GP130/STAT3 signalling in articular cartilage development and regeneration

项目总结 关节软骨是一种高度专门化的组织，可以保护腹股沟关节免受与负荷相关的力的伤害。 轴承，并允许关节表面之间几乎无摩擦的运动。关节软骨损伤常导致 骨性关节炎(OA)。目前，仅在美国就有2500多万人受到影响，使联合 表面修复是现代医学的主要优先事项.成人关节软骨的再生能力 传统上被认为是微不足道的，但最近的几份报告表明，再生潜力 关节软骨的比例可能被低估了。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/信号转导和 转录激活子3(LIFR/gp130/JAK/STAT3)通路在细胞的发育过程中起着至关重要的作用。 刺激成人软骨细胞呈现增殖和迁移表型，类似于 胎儿关节发育，从而促进关节软骨的维护。此外，我们确定了一种 新型软骨生长分化调节因子423(RCGD 423) 并以gp130依赖的方式选择性地刺激这一途径。因此，我们测试操纵行为是否 Gp130-STAT3信号的表达，无论是从遗传上还是从药理学上，都可以调节肿瘤的发育和 骨性关节炎的进展。首先，LIFR和STAT3信号在小鼠的建立和维持中的作用 将对发育过程中的软骨进行定义。接下来，我们将测试STAT3的获得和损失的后果 在模拟骨性关节炎的小鼠损伤模型中软骨再生的作用。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 小鼠软骨修复和退变中的信号转导。这项提案中的实验预计将 确定LIFR-gp130/STAT3信号在软骨建立和修复中的新功能，并 证明操纵这一途径可以防止骨性关节炎小鼠模型的退化。如果 这些实验是成功的，是调控软骨发育、修复和修复的关键新途径。 退化就会被识别出来。此外，一种gp130信号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的测试和开发做好准备。

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.