FGF2 Isoforms in Bone and Phosphate Homeostasis

骨和磷酸盐稳态中的 FGF2 同工型

• 批准号: 10026143
• 负责人: Marja Marie Hurley
• 金额: $ 5.82万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026143
• 关键词: Ablation; Adult; Age; Area; Arthritis; Blocking Antibodies; Cartilage; Cell Line; Cell Lineage; Chondrocytes; Complementary DNA; Data; Degenerative polyarthritis; Development; Diagnostic radiologic examination; Disease; FGF2 gene; FGFR1 gene; FGFR3 gene; Familial hypophosphatemic bone disease; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Proteins; Genes; Genetic Transcription; Health Care Costs; Healthcare Systems; Histologic; Histology; Homeostasis; Homologous Gene; Human; Hypertrophy; Image; In Vitro; Individual; Joints; Knee joint; MAP Kinase Gene; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Molecular Weight; Monitor; Morbidity - disease rate; Mus; Operative Surgical Procedures; Osteoblasts; Osteocytes; Pathogenesis; Periodicity; Phenocopy; Phenotype; Process; Protein Isoforms; Publishing; RNA Interference; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Time; Up-Regulation; WNT Signaling Pathway; Work; aged; antibody inhibitor; bone; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; lubricin; microCT; neutralizing antibody; new therapeutic target; novel; overexpression; pre-clinical; prevent; protein biomarkers; vector

Project Summary: The long-term objective of this project is to determine how the high molecular weight isoforms of Fibroblast growth factor 2 (HMWFGF2) contribute to osteoarthropathy. Osteoarthritis (OA) is the most common form of arthritis and has a major negative impact on human health and cost to the health care system. Degenerative osteoarthropathy, a form of OA is prevalent in young individuals with X-linked hypophosphatemia (XLH) and common to all older XLH individuals and is a major cause of morbidity in these subjects. HMWTg mice phenocopy the Hyp mouse homolog of XLH that develops severe OA. We also previously published that HMWFGF2 isoforms are overexpressed in osteoblasts and osteocytes of Hyp mice. Of relevance we recently published that similar to Hyp mice, HMWTg mice develop progressively severe OA with age. In contrast mice overexpressing low molecular weight FGF2 isoform (LMWTg) in osteoblast lineage cells do not develop OA. Our preliminary data also show that mice in which the FGF2HMW isoforms are selectively ablated do not develop OA compared with aged WT littermates. Of mechanistic relevance our preliminary studies show upregulation of FGF23/FGFR1/MAPK and BMP/Smad1/5/8 in HMWTg knee joints but not LMWTg joints. We therefore wish to explore the potential role of FGF23 in HMWTg induced OA since we published that HMW but not LMW FGF2 transcriptionally regulates FGF23. Furthermore, FGF23 in OA is an understudied area thus studies of FGF2 isoforms modulating FGF23 in OA could also impact the field. We provide novel preliminary data that in vivo administration of FGF23 neutralizing antibody ameliorates the OA phenotype in HMWTg mice. These findings support our overall hypothesis that HMWFGF2 isoforms contribute to OA via FGF23/FGFR1/MAPK signaling. We also wish to investigate the mechanism of joint homeostasis in LMWTg and HMWKO mice since LMWFGF2 appears to protect the joint from OA development. Our aims are: Aim 1a:Define the role of FGF23/FGFReceptor signaling in HMWFGF2 induces osteoarthropathy. Aim 1b: Determine the functional effects of overexpressing of low molecular weight FGF2 or selective ablation of HMWFGF2 isoforms to confer resistance against osteoarthropathy progression in mice. Aim 2: Define the mechanism(s) by which HMWFGF2 induces osteoarthropathy. Our preliminary in vitro studies suggest differential activation of FGF23/FGF receptors and downstream signaling pathways for the catabolic effects of HMWFGF2 versus anabolic effect of LMWFGF2 in joint homeostasis. Murine chondrogenic cell line ATDC5 transduced with FGF2HMW and FGF2LMW cDNAs and primary murine articular chondrocytes obtained from Vector, HMWTg and LMWTg mice will be used to interrogate intracellular signaling pathways that are unique for HMW or LMW in developing or preventing development of OA. Since the role of FGF2 in OA is controversial with studies supporting both catabolic and anabolic effects of FGF2 and since the potential role of FGF2 isoforms in OA has not been investigated, our studies could significantly impact the field.

项目摘要： 该项目的长期目标是确定成纤维细胞的高分子量同工型 生长因子2（HMWFGF2）有助于骨关节炎。骨关节炎（OA）是最常见的形式 关节炎，对人类健康和卫生保健系统的成本产生重大负面影响。退化 骨关节炎，一种OA形式在X连锁低磷酸血症（XLH）和 所有年龄较大的XLH个体共有，是这些受试者发病率的主要原因。 HMWTG小鼠 表仿XLH的催眠小鼠同源物会发展出严重的OA。我们以前还发表了 HMWFGF2同工型在催眠小鼠的成骨细胞和骨细胞中过表达。我们最近的相关性 HMWTG小鼠发表了类似于催眠小鼠的那样，随着年龄的增长而逐渐严重的OA。相反的小鼠 过表达成骨细胞谱系细胞中的低分子量FGF2同工型（LMWTG）不会发展OA。 我们的初步数据还表明，其中FGF2HMW同工型的小鼠有选择地烧蚀 与老年wt同窝仔相比，开发OA。我们的初步研究表明的机理相关性 HMWTG膝关节中的FGF23/FGFR1/MAPK和BMP/SMAD1/5/8的上调，而不是LMWTG关节。我们 因此，希望探索FGF23在HMWTG诱导的OA中的潜在作用，因为我们发表了HMW，但是 不是LMW FGF2转录调节FGF23。此外，OA中的FGF23是一个研究的区域 在OA中调节FGF23的FGF2同工型的研究也可能影响该领域。我们提供新颖的初步 在体内施用FGF23中和抗体的数据可以改善HMWTG小鼠的OA表型。 这些发现支持我们的总体假设，即HMWFGF2同工型通过 FGF23/FGFR1/MAPK信号传导。我们还希望研究LMWTG联合稳态的机制 由于LMWFGF2似乎可以保护关节免受OA发育的影响，因此HMWKO小鼠和HMWKO小鼠。我们的目标是：目标 1A：定义FGF23/FGFRECEPTOR信号在HMWFGF2中的作用会诱导骨关节炎。 AIM 1B： 确定低分子量FGF2过表达或选择性消融的功能效应 HMWFGF2同工型可赋予小鼠骨关节炎进展的耐药性。目标2：定义 HMWFGF2诱导骨关节炎的机制。我们的初步体外研究表明 FGF23/FGF受体的差异激活和下游信号通路的分解代谢效应 LMWFGF2在联合稳态中的HMWFGF2与合成代谢作用。鼠软骨细胞系ATDC5 用FGF2HMW和FGF2LMW cDNA和原代鼠关节软骨细胞转导 向量，HMWTG和LMWTG小鼠将用于询问独特的细胞内信号通路 用于HMW或LMW开发或预防OA的发展。由于FGF2在OA中的作用是 与支持FGF2的分解代谢和合成代谢作用的研究有争议，并且由于潜在的作用 OA中的FGF2同工型尚未进行研究，我们的研究可能会对该领域产生重大影响。