GP130/STAT3 signalling in articular cartilage development and regeneration

GP130/STAT3信号在关节软骨发育和再生中的作用

基本信息

批准号：
10440806
负责人：
DENIS EVSEENKO
金额：
$ 7.1万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440806
关键词：
Ablation Acute Adult Affect Agonist American Animal Model Animals Apoptosis Cartilage Cartilage injury Cell Cycle Cells Characteristics Chondrocytes Chondrogenesis Clinical Research Data Defect Degenerative polyarthritis Development Developmental Cell Biology Differentiation and Growth Disease Exhibits Family Functional disorder Genes Genetic Genetic Transcription Heterodimerization Hip Joint Human Human Development Hyperactivity IL6ST gene Impairment Injury Interleukin-6 Investigation Janus kinase Joints Knee joint LIF gene Laboratories Lead Life Ligands Literature MYC Family Protein Maintenance Mediating Metabolism Modeling Modern Medicine Molecular Morbidity - disease rate Motion Mus Mutation Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Pilot Projects Preclinical Testing Process Publishing Rattus Regenerative capacity Reporting Rodent Role STAT3 gene Signal Transduction Site Stat3 protein Surface Synovial joint Testing Therapeutic Tissues Transgenic Mice United States Variant Weight-Bearing state articular cartilage autocrine base cartilage cell cartilage degradation cartilage development cartilage regeneration cartilage repair clinical development cytokine experimental study fetal fetus cell glycoprotein 130 improved in vivo injury and repair joint destruction joint formation joint injury leukemia inhibitory factor receptor member migration model design molecular phenotype mouse model novel oncostatin M paracrine postnatal prevent progenitor public health relevance receptor regeneration potential repaired reparative capacity response response to injury restoration skeletal small molecule stem subchondral bone

项目摘要

PROJECT SUMMARY Articular cartilage is a highly specialized tissue that protects diarthrodial joints from forces associated with load bearing, and allows nearly frictionless motion between articular surfaces. Articular cartilage injury often leads to osteoarthritis (OA). OA currently affects more than 25 million people in the United States alone, making joint surface restoration a major priority in modern medicine. The regenerative capacity of adult articular cartilage has traditionally considered to be negligible, but several recent reports suggest that the regenerative potential of articular cartilage may be underestimated. Based on our preliminary data, we hypothesize that signaling through the Leukemia Inhibitory Factor Receptor-Glycoprotein 130/Janus Kinase/Signal Transducer and Activator of Transcription 3 (LIFR/gp130/JAK/STAT3) pathway is essential during devleopment, and can stimulate adult chondrocytes to assume a proliferative and migratory phenotype, similar to what occurs during fetal joint development, thereby promotimg the maintenance of articular cartilage. Moreover, we identified a novel small molecule termed Regulator of Cartilage Growth and Differentiation 423 (RCGD 423) that potently and selectively agonizes this pathway in a gp130-dependent manner. We therefore test whether manipulation of gp130-STAT3 signaling, both genetically or pharmacologically, can modulate the development and progression of OA. First, the role of LIFR and STAT3 signaling in establishment and maintenance of mouse cartilage during development will be defined. Next, we will test the consequences of gain and loss of STAT3 function in cartilage regeneration in a mouse injury model designed to mimic OA. The final set of experiments will evaluate the effects of RCGD 423 and test the hypothesis that this molecule acts by modulating gp130 signaling in mouse cartilage repair and degeneration. The experiments in this proposal are anticipated to define a novel function for LIFR-gp130/STAT3 signaling in cartilage establishment and repair, and to demonstrate that manipulation of this pathway can prevent degeneration in mouse models of osteoarthritis. If these experiments are successful, a critical new pathway regulating cartilage development, repair and degeneration will have been identified. In addition, a small molecule agonist of gp130 signaling that can slow the progression of articular cartilage degradation will be ready for pre-clinical testing and development.

项目概要关节软骨是一种高度专业化的组织，可保护关节免受与负载相关的力的影响轴承，并允许关节表面之间几乎无摩擦的运动。关节软骨损伤常常导致骨关节炎（OA）。目前，仅在美国就有超过 2500 万人受到 OA 的影响，这使得表面修复是现代医学的一个主要优先事项。成人关节软骨的再生能力传统上被认为可以忽略不计，但最近的几份报告表明，再生潜力关节软骨的作用可能被低估。根据我们的初步数据，我们假设信号通过白血病抑制因子受体-糖蛋白 130/Janus 激酶/信号转导器和转录激活剂 3 (LIFR/gp130/JAK/STAT3) 通路在发育过程中至关重要，并且可以刺激成体软骨细胞呈现增殖和迁移表型，类似于在胎儿关节发育，从而促进关节软骨的维护。此外，我们确定了一个称为软骨生长和分化调节剂 423 (RCGD 423) 的新型小分子，可有效并以 gp130 依赖性方式选择性地激动该通路。因此，我们测试是否存在操纵 gp130-STAT3 信号传导，无论是遗传上还是药理学上，都可以调节发育和 OA 的进展。一、LIFR和STAT3信号在小鼠建立和维持中的作用发育过程中的软骨将被定义。接下来我们来测试一下STAT3的得失后果在模拟 OA 的小鼠损伤模型中软骨再生中的功能。最后一组实验将评估 RCGD 423 的效果并测试该分子通过调节 gp130 发挥作用的假设小鼠软骨修复和退化中的信号传导。本提案中的实验预计定义了 LIFR-gp130/STAT3 信号在软骨建立和修复中的新功能，并证明操纵该途径可以防止小鼠骨关节炎模型的退化。如果这些实验是成功的，这是调节软骨发育、修复和发育的关键新途径退化将被识别。此外，gp130 信号传导的小分子激动剂可以减缓关节软骨退化的进展将为临床前测试和开发做好准备。