FGF2 Isoforms in Bone and Phosphate Homeostasis

骨和磷酸盐稳态中的 FGF2 同工型

• 批准号: 8628923
• 负责人: Marja Marie Hurley
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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/8628923
• 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

Project Summary 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.

项目摘要 成纤维细胞生长因子23(FGF23)是人类病理疾病中的主要磷酸调节因子 与异常骨矿化和肾脏磷酸盐消耗(PI)相关。然而，中国的监管机构 FGF23的产生，FGF23诱导的PI浪费和矿化缺陷的信号通路(S)不是 完全理解。我们的研究支持成纤维细胞生长因子2的核异构体的重要作用 (FGF2)在FGF23的生产和生物学功能中的作用。利用新的小鼠模型表达HMW异构体 成骨细胞系小鼠(HMWTg)和选择性缺失HMW异构体(HMWKO)小鼠 我们证明HMWTg组小鼠血清和骨骼中FGF23增加，侏儒症，骨质减少。 骨密度(BMD)、骨软化、低磷血症和FGF23/FGFReceptor/Klotho/MAPK异常 骨骼和肾脏中的Wnt信号。初步数据显示，HMWFGF2亚型的消融 增加小鼠骨密度，升高血磷，显著降低FGF23基因的表达。我们也 Hyp小鼠成骨细胞/骨细胞HMWFGF2核表达增强 X连锁低磷血症性软骨病(XLH)。我们也有令人兴奋的初步数据，HMW亚型是 XLH患者的B淋巴细胞过表达支持这些研究的临床相关性。我们的 中心假说是HMWFGF2：I)在肾脏PI的动态平衡中起重要作用。 FGF23在骨骼中的产生。Ii)通过FGF23依赖和非依赖来调节骨基质矿化 效果。(Iii)造成Hyp小鼠体内PI浪费和基质矿化缺陷。目标1将决定 HMWFGF2亚型在HMW转基因小鼠肾脏PI稳态中的作用：我们的工作假说 HMWFGF2亚型增加骨中FGF23的产生以及内分泌FGF23介导异常 肾脏FGFR/Klotho/MAPK信号转导导致PI消耗。目标2将评估HMWFGF2的作用 异构体/FGF23/FGFR和Wnt信号在成骨细胞分化和矿化中的作用封锁的效果 将测定FGF23、FGFR、MAPK/ERK和硬化素对HMWTg小鼠骨形成的影响。目标3将 检测HMWFGF2基因敲除对PI和骨稳态的功能影响以及HMWFGF2基因敲除是否 在Hyp小鼠异常的PI浪费和基质矿化缺陷中起重要作用。我们的工作假设是 HMWFGF2亚型介导PI稳态异常和骨矿化缺陷。检视 磷稳态与HMW-/-小鼠和Hyp小鼠的骨骼和肾脏表型 HMWFGF2与野生型窝产仔的对比将检验这一假设。我们还将评估成纤维细胞生长因子/成纤维细胞生长因子受体和 这些小鼠体内的下游信号通路。建议中的研究将大大加深我们对 HMWFGF2亚型在PI动态平衡和基质矿化中的作用 对调节人类磷酸盐消耗过程中这些过程的机制的基本见解 精神错乱。