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

摘要 镰状细胞病(SCD)是一种与严重的骨骼异常有关的血红蛋白病，包括 骨质疏松。80%的SCD成人具有与风险无关的低骨密度(BMD) 年龄、性别和绝经状况等因素，表明SCD的骨质疏松症病因不同于 普通民众。已提出的SCD骨丢失的促成因素包括继发性骨髓增生 慢性贫血、炎症、缺血和维生素D缺乏症。然而，骨丢失的机制 SCD受试者尚未得到充分的调查，也没有针对性的治疗方法。激素性成纤维细胞生长 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，矿化作用在人类贫血中增加。根据我们令人兴奋的初步数据显示 这增加了贫血的Townes SCD人源化小鼠的血清FGF23和低磷血症 但在肾功能衰竭中不是这样，在体外和体内阻断FGF23部分挽救了受损的 矿化和改善SCD小鼠的骨密度降低，我们假设串扰涉及骨髓 红细胞生成、肾脏和骨骼对SCD小鼠的骨质疏松有贡献。具体地说，我们假设1)镰刀 红血球和由此引起的贫血导致肾脏产生更多的促红细胞生成素，这 增加骨骼FGF23的产生，从而损害磷酸盐的重吸收；以及2)贫血导致的FGF23结果 低磷血症致SCD小鼠成骨细胞分化、矿化和骨强度受损 和焦磷酸盐异常，通过受损的磷酸钠转运蛋白PIT1和PIT2信号在骨骼。 此外，FGF23的增加减少了可能干扰红细胞分化的PIT1信号，进一步 使贫乏状态永久化。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 FGF23促进SCD小鼠磷酸盐消耗的分子机制；目标2：评估 FGF23促进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。我们的建议 研究可能确定FGF23是SCD小鼠骨丢失和贫血发病机制中的一个新的贡献者。 由于FGF23Ab现在已被FDA批准用于治疗X连锁低磷血症，它也可能是一种 预防骨质流失和改善人类SCD未来贫血的有用疗法。

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.