Regulation and Function of FGF23

描述（由申请人提供）：有新的证据表明骨的内分泌功能通过成骨细胞和骨细胞释放激素FGF 23在调节磷酸盐稳态和维生素D代谢中起关键作用。确定控制骨骼产生FGF 23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。阐明遗传性低磷酸盐血症疾病和突变小鼠模型的遗传基础的研究已经鉴定了内肽酶Phex、SIBLING蛋白Dmp 1和内切核酸酶Enpp 1作为骨中细胞外基质矿化和Fgf 23产生的局部调节剂。FGFR 1/PI 3 K/Akt/β-的激活连环蛋白和HMW-FGF 2依赖性整合成纤维细胞生长因子受体信号传导（INFS）似乎将骨矿化与FGF 23释放偶联，并整合全身性因素的作用，如PTH受体/GNAS途径，其对成骨细胞/骨细胞中的FGF 23基因转录具有背景依赖性作用。此外，1，25（OH）2D作为FGF 23的反调节激素发挥作用，通过VDR介导的机制直接调节FGF 23基因转录，并且是PTH调节FGF 23表达所需的。该项目旨在了解FGF 23，维生素D，PTH，Phex，Dmp 1和FGFR 1如何整合到一个生物网络中，该网络允许全身因素，细胞外基质矿化过程和成骨细胞/成骨细胞产生FGF 23之间的串扰，以协调全身磷酸盐和维生素D稳态以及骨形成/矿化。我们提出的研究，调查这些局部骨和全身因素的收敛，通过典型的FGFR 1，INFS，PTH和VDR依赖性信号通路，以控制基础和刺激转录成骨细胞和骨细胞中的FGF 23。我们还建议评估典型的FGFR 1和INFS在调节FGF 23基因转录中的相对作用，无论是在体外使用来自Phex缺陷Hyp和Dmp 1-/-小鼠的成骨细胞，还是在体内通过从Hyp和Dmp 1-/-小鼠的成骨细胞和骨细胞中有条件地删除FGFR 1。此外，我们还将在体外研究1，25（OH）2D、PTH和FGFR 1通路在成骨细胞中调控FGF 23基因转录中的相互作用。这些研究将导致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代谢和骨矿化。这些知识将有助于我们了解和更好地管理高血磷和低血磷疾病的患者。 公共卫生相关性：我们发现骨是一种内分泌器官，其中成骨细胞和骨细胞释放FGF 23，FGF 23是一种磷酸尿激素，参与骨-肾轴调节磷酸盐、维生素D和矿物质稳态。我们正在进行研究，以确定连接骨中细胞外基质矿化与FGF 23产生的精确信号通路，以确定FGF 23的生理功能是协调骨矿化和磷酸盐的肾脏处理，并了解PTH和1，25（OH）2D之间的复杂相互作用以及局部骨衍生因子通过FGFR 1调节FGF 23基因转录的作用。总的来说，我们的工作是建立一个新的概念框架，使骨骼与其他器官沟通，以调节磷酸盐和维生素D代谢，以应对不断变化的生理需求，并导致更好地了解高磷酸盐血症和低磷酸盐血症疾病的发病机制，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.