Novel Control of FGF23 in Metabolic Bone Disease

项目概要/摘要：我们在定位克隆中鉴定了成纤维细胞生长因子-23（FGF 23） 一种分离常染色体显性低磷血症性佝偻病（ADHR）基因的方法，其特征在于： 继发于肾性磷酸盐消耗、佝偻病/骨软化和骨折的低磷酸盐血症。我们做了钥匙 铁和磷酸盐交换调节FGF 23表达的机制联系 代谢，表明贫血引起迟发型ADHR在这种疾病的小鼠基因敲入模型。 这些发现显著地改变了当前的内分泌反馈范例，确定了生物学的 在已知的FGF 23控制效应物之外的刺激，即贫血，可以驱动FGF 23的产生。 因此，FGF 23被调节和控制磷酸盐处理的分子机制是 不完全理解。这项工作是有关慢性肾脏病-矿物质骨疾病（CKD- MBD），磷酸盐处理共紊乱的最大患者人群（显著增加 FGF 23导致代谢性骨病）和铁代谢（肾衰竭时进行性贫血） 导致骨折风险和死亡率增加。我们新的初步数据现在将这些联系起来 通过证明红细胞生成素（EPO）的递送，一种治疗贫血的基石， CKD-MBD小鼠骨Fgf 23 mRNA和循环FGF 23蛋白显著升高。此外，这些 增加通过通常抑制FGF 23产生的超控机制发生。最近使用A 我们开发了携带条件性EPO-Fgf 23等位基因的小鼠模型，我们的初步发现也支持EPO FGF 23的控制可能发生在骨细胞的“传统”表达位点之外， 成骨细胞/骨细胞，从而潜在地揭示了磷酸盐代谢的新的调节系统。在 根据这些新的结果，决定EPO介导的FGF 23调节的分子机制， 肾脏疾病发作和进展，仍有待确定。这一提议的核心假设是： FGF 23在成骨细胞/骨细胞和造血祖细胞中被EPO刺激，导致 改变矿物质代谢该轴可能是CKD-MBD的一个可改变的风险因素，因此我们希望我们的 基本的生物学发现，为罕见和常见的综合征提供新的翻译见解， 改变FGF 23的表达，并进入磷酸盐代谢的基础生物学。

Project Summary/Abstract: We identified Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. We made key mechanistic connections regarding the regulation of FGF23 expression by crossover iron and phosphate metabolism, showing that anemia caused late-onset ADHR in a mouse knock-in model of this disease. These findings significantly modify the current endocrine feedback paradigms, determining that biological stimuli outside of the known effectors of FGF23 control, namely anemia, could drive FGF23 production. Therefore, the molecular mechanisms by which FGF23 is regulated and controls phosphate handling are incompletely understood. This work is relevant to chronic kidney disease-mineral bone disorder (CKD- MBD), the largest patient population with co-disturbances in phosphate handling (markedly increased FGF23 leading to metabolic bone disease) and iron metabolism (progressive anemia as the kidneys fail) leading to increased fracture risk and mortality. Our novel preliminary data now make a link between these metabolic systems by demonstrating that erythropoietin (EPO) delivery, a cornerstone therapy for anemia in CKD-MBD, markedly elevated bone Fgf23 mRNA and circulating FGF23 protein in mice. Further, these increases occur by over-riding mechanisms that typically inhibit FGF23 production. Using a recently developed mouse model carrying conditional flox-Fgf23 alleles, our initial findings also support that EPO control of FGF23 may occur in bone cells outside of the ‘traditional’ expression sites of osteoblasts/osteocytes, thus potentially revealing novel regulatory systems for phosphate metabolism. In light of these new results, the molecular mechanisms dictating EPO-mediated FGF23 regulation during kidney disease onset and progression, remain to be defined. The central hypothesis for this proposal is: FGF23 is stimulated by EPO in osteoblasts/osteocytes and in hematopoietic progenitor cells leading to altered mineral metabolism. This axis may be a modifiable risk factor in CKD-MBD, therefore we expect our fundamental biological discoveries to provide novel translational insight into rare and common syndromes of altered FGF23 expression, and into the basic biology of phosphate metabolism.