Roles of SOX8 and SOX9 in Adult Articular Cartilage

SOX8 和 SOX9 在成人关节软骨中的作用

• 批准号: 10198770
• 负责人: VERONIQUE M LEFEBVRE
• 金额: $ 56.88万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198770
• 关键词: Achievement; Address; Adult; Affect; Aging; Anabolism; Automobile Driving; Behavior; Cartilage; Catabolism; Cell surface; Cells; Chondrocytes; Chondrogenesis; Data; Degenerative polyarthritis; Deterioration; Development; Disease; Disease Progression; Down-Regulation; Economic Burden; Ensure; Event; Failure; Foundations; Genes; Health; High Prevalence; Homeostasis; Human; Impairment; In Vitro; Inflammatory; Joints; Knee; Knee Osteoarthritis; Knowledge; Medial meniscus structure; Molecular; Mus; Natural regeneration; Normalcy; Operative Surgical Procedures; Pain; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Predisposition; Preventive; Proteins; Proteoglycan; Publishing; Reporter; Repression; Research Personnel; Role; SOX8 gene; Severities; Signal Transduction; Solid; Structure; Testing; Tissues; articular cartilage; base; cartilage cell; cell behavior; cytokine; design; effective therapy; innovation; knock-down; novel; overexpression; preclinical trial; programs; regenerative approach; regenerative tissue; regenerative treatment; response; socioeconomics; transcription factor

PROJECT SUMMARY Progressive and irreversible deterioration of articular cartilage is a central event in osteoarthritis (OA) and other forms of degenerative joint disease (DJD), but despite the high prevalence of these painful and disabling conditions, no treatment is yet available to effectively protect and restore healthy tissue. Cartilage breakdown occurs as a result of both increased tissue catabolism and impaired anabolism. Strategies are being developed to block catabolism, but major knowledge gaps preclude the design of strategies to restore proper cartilage anabolism. This project is designed to fill key gaps. One gap is on the exact roles of the SOX9 transcription factor in adult articular cartilage. SOX9 drives chondrocyte specification and differentiation in developmental chondrogenesis, but its roles in adult cartilage homeostasis and pathology remain unclear. Another gap is on the role of SOX8, the closest relative of SOX9, in cartilage. New data reveal that SOX8 is co-expressed with SOX9 in articular chondrocytes and contributes to adult articular cartilage integrity. Pro-inflammatory and other pathways driving DJD elicit chondrocyte catabolic actions and downregulate cartilage-specific anabolism, including SOX9 expression, and in vitro studies suggest that the catabolic response of chondrocytes to pro- inflammatory cytokines is greatly reduced upon forced expression of SOX8 or SOX9. Together, these data suggest the innovative hypothesis that SOX8 and SOX9 share key roles in articular chondrocytes and that their pathogenic downregulation exacerbates cartilage anabolism repression and catabolism stimulation. Three specific aims are proposed to test this hypothesis. Aim 1 is to define the roles of SOX8 and SOX9 in adult articular chondrocytes in healthy conditions. Either or both genes will be knocked down in human primary articular chondrocytes and conditionally inactivated in articular chondrocytes in adult mice, and consequences will be assessed. Aim 2 is to test whether SOX8 and SOX9 repression impacts OA development. SOX8 and SOX9 expression and activities will be examined for correlations with OA severity in humans. Also, OA will be induced in adult mice and the effect of SOX8/SOX9 inactivation on disease development will be analyzed and mechanistically dissected. Aim 3 is to test whether and how forced expression of SOX8 or SOX9 helps maintain articular chondrocyte normalcy in OA conditions. The SOX proteins will be overexpressed in primary human articular chondrocytes from normal and OA knees and their impact on cell behavior assessed. Mice will be conditionally forced to express the SOX proteins in articular chondrocytes and will be tested for cartilage fate under normal and OA conditions. A team of expert investigators and clinicians has been assembled to ensure the successful achievement of the project. Novel discoveries are expected to transform current understanding of key mechanisms dictating articular chondrocyte specification and activities in health and disease, and thereby to spark novel ideas for the design of highly needed effective treatments for the millions of patients suffering from OA and other joint degenerative diseases around the world.

项目摘要 关节软骨的进行性和不可逆的恶化是骨关节炎（OA）和其他关节炎的中心事件。 形式的退行性关节病（DJD），但尽管这些痛苦和致残的高患病率 在这种情况下，还没有治疗方法可以有效地保护和恢复健康组织。软骨破坏 是由于组织catenation增加和anterior受损的结果。正在制定战略 阻止软骨炎，但主要的知识差距妨碍了恢复适当软骨的策略的设计 安东该项目旨在填补关键空白。一个缺口是SOX 9转录的确切作用 成人关节软骨中的因子。SOX 9驱动发育中的软骨细胞特化和分化 软骨形成，但其在成人软骨稳态和病理学中的作用仍不清楚。另一个缺口出现了 SOX 8是SOX 9的近亲，在软骨中的作用。新的数据显示，SOX 8与 S 0X 9在关节软骨细胞中的表达，并有助于成人关节软骨的完整性。促炎和其他 驱动DJD的途径引起软骨细胞分解代谢作用并下调软骨特异性抗体， 包括SOX 9表达，体外研究表明软骨细胞对促软骨素的分解代谢反应， 在S 0X 8或S 0X 9的强制表达后，炎性细胞因子大大减少。这些数据一起 提出了一个创新的假设，即SOX 8和SOX 9在关节软骨细胞中具有关键作用， 致病性下调加剧了软骨细胞的抑制和软骨细胞的刺激。三 提出了具体目标来检验这一假设。目的1：明确SOX 8和SOX 9在成年人中的作用。 关节软骨细胞的情况。其中一个或两个基因将在人类初级阶段被敲除。 成年小鼠关节软骨细胞和条件灭活关节软骨细胞及其后果 将予以评估。目的2是测试SOX 8和SOX 9抑制是否影响OA的发展。SOX 8和 将检查S 0X 9表达和活性与人类中OA严重程度的相关性。此外，OA将 将分析S 0X 8/S 0X 9失活对疾病发展的影响， 机械解剖。目的3是测试SOX 8或SOX 9的强制表达是否以及如何帮助 维持OA条件下关节软骨细胞的正常状态。SOX蛋白将在原代细胞中过表达， 来自正常和OA膝关节的人关节软骨细胞及其对细胞行为的影响。小鼠将 有条件地被迫在关节软骨细胞中表达SOX蛋白， 在正常和OA条件下的命运。一个由专家调查员和临床医生组成的小组已经成立， 确保项目的顺利完成。新的发现有望改变当前的 了解决定关节软骨细胞规格和健康活动的关键机制， 疾病，从而激发新的想法，为数百万人设计急需的有效治疗方法， 在全球范围内，患有OA和其他关节退行性疾病的患者中，