Novel Control of FGF23 in Metabolic Bone Disease

项目摘要/摘要：我们在定位克隆中鉴定了成纤维细胞生长因子-23(FGF23) 常染色体显性遗传性低磷性软骨病(ADHR)基因分离方法 继发于肾磷耗竭、软骨病/软骨病和骨折的低磷血症。我们做了钥匙 交叉铁和磷酸盐对FGF23表达调控的机制联系 代谢方面的研究表明，在这种疾病的小鼠敲入模型中，贫血导致了迟发性ADHR。 这些发现显著改变了目前的内分泌反馈范式，确定了生物学上的 已知的FGF23调控效应器之外的刺激，即贫血，可以推动FGF23的产生。 因此，FGF23调节和控制磷酸盐转运的分子机制是 不完全理解。这项工作与慢性肾脏疾病-矿物性骨病(CKD- Mbd)，在磷酸盐处理方面存在协同障碍的最大患者群体(显著增加 FGF23导致代谢性骨病)和铁代谢(肾脏衰竭导致进行性贫血) 导致骨折风险和死亡率增加。我们新的初步数据现在将它们之间的联系 代谢系统通过证明促红细胞生成素(EPO)的传递，一种治疗贫血的基石疗法 CKD-MBD可显著提高小鼠骨组织FGF23 mRNA和循环FGF23蛋白的表达。此外，这些 增加是通过通常抑制FGF23产生的覆盖机制发生的。使用最近的 建立了携带条件FLOX-FGF23等位基因的小鼠模型，我们的初步发现也支持EPO FGF23的调控可能发生在骨细胞中，而不是传统的 成骨细胞/骨细胞，从而潜在地揭示了磷酸盐代谢的新的调控系统。在……里面 根据这些新的结果，决定EPO介导的FGF23调控的分子机制 肾脏疾病的发病和进展仍有待确定。这一提议的中心假设是： 在成骨细胞/骨细胞和造血祖细胞中，EPO刺激FGF23导致 矿物质新陈代谢改变。这个轴可能是CKD-MBD的一个可修改的危险因素，因此我们预计我们的 基础生物学发现为罕见和常见的霍乱综合征提供了新的翻译洞察力 改变了FGF23的表达，并转化为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.