FGF-23 Regulation of Phosphate Homeostasis

描述（由申请人提供）：研究矿物质代谢紊乱引起的疾病的分子病因有助于确定磷酸盐稳态的新循环调节因子，统称为“磷酸素”。我们通过定位克隆方法鉴定了磷酸素成纤维细胞生长因子-23 (FGF23)，以分离常染色体显性低磷血症佝偻病（ADHR）的基因，其特征是肾磷酸盐消耗，佝偻病/骨软化和骨折。将ADHR与其他与FGF23升高相关的疾病区分开来的一个独特且临床上重要的方面是，ADHR患者可以从携带者状态的正常磷血症迅速进展到完全发病，从而具有症状循环。此外，尚不清楚为什么低磷血症ADHR患者在活动力疾病期间不能下调FGF23，因为体内低血清磷酸盐通常是该基因的强抑制因子。这一悖论强调了一种假设，即已知的“正常”内分泌反馈回路之外的生物刺激可以驱动FGF23的产生。因此，FGF23指导磷酸盐处理的分子机制尚不完全清楚。根据我们目前的目标，我们已经确定了控制Fgf23表达和调控的新机制，这可能是迟发性ADHR的基础。ADHR患者病程的延迟可能与易出现低铁状态的生理状态有关，如青春期和妊娠期。使用一种新型ADHR R176Q-Fgf23敲入小鼠，我们的研究结果表明低血清铁显著增加骨Fgf23 mRNA。此外，我们提出这种mRNA的增加是通过一个关键的铁/缺氧感应反应发生的，这将显著改变目前解释磷酸盐稳态的范式。我们的研究结果还支持WT小鼠可以通过在二级调节步骤中蛋白水解切割多余的激素来补偿低铁诱导的Fgf23 mRNA，以维持正常的血清完整的Fgf23和磷酸盐代谢。相反，由于R176Q-Fgf23的蛋白酶抵抗，ADHR小鼠可能无法完全补偿Fgf23 mRNA的升高，从而导致血清完整激素升高和低磷血症性骨病。根据我们的初步发现，Fgf23生物学的重要方面，包括在ADHR发病和进展过程中决定Fgf23增加的分子机制，以及循环完整Fgf23的调节，以及通过其受体系统的生物活性，仍有待确定。因此，需要验证的中心假设是：铁状态降低刺激细胞铁/缺氧感知反应，在ADHR突变的背景下，导致Fgf23不适当的表达升高和Fgf23受体信号复合物的过度活性，导致低磷血症骨病。我们希望这些研究能够为罕见和常见的FGF23表达改变综合征以及磷酸盐稳态的基本生物学提供新的、可转化的见解。

DESCRIPTION (provided by applicant): Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis, collectively referred to as 'phosphatonins.' We identified the phosphatonin Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by renal phosphate wasting, rickets/osteomalacia, and fracture. A unique and clinically important aspect of ADHR that distinguishes this syndrome from other disorders associated with elevated FGF23 is that ADHR patients can have symptomatic cycling by rapidly progressing from normophosphatemia in carrier status, to full disease onset. Further, it is not known why hypophosphatemic ADHR patients are unable to down-regulate FGF23 during active disease, as low serum phosphate is typically a strong suppressor of this gene in vivo. This paradox highlights the hypothesis that a biological stimulus outside of the known 'normal' endocrine feedback loops can drive FGF23 production. Therefore, the molecular mechanisms by which FGF23 directs phosphate handling are incompletely understood. In accord with our current aims, we have identified novel mechanisms controlling Fgf23 expression and regulation that may underlie late-onset ADHR. The delayed disease course in ADHR patients can be associated with physiological states prone to low iron status, such as puberty and following pregnancy. Using a novel ADHR R176Q-Fgf23 knock-in mouse, our results show that low serum iron markedly increases bone Fgf23 mRNA. Additionally, we propose that this mRNA increase occurs through a key iron/hypoxic sensing response, which would significantly modify the current paradigms explaining phosphate homeostasis. Our results also support that WT mice can compensate for low-iron induced Fgf23 mRNA by proteolytically cleaving the excess hormone in a secondary regulatory step to maintain normal serum intact Fgf23 and phosphate metabolism. In contrast, the ADHR mice may not fully compensate for elevated Fgf23 mRNA due to the protease resistance of R176Q-Fgf23, leading to increased serum intact hormone and to hypophosphatemic bone disease. In light of our initial findings, important aspects of Fgf23 biology, including the molecular mechanisms dictating increased Fgf23 during onset and progression of ADHR, as well as the regulation of circulating intact Fgf23, and bioactivity through its receptor systems, remain to be defined. Thus, the central hypothesis to be tested is: reduced iron status stimulates a cellular iron/hypoxic sensing response that, in the context of an ADHR mutation, leads to inappropriate, elevated expression of Fgf23 and to over-activity of the Fgf23 receptor signaling complex, resulting in hypophosphatemic bone disease. We expect these studies to provide novel, translational insight into rare and common syndromes of altered FGF23 expression and into the basic biology of phosphate homeostasis. PUBLIC HEALTH RELEVANCE: The regulation of serum phosphate concentrations is critical for normal skeletal formation and cellular function. Pathophysiologic disturbances in phosphate homeostasis, such as those in autosomal dominant hypophosphatemic rickets (ADHR) and hyperphosphatemic tumoral calcinosis (TC), or common disorders such as chronic kidney disease (CKD), lead to severe hormonal and skeletal disease. We expect that our proposed studies will reveal new mechanisms involved in phosphate homeostasis, which will provide novel therapeutic targets.