Analyzing the role of cAMP and STAT3 signaling in cartilage homeostasis and osteoarthritis development

项目摘要 骨关节炎是影响数百万人的最常见的退行性关节疾病 并导致巨大的财政负担。目前还没有治疗疾病的方法。 可用于骨性关节炎，由于对骨性关节炎进展的遗传因素和途径的了解有限。 因此，全面了解推动骨性关节炎发病机制的信号通路将有助于 创新早期诊断和疾病修正疗法。这项提议将进一步推动分子 黏附G蛋白偶联受体G6(Adgrg6)基因突变小鼠的特征 ADGRG6在人和小鼠的关节软骨中都是丰富的，我们已经证明了它参与了 人类的办公自动化。Adgrg6在小鼠关节软骨中的丢失导致骨关节炎样关节病理，并 CAMP和STAT3信号通路异常。有趣的是，cAMP信号之前 提示驱动软骨保护机制，并且STAT3激活与骨性关节炎的发生有关 人类。基于这些新发现，我们假设关节软骨的动态平衡需要精确的 CAMP和STAT3信号的调节。这一假设将在三个具体目标下进行检验： 1.我们将使用一种新的Gs偶联DREADD来特异性激活关节软骨中的cAMP信号 小鼠，并确定cAMP信号调节的转录网络。我们将确定 Adgrg6突变小鼠和创伤后骨性关节炎发育过程中cAMP信号的细胞效应 小鼠骨性关节炎模型。 2.我们将确定在骨关节炎进展过程中STAT3介导的信号的下游效应器 通过分析STAT3依赖的基因调控建立创伤后小鼠骨性关节炎模型。 3.我们将确定靶向STAT3和cAMP信号通路治疗类骨关节炎的疗效 关节病理学采用创伤后骨性关节炎小鼠模型。我们将利用创新药物 针对这些途径的局部、缓释疾病修饰疗法的方法。 总而言之，这项拟议的研究将利用小鼠遗传学，结合现代基因组学和 确定cAMP和STAT3信号在关节软骨内稳态中作用的药物途径 以及骨性关节炎的发病机制，可能会加速我们对人类骨性关节炎的诊断和治疗。

Project Summary Osteoarthritis (OA) is the most common form of degenerative joint disease affecting millions of people worldwide and lead to a tremendous financial burden. Currently there are no disease modifying therapies available for OA, due to limited understanding of the genetic factors and pathways underling OA progression. Therefore, a comprehensive understanding of signaling pathways driving the pathogenesis of OA will motivate innovation for early diagnosis and disease modifying therapeutics. This proposal will further the molecular characterization of a genetic mutant mouse of the Adhesion G protein-coupled receptor G6 (Adgrg6) gene. ADGRG6 is enriched in articular cartilage in human and mouse, and we have demonstrated its involvement in human OA. Loss of Adgrg6 in the articular cartilage in mouse leads to OA-like joint pathology, and dysregulation of both cAMP and STAT3 signaling pathway. Interestingly, cAMP signaling is previously indicated to drive chondroprotective mechanisms, and STAT3 activation is associated with OA development in human. Based on these novel findings, we hypothesize that homeostasis of articular cartilage requires precise regulation of both cAMP and STAT3 signaling. This hypothesis will be tested under three specific aims: 1. We will specifically activate cAMP signaling in articular cartilage using a novel Gs-coupled DREADD mouse, and determine the transcriptional network regulated by cAMP signaling. We will determine the cellular effectors of cAMP signaling during OA development in Adgrg6 mutant mice and in post-traumatic mouse model of OA. 2. We will determine the downstream effectors of STAT3-mediated signaling during OA progression using the post-traumatic mouse model of OA by analysis of STAT3 dependent gene regulation. 3. We will determine the efficacy of targeting STAT3 and cAMP signaling pathways for treatment of OA-like joint pathology using the post-traumatic mouse model of OA. We will utilize innovative pharmaceutical approaches for localized, slow-release delivery of disease modifying therapies targeting these pathways. Taken together, this proposed study will utilize mouse genetics, combined with modern genomics and pharmaceutic approaches to define the role of cAMP and STAT3 signaling in articular cartilage homeostasis and OA pathogenesis, which may accelerate our diagnosis and treatment of human OA.