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

总结 镰状细胞病（SCD）是一种与严重骨骼异常相关的血红蛋白病， 骨质疏松80%的SCD成年人具有与风险无关的低骨矿物质密度（BMD）。 年龄、性别和绝经状态等因素，提示SCD中骨质疏松症的病因不同于 普通民众。SCD中骨丢失的拟定促成因素包括继发性骨髓增生 慢性贫血、炎症、局部缺血和维生素D缺乏。然而，骨丢失的机制， 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（FGF 23），控制磷酸盐稳态，对骨有直接和间接影响 据报道，在人类贫血症中矿化增加。根据我们令人兴奋的初步数据显示 在贫血的人源化TownesSCD小鼠中， 但在肾衰竭中没有，体外和体内FGF 23阻断部分挽救了受损的 矿化和改善减少骨密度在SCD小鼠，我们认为， 红细胞生成、肾和骨的变化导致SCD小鼠的骨质疏松症。具体地说，我们认为镰刀形 红细胞的减少和由此产生的贫血导致肾脏产生的促红细胞生成素增加， 增加骨FGF 23的产生，损害磷酸盐重吸收;和2）贫血诱导的FGF 23导致 在SCD小鼠中由于低磷酸盐血症导致的成骨细胞分化、矿化和骨强度受损 和通过受损的磷酸钠转运蛋白PIT 1和PIT 2信号传导的骨中的焦磷酸盐异常。 此外，增加的FGF 23减少了可干扰红细胞分化的PIT 1信号传导， 使贫血状态持续下去为了验证我们的假设，我们提出了以下具体目标：目标1：检查 FGF 23促进SCD小鼠磷酸盐消耗的分子机制;目的2：评估FGF 23对SCD小鼠磷酸盐消耗的影响。 FGF 23促进SCD小鼠中骨矿化受损的分子机制;以及目的3： 确定FGF 23中和抗体是否调节SCD小鼠的贫血表型。我们提出的 研究可以鉴定FGF 23是SCD小鼠中骨丢失和贫血发病机制的新贡献者。 由于FGF 23 Ab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治疗X连锁低磷血症的药物。 在未来预防骨丢失和改善人类SCD贫血的有用疗法。

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.