The Role of PGRN Growth Factor in Osteoarthritis

PGRN 生长因子在骨关节炎中的作用

• 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
• 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

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）是一种退化性关节疾病，影响了美国超过4600万人 独自的。由于OA确保在很大程度上未知的机制，因此没有有效的治疗靶标 预防和治疗疾病。但是，生长因子，细胞因子和基质降解酶是 在发起和加重OA病变时强烈实施。那是对互动的分子理解 在这些分子中，将提供宝贵的信息，以寻找新的热目标 OA。我们针对OA中新颖的，不同表达基因的全基因组筛选导致了程序努尔蛋白的隔离 （PGRN）是一种新型OA相关的生长因子。在随后的PGRN结合蛋白的全局筛选中， 我们惊讶地发现PGRN与TNF受体（TNFR）结合。 PGRN直接与TNFR2结合 比TNFα高约600倍，软骨细胞中PGRN激活的靶基因表达 取决于TNFR2。另外，PGRN阻止了TNFα与TNFR的结合并抑制TNFα诱导的 软骨寡聚基质蛋白（COMP）的ADAMTS裂解。 PGRN基因的删除加剧， 重组PGRN阻止了TNF转基因小鼠多发性关节炎的赞助商样发育。 该提案专门介绍了PGRN在发病机理中执行其软骨保护作用的假设 通过与TNFR相互作用的OA。具体目的是：（1）分子机制是什么 以及PGRN调节软骨细胞代谢的信号通路？我们将定义 PGRN和TNFα在软骨细胞代谢上，信号通路，靶基因表达和相互作用 在软骨细胞中。我们将确定PGRN函数对软骨细胞中TNFR的依赖性和 表征PGRN/TNFR受体复合物。正常和艺术的人类软骨细胞以及野生型 将使用PGRN - / - 鼠关节软骨细胞。 （2）PGRN在该计划中起重要作用 OA的进展，其在OA中的作用机制是什么？我们将利用 系统的和诱导的PGRN敲除小鼠，以产生手术诱导的OA模型。我们也会 确定重组PGRN是否可以保护小鼠免受OA挑战以及PGRN的改善 现有的OA。我们将确定哪种TNFR对于介导PGRN在OA中的保护作用很重要。通过申请 从体外研究（在AIM1中提出）到小鼠模型中早期和晚期事件的见解， 我们将了解OA主动性和进展的基础事件的分子事件。成功的 拟议研究的完成不仅将使我们对分子机制的理解有利 生长因子和细胞因子在软骨细胞和OA中的协同作用，但也可能导致 开发包括OA在内的退行性疾病的新型热干预策略。