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

项目摘要 骨关节炎（OA）是退行性关节疾病的最常见形式，影响数百万人 在全球范围内，这将带来巨大的经济负担。目前没有疾病修饰疗法 由于对OA进展的遗传因素和途径的了解有限， 因此，全面了解驱动OA发病机制的信号通路将促进 早期诊断和疾病改善疗法的创新。该提案将进一步推动分子 粘附G蛋白偶联受体G6（Adgrg6）基因的遗传突变小鼠的表征。 ADGRG 6在人类和小鼠的关节软骨中富集，我们已经证明它参与了关节软骨的形成。 人OA。小鼠关节软骨中Adgrg6的缺失导致OA样关节病理学， cAMP和STAT3信号通路的失调。有趣的是，cAMP信号传导以前是 表明驱动软骨保护机制，STAT3激活与OA的发展有关， 人类基于这些新的发现，我们假设关节软骨的稳态需要精确的 cAMP和STAT3信号传导的调节。将在三个具体目标下检验这一假设： 1.我们将使用一种新的Gs-coupled DREADD特异性激活关节软骨中的cAMP信号传导。 小鼠，并确定由cAMP信号调节的转录网络。康贝特人将以 Adgrg6突变小鼠和创伤后OA发生过程中cAMP信号传导的细胞效应物 OA小鼠模型。 2.我们将使用以下方法确定OA进展过程中STAT3介导的信号传导的下游效应物： 通过分析STAT3依赖性基因调控，建立创伤后OA小鼠模型。 3.我们将确定靶向STAT3和cAMP信号通路治疗OA样 使用创伤后OA小鼠模型的关节病理学。我们将利用创新的药物 用于靶向这些途径的疾病修饰疗法的局部、缓释递送的方法。 总之，这项拟议的研究将利用小鼠遗传学，结合现代基因组学， 确定cAMP和STAT3信号传导在关节软骨稳态中作用的药物方法 和OA发病机制的关系，这可能有助于我们对人类OA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.