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: 8162691
• 负责人: Chuanju Liu
• 金额: $ 38.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8162691
• 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; Proteins; 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 Factors; United States; base; cytokine; genome wide association study; insight; mammalian COMP; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; receptor binding; therapeutic target

DESCRIPTION (provided by applicant): 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 TNF?, and PGRN-activated target gene expressions in chondrocytes depend on TNFR2. In addition, PGRN blocks the binding of TNF? to TNFR and inhibits TNF?-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 TNF? on chondrocyte metabolism, their signaling pathways, target gene expressions and inter-plays 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 wild- type 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 Aim 1) 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. PUBLIC HEALTH RELEVANCE: The proposed studies will present a novel chondroprotective growth factor and provide a better understanding of growth factor and cytokine in chondrocytes and in the pathogenesis of OA. Identification of novel molecules and their derivatives relevant to chondrocytes is the basis for developing and optimizing the application of the novel therapeutic targets in cartilage disorders, including OA.

描述（由申请人提供）：骨关节炎（OA）是一种退化性关节疾病，仅影响了美国超过4600万人。由于OA随后的机制在很大程度上是未知的，因此没有有效预防和治疗疾病的治疗靶标。然而，生长因子，细胞因子和基质降解酶强烈涉及引发和加重OA病变。因此，对这些分子之间相互作用的分子理解将为寻找新型OA治疗靶标提供宝贵的信息。我们针对OA中新型的，差异表达的基因的全基因组筛选，导致将前体素（PGRN）分离为新型OA相关生长因子。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与TNF高约600倍直接与TNFR2结合，而软骨细胞中PGRN激活的靶基因表达取决于TNFR2。另外，PGRN阻止了TNF的结合？对于TNFR并抑制TNF？诱导的软骨寡聚基质蛋白（COMP）的ADAMTS裂解。 PGRN基因的删除加剧，而重组PGRN则阻止了TNF转基因小鼠的多性关节炎自发发展。该提案特别着重于以下假设，即PGRN通过与TNFR相互作用在OA的发病机理中发挥其软骨保护作用。具体目的是：（1）PGRN调节软骨细胞代谢的分子机制和信号通路是什么？我们将定义PGRN和TNF的影响？在软骨细胞代谢上，其信号通路，靶基因表达和软骨细胞中的互动。我们将确定PGRN功能对软骨细胞中TNFR的依赖性，并表征PGRN/TNFR受体复合物。正常和关节炎的人软骨细胞以及野生型和PGRN - / - 鼠关节软骨细胞将使用。 （2）PGRN在OA的启动和进展中起重要作用，其在OA中的作用机制是什么？我们将利用系统的和可诱导的PGRN敲除小鼠来产生手术诱导的OA模型。我们还将确定重组PGRN是否可以保护小鼠免受OA挑战，以及PGRN是否可以改善现有的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。通过将体外研究中的见解（在目标1中提出）应用于小鼠模型中早期和晚期事件的分析，我们将了解OA启动和进展的分子事件。成功完成拟议的研究不仅将有益于我们对生长因子和细胞因子在软骨细胞和OA中起作用的分子机制的理解，而且还可能导致开发新的退化性疾病治疗干预策略，包括OA。 公共卫生相关性：拟议的研究将提出一种新型的软骨保护生长因子，并更好地了解软骨细胞和OA发病机理中生长因子和细胞因子。与软骨细胞相关的新分子及其衍生物的鉴定是开发和优化新型治疗靶标在软骨疾病（包括OA）中的应用的基础。