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 研究可能确定 FGF23 是 SCD 小鼠骨质流失和贫血发病机制的新贡献者。 由于 FGF23Ab 现已被 FDA 批准用于治疗 X 连锁低磷血症，因此它也可能是一种 未来预防骨质流失和改善人类 SCD 贫血的有效疗法。