The Role of PGRN Growth Factor in Osteoarthritis

PGRN 生长因子在骨关节炎中的作用

基本信息

批准号：
8698896
负责人：
Chuanju Liu
金额：
$ 47.49万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2013-11-23 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698896
关键词：
ADAMTS Affect Affinity Affinity Chromatography Arthritis Binding Binding Proteins Biochemical Cartilage Cartilage Diseases Cell membrane Chondrocytes Complex Data Degenerative Disorder Degenerative polyarthritis Dependence Development Disease Enzymes Etiology Event Exhibits Extracellular Matrix Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Growth Factor Human In Vitro Inflammation Intervention Joints Knock-out Knockout Mice Lead Lesion Mass Spectrum Analysis Mediating Metabolic Metabolism Modeling Molecular Mus PGRN gene Pain Pathogenesis Pharmaceutical Preparations Play Polyarthritides Population Predisposition Prevention Progranulin Recombinants Recruitment Activity Regulation Research Role Series Signal Pathway Signal Transduction Symptoms TNF gene TNFRSF1A gene TNFRSF1B gene Testing Transgenic Mice Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States base cytokine genome wide association study insight mammalian COMP mouse model new therapeutic target novel novel therapeutic intervention prevent receptor receptor binding therapeutic target

项目摘要

Osteoarthritis (OA) is a degenerative joint disease that affects more than 46 million people in the United States alone. Since mechanisms by which OA ensues are largely unknown, there are no therapeutic targets that effectively prevent and treat the disease. However, growth factors, cytokines and matrix-degrading enzymes are strongly implicated in initiating and aggravating OA lesions. Thus, a molecular understanding of interplays among these molecules will provide invaluable information toward the search for novel therapeutic targets for OA. Our genome-wide screen for novel, differentially expressed genes in OA led to the isolation of progranulin (PGRN) as a novel OA-associated growth factor. In subsequent global screen for the binding proteins of PGRN, we were surprised to find that PGRN bound to TNF Receptors (TNFR). PGRN directly binds to TNFR2 with an approximately 600-fold higher affinity than TNFα, and PGRN-activated target gene expressions in chondrocytes depend on TNFR2. In addition, PGRN blocks the binding of TNFα to TNFR and inhibits TNFα-induced ADAMTS cleavage of cartilage oligomeric matrix protein (COMP). Deletion of the PGRN gene exacerbates, whereas recombinant PGRN prevents, the spontaneous development of polyarthritis in TNF transgenic mice. This proposal specifically focuses on the hypothesis that PGRN exerts its chondroprotective role in the pathogenesis of OA by interacting with TNFR. The Specific Aims are: (1) what are the molecular mechanisms and signaling pathways by which PGRN regulates chondrocyte metabolism? We will define the effects of PGRN and TNFα on chondrocyte metabolism, their signaling pathways, target gene expressions and interplays in chondrocytes. We will determine the dependence of the PGRN function on TNFR in chondrocytes and characterize the PGRN/TNFR receptor complexes. Normal and arthritic human chondrocytes, as well as wildtype and PGRN-/- murine articular chondrocytes, will be used. (2) Does PGRN play an important role in the initiation and progression of OA, and what are the mechanisms of its action in OA? We will take advantage of both systematic and inducible PGRN knockout mice to generate surgically-induced OA models. We will also determine whether recombinant PGRN protects mice against OA challenge and whether PGRN ameliorates existing OA. We will determine which TNFR is important for mediating PGRN’s protective role in OA. By applying insights from in vitro studies (proposed in Aim1) to the analysis of early and late events in the mouse models, we will gain understanding of the molecular events underlying the initiation and progression of OA. Successful completion of the proposed research will not only benefit our understanding of the molecular mechanisms by which growth factor and cytokine act in concert in chondrocytes and in OA, but may also lead to the development of novel therapeutic intervention strategies for degenerative diseases, including OA.

骨关节炎 (OA) 是一种退行性关节疾病，影响美国超过 4600 万人由于 OA 发生的机制很大程度上未知，因此没有有效的治疗靶点。然而，生长因子、细胞因子和基质降解酶是疾病的预防和治疗方法。与 OA 病变的发生和加重有关，因此，对相互作用的分子理解非常深入。这些分子将为寻找新的治疗靶点提供宝贵的信息我们对 OA 中新的差异表达基因进行全基因组筛选，从而分离出颗粒体蛋白前体。 (PGRN) 作为一种新型 OA 相关生长因子，在随后对 PGRN 结合蛋白的全球筛选中，我们惊讶地发现 PGRN 与 TNF 受体 (TNFR) 结合，PGRN 直接与 TNFR2 结合。亲和力比 TNFα 高约 600 倍，并且软骨细胞中 PGRN 激活的靶基因表达依赖于 TNFR2 此外，PGRN 阻断 TNFα 与 TNFR 的结合并抑制 TNFα 诱导的。 ADAMTS 切割软骨寡聚基质蛋白 (COMP) 删除 PGRN 基因加重，而重组 PGRN 可防止 TNF 转基因小鼠自发发生多关节炎。该提案特别关注 PGRN 在发病机制中发挥软骨保护作用的假设通过与 TNFR 相互作用来治疗 OA 的具体目标是：（1）分子机制是什么。 PGRN 调节软骨细胞代谢的信号通路？ PGRN 和 TNFα 对软骨细胞代谢、信号通路、靶基因表达和相互作用的影响我们将确定软骨细胞中 PGRN 功能对 TNFR 的依赖性。表征正常和关节炎人类软骨细胞以及野生型。和 PGRN-/- 小鼠关节软骨细胞，将被使用 (2) PGRN 在启动中是否发挥重要作用。 OA 的作用机制是什么？我们将利用哪些机制？我们还将使用系统性和诱导性 PGRN 敲除小鼠来生成手术诱导的 OA 模型。确定重组 PGRN 是否可以保护小鼠免受 OA 攻击以及 PGRN 是否可以改善我们将通过应用来确定哪种 TNFR 对于介导 PGRN 在 OA 中的保护作用很重要。从体外研究（Aim1 中提出）到小鼠模型早期和晚期事件分析的见解，我们将了解 OA 成功发生和进展的分子事件。完成拟议的研究不仅有利于我们对分子机制的理解生长因子和细胞因子在软骨细胞和 OA 中协同作用，但也可能导致开发针对退行性疾病（包括 OA）的新型治疗干预策略。