Regulation and Function of FGF23

描述(由申请人提供)：有新的证据表明，骨骼的内分泌功能通过成骨细胞和骨细胞释放激素FGF23，在调节磷酸盐稳态和维生素D代谢方面发挥关键作用。明确控制骨骼产生FGF23的分子机制对于理解这种激素的生理和病理作用至关重要。研究阐明了遗传性低磷血症和突变小鼠模型的遗传基础，已确定内肽酶PHEX、兄弟蛋白Dmp1和核酸内切酶Enpp1是骨中细胞外基质矿化和FGF23产生的局部调节因子。FGFR1/PI3K/Akt/β-catenin和HMW-FGF2依赖的整合性成纤维细胞生长因子受体信号通路的激活似乎将骨矿化与FGF23的释放结合在一起，并整合了系统因素的影响，如PTH受体/GNAS途径，这对成骨细胞/骨细胞中的FGF23基因转录具有上下文依赖性的影响。此外，1，25(OH)2D作为FGF23的反向调节激素，通过VDR介导的机制直接调节FGF23基因的转录，并且是PTH调节FGF23表达所必需的。该项目旨在了解FGF23、维生素D、PTH、PHEX、DMP1和FGFR1是如何整合到一个生物网络中的，该网络允许系统因素、细胞外基质矿化过程和FGF23的成骨细胞/骨细胞产生之间的相互作用，以协调全身磷酸盐和维生素D的动态平衡和骨形成/矿化。我们建议研究通过典型的FGFR1、INFS、PTH和VDR依赖的信号通路来控制成骨细胞和骨细胞中FGF23的基础和刺激转录，从而研究这些局部骨和全身因子的汇聚。我们还建议评估规范的FGFR1和INFS在体外和体内通过有条件地从Hyp和Dmp1-/-小鼠的成骨细胞和骨细胞中删除FGFR1来调节FGF23基因转录的相对作用。此外，我们还将在体外研究1，25(OH)2D、PTH和FGFR1信号通路在调节成骨细胞FGF23基因转录中的相互作用。这些研究将带来对复杂系统生物学的新知识，该系统生物学已经进化到允许骨骼和肾脏之间的相互作用，以协调磷酸盐平衡、维生素D代谢和骨骼矿化。这些知识将有助于我们了解和更好地处理高磷血症和低磷血症患者。 公共卫生相关性：我们发现骨是成骨细胞和骨细胞释放FGF23的内分泌器官，FGF23是一种参与骨-肾轴调节磷酸盐、维生素D和矿物质动态平衡的磷酸激素。我们正在进行研究，以确定细胞外基质的矿化与骨中FGF23产生的准确信号通路，以确定FGF23的生理功能是协调骨的矿化和肾脏对磷酸盐的处理，并了解PTH与1，25(OH)2D之间的复杂相互作用以及局部骨源性因子通过FGFR1调节FGF23基因转录的作用。总体而言，我们的工作是建立一个新的概念性框架，通过该框架，骨骼与其他器官通信，以调节磷酸盐和维生素D代谢，以响应不断变化的生理需求，并有助于更好地理解高磷血症和低磷血症的发病机制、诊断和治疗。

DESCRIPTION (provided by applicant): There is emerging evidence for an endocrine function of bone that plays a key role in regulating phosphate homeostasis and vitamin D metabolism through the release of the hormone FGF23 by osteoblasts and osteocytes. Defining the molecular mechanisms controlling FGF23 production by bone is of critical importance in understanding the physiological and pathological role of this hormone. Studies elucidating the genetic basis for hereditary hypophosphatemic disorders and mutant mouse models have identified the endopeptidase Phex, the SIBLING protein Dmp1, and the endonuclease Enpp1, as local regulators of both the mineralization of extracellular matrix and Fgf23 production in bone. Activation of FGFR1/PI3K/Akt/?-catenin and HMW-FGF2-dependent integrative fibroblastic growth factor receptor signaling (INFS) appear to couple bone mineralization with FGF23 release as well as integrate the effects of systemic factors, such as the PTH receptor/GNAS pathway, which has context-dependent effects on FGF23 gene transcription in osteoblasts /osteocytes. In addition, 1,25(OH)2D functions as a counter-regulatory hormone for FGF23, directly regulates FGF23 gene transcription through VDR-mediated mechanisms and is required for PTH regulation of FGF23 expression. This project proposes to understand how FGF23, vitamin D, PTH, Phex, Dmp1, and FGFR1 are integrated into a biological network that permits cross talk between systemic factors, the extracellular matrix mineralization process and osteoblast/osteocyte production of FGF23 to coordinate systemic phosphate and vitamin D homeostasis and bone formation/ mineralization. We propose studies that investigate the convergence of these local bone and systemic factors through canonical FGFR1, INFS, PTH and VDR-dependent signaling pathways to control basal and stimulated transcription of FGF23 in osteoblasts and osteocytes. We also propose to assess the relative roles of canonical FGFR1 and INFS in regulating FGF23 gene transcription both in vitro using osteoblasts derived from Phex-deficient Hyp and Dmp1-/- mice and in vivo by the conditional deletion of FGFR1 from osteoblasts and osteocytes of Hyp and Dmp1-/- mice. In addition, we will investigate cross-talk between 1,25(OH)2D, PTH and FGFR1 pathways in regulating FGF23 gene transcription in osteoblasts in vitro. These studies will lead to new knowledge of a complex systems biology that has evolved to permit cross-talk between bone and kidney to coordinate phosphate balance, vitamin D metabolism and bone mineralization. Such knowledge will help us understand and better manage patients with hyperphosphatemic and hypophosphatemic disorders. PUBLIC HEALTH RELEVANCE: We have discovered that bone is an endocrine organ in which osteoblasts and osteocytes release FGF23, a phosphaturic hormone that participates in a bone-kidney axis to regulate phosphate, vitamin D and mineral homeostasis. We are pursuing studies to define the precise signaling pathways linking the mineralization of extracellular matrix with FGF23 production in bone, to establish that a physiological function of FGF23 is to coordinate bone mineralization and renal handling of phosphate, and to understand the complex interactions between PTH and 1,25(OH)2D and actions of local bone derived factors through FGFR1 to regulate FGF23 gene transcription. Overall our work is establishing a new conceptual framework whereby bone communicates with other organs to regulate phosphate and vitamin D metabolism in response to changing physiological requirements and is leading to a better understanding of the pathogenesis, diagnosis and treatment of hyperphosphatemic and hypophosphatemic disorders.