FGF-23 Regulation of Phosphate Homeostasis

描述（由申请人提供）：研究由矿物质代谢紊乱引起的疾病的分子病因学有助于鉴定磷酸盐稳态的新循环调节剂，统称为“磷酸酶”。“我们在定位克隆方法中鉴定了磷酸化成纤维细胞生长因子-23（FGF 23），以分离常染色体显性低磷酸盐血症性佝偻病（ADHR）的基因，其特征是肾磷酸盐消耗，佝偻病/骨软化和骨折。ADHR的一个独特的和临床上重要的方面，区分这种综合征与其他疾病相关的FGF 23升高是ADHR患者可以有症状的循环，从携带者状态的正常磷酸盐血症迅速进展，以充分的疾病发作。此外，尚不清楚为什么低磷酸盐血症ADHR患者在活动性疾病期间不能下调FGF 23，因为低血清磷酸盐通常是该基因在体内的强抑制因子。这个悖论突出了一个假设，即已知的“正常”内分泌反馈回路之外的生物刺激可以驱动FGF 23的产生。因此，FGF 23指导磷酸盐处理的分子机制尚未完全理解。 与我们目前的目标雅阁，我们已经确定了控制Fgf 23表达和调节的新机制，这可能是晚发型ADHR的基础。ADHR患者的延迟病程可能与易出现低铁状态的生理状态相关，如青春期和妊娠后。使用一种新的ADHR R176 Q-Fgf 23基因敲入小鼠，我们的研究结果表明，低血清铁显着增加骨Fgf 23 mRNA。此外，我们提出，这种mRNA的增加发生通过一个关键的铁/缺氧感应反应，这将显着修改目前的范例解释磷酸盐稳态。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裂解过量的激素来补偿低铁诱导的Fgf 23 mRNA，以维持正常的血清完整的Fgf 23和磷酸盐代谢。相反，ADHR小鼠可能无法完全补偿由于R176 Q-Fgf 23的蛋白酶抗性而升高的Fgf 23 mRNA，导致血清完整激素增加和低磷酸盐血症性骨病。根据我们的初步发现，Fgf 23生物学的重要方面，包括ADHR发作和进展期间决定Fgf 23增加的分子机制，以及循环完整Fgf 23的调节，以及通过其受体系统的生物活性，仍有待确定。因此，要测试的中心假设是：铁减少状态刺激细胞铁/缺氧感应反应，在ADHR突变的背景下，导致Fgf 23的不适当的、升高的表达和Fgf 23受体信号传导复合物的过度活性，导致低磷酸盐血症性骨病。我们希望这些研究能为FGF 23表达改变的罕见和常见综合征以及磷酸盐稳态的基础生物学提供新的、翻译性的见解。 公共卫生相关性：血清磷酸盐浓度的调节对正常骨骼形成和细胞功能至关重要。磷酸盐稳态的病理生理紊乱，如常染色体显性遗传性低磷酸盐血症性佝偻病（ADHR）和高磷酸盐血症性肿瘤性钙质沉着症（TC），或常见疾病，如慢性肾病（CKD），导致严重的激素和骨骼疾病。我们期望我们提出的研究将揭示磷酸盐稳态的新机制，这将提供新的治疗靶点。

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.