FGF2 Isoforms in Bone and Phosphate Homeostasis

骨和磷酸盐稳态中的 FGF2 同工型

基本信息

批准号：
8735135
负责人：
Marja Marie Hurley
金额：
$ 34.32万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8735135
关键词：
Ablation B-Lymphocytes Biochemical Markers Blocking Antibodies Bone Density Bone Matrix Calcium Cell Lineage Conditioned Culture Media Data Defect Diphosphates Disease Dwarfism Endocrine Enzymes Etiology FGF2 gene Familial hypophosphatemic bone disease Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblast Growth Factor Receptors Gene Expression Genes Homeostasis Human Hydrolysis Hypophosphatemia In Vitro Kidney Knock-out MAP Kinase Gene MAPK3 gene Mediating Messenger RNA Metabolism Minerals Mixed Function Oxygenases Modeling Molecular Weight Mus Nuclear Osteoblasts Osteocytes Osteogenesis Osteomalacia Pathologic Patients Phenotype Physiologic calcification Physiological Play Process Production Protein Isoforms Rickets Role Serum Signal Pathway Signal Transduction Testing Tissues Transgenic Mice Urine Work bone bone turnover clinically relevant fibroblast growth factor 23 in vivo inhibitor/antagonist inorganic phosphate insight interest mRNA Expression mineralization mouse model novel osteoblast differentiation overexpression protein expression public health relevance skeletal sodium-phosphate cotransporter proteins symporter wasting

项目摘要

DESCRIPTION (provided by applicant): Fibroblast Growth Factor 23 (FGF23) is the major phosphate regulator in human pathologic disorders associated with abnormal bone mineralization and renal phosphate wasting (Pi). However the regulators of FGF23 production, the signal pathway(s) for FGF23 induced Pi wasting and defective mineralization are not fully understood. Our studies support an important role for the nuclear isoforms of Fibroblast Growth Factor 2 (FGF2) in FGF23 production and biologic function. Using novel mouse models expressing HMW isoforms in osteoblast lineage cells (HMWTg) mice, and mice with selective deletion of the HMW isoforms (HMWKO) mice we demonstrate that HMWTg mice have increased FGF23 in serum and bone, dwarfism, decreased bone mineral density (BMD), osteomalacia, hypophosphatemia, and abnormal FGF23/FGFReceptor/ klotho/MAPK and Wnt signaling in bone and kidney. Preliminary data shows that ablation of the HMWFGF2 isoforms increased BMD, increased serum phosphate and significantly reduced FGF23 mRNA in mice. We also observed increased expression of nuclear HMWFGF2 in osteoblasts/osteocytes in Hyp mice, a murine model of X-linked hypophosphatemic rickets (XLH). We also have exciting preliminary data that HMW isoforms are overexpressed in B-lymphocytes from a patient with XLH supporting clinical relevance of these studies. Our Central Hypotheses are that HMWFGF2: i) plays an important role in Pi homeostasis in kidney by increasing FGF23 production in bone. ii) regulates bone matrix mineralization via FGF23 dependent and independent effects. iii) contributes to Pi wasting and defective matrix mineralization in Hyp mice. Aim 1 will determine the role of HMWFGF2 isoforms in Pi homeostasis in the kidney of HMW transgenic mice: Our working hypothesis is that HMWFGF2 isoforms increase FGF23 production in bone and that endocrine FGF23 mediates abnormal FGFR/klotho/MAPK signaling in kidney that leads to Pi wasting. Aim 2 will assess the role of HMWFGF2 isoforms/FGF23/FGFR and Wnt signaling in osteoblast differentiation and mineralization. Effects of blockade of FGF23, FGFR, MAPK/ERK and sclerostin on bone formation in HMWTg mice will be determined. Aim 3 will examine functional effects of knockout of HMWFGF2 on Pi and bone homeostasis and whether HMWFGF2 is important in the abnormal Pi wasting and matrix mineralization defect in Hyp mice. Our working hypothesis is that HMWFGF2 isoforms mediate abnormal Pi homeostasis and defective bone mineralization. Examining phosphate homeostasis, the skeletal and kidney phenotypes of HMW-/- mice and Hyp mice with deletion of HMWFGF2 versus wild type littermates will test this hypothesis. We will also assess FGF/FGF Receptor and downstream signaling pathways in these mice. The proposed studies will greatly enhance our understanding of the role of HMWFGF2 isoforms in Pi homeostasis and matrix mineralization and may provide novel and fundamental insights into the mechanisms that regulate these processes in human phosphate wasting disorders.

描述（由申请人提供）：成纤维细胞生长因子23（FGF23）是与异常骨矿化和肾磷酸盐浪费（PI）相关的人类病理疾病的主要磷酸盐调节剂。但是，FGF23产生的调节剂，FGF23诱导的PI浪费和有缺陷的矿化的信号途径尚不完全了解。我们的研究支持成纤维细胞生长因子2（FGF2）在FGF23生产和生物学功能中的核同工型的重要作用。使用在成骨细胞谱系细胞（HMWTG）小鼠中表达HMW同工型的新型鼠标模型，以及具有选择性缺失的HMW同工型（HMWKO）小鼠的小鼠，我们证明HMWTG小鼠在血清和骨，dwarfism中的FGF23中的FGF23增加了，bonseral boneaser neaster neaser neaser neaster Menter and seral bonseral deaste n offfgf23骨和肾脏中的低磷酸血症和异常FGF23/FGFF23/FGFRECEPTOR/KLOTHO/MAPK和WNT信号传导。初步数据表明，HMWFGF2同工型的消融增加了BMD，血清磷酸盐增加并显着降低了小鼠的FGF23 mRNA。我们还观察到在成骨细胞/成骨细胞中核HMWFGF2的表达增加，这是一种X连锁性下磷酸rick鼠（XLH）的鼠模型。我们还拥有令人兴奋的初步数据，即HMW同工型在患有XLH患者的B淋巴细胞中过表达，支持这些研究的临床相关性。我们的中心假设是HMWFGF2：i）通过增加骨骼中FGF23的产生，在肾脏的PI稳态中起着重要作用。 ii）通过FGF23依赖和独立效应来调节骨基质矿化。 iii）在催眠小鼠中有助于PI浪费和缺陷基质矿化。 Aim 1 will determine the role of HMWFGF2 isoforms in Pi homeostasis in the kidney of HMW transgenic mice: Our working hypothesis is that HMWFGF2 isoforms increase FGF23 production in bone and that endocrine FGF23 mediates abnormal FGFR/klotho/MAPK signaling in kidney that leads to Pi wasting. AIM 2将评估HMWFGF2同工型/FGF23/FGFR和WNT信号在成骨细胞分化和矿化中的作用。将确定FGF23，FGFR，MAPK/ERK和硬化蛋白对HMWTG小鼠骨形成的封锁的影响。 AIM 3将检查HMWFGF2敲除PI和骨稳态的功能效应，以及HMWFGF2是否在催眠小鼠的异常PI浪费和基质矿化缺陷中是否重要。我们的工作假设是HMWFGF2同工型介导异常的PI稳态和有缺陷的骨矿化。检查HMW - / - 小鼠的磷酸盐稳态，骨骼和肾脏表型，以及用HMWFGF2缺失与野生型同窝仔的缺失将检验该假设。我们还将评估这些小鼠的FGF/FGF受体和下游信号通路。拟议的研究将大大增强我们对HMWFGF2同工型在PI稳态和基质矿化中的作用的理解，并可能对调节人类磷酸盐浪费障碍中这些过程的机制提供新颖和基本的见解。