Roles of SOX8 and SOX9 in Adult Articular Cartilage

SOX8 和 SOX9 在成人关节软骨中的作用

基本信息

批准号：
10443610
负责人：
VERONIQUE M LEFEBVRE
金额：
$ 58.06万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2018-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443610
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 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

项目摘要

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转的恶化是骨关节炎（OA）和其他退化性关节疾病（DJD）的形式，但是尽管这些痛苦和残疾人条件，尚无治疗可有效保护和恢复健康组织。软骨故障由于组织的分解代谢增加和合成代谢受损而发生。正在制定策略阻止分解代谢，但是主要的知识差距排除了恢复适当软骨的策略的设计代谢。该项目旨在填补关键空白。一个差距是Sox9转录的确切作用成人关节软骨的因素。 Sox9驱动软骨细胞的规范和发育中的分化软骨发生，但其在成人软骨稳态和病理学中的作用尚不清楚。另一个差距是 Sox8（Sox8）在软骨中的作用，最接近Sox9。新数据显示Sox8与关节软骨细胞中的Sox9并有助于成人关节软骨完整性。亲炎和其他驱动DJD的途径会引起软骨细胞分解代谢作用并下调软骨特异性的合成代谢，包括SOX9表达和体外研究表明软骨细胞对促进的分解代谢反应 Sox8或Sox9强迫表达后，炎症细胞因子大大降低。在一起，这些数据提出创新的假设，即Sox8和Sox9在关节软骨细胞中享有关键作用，并且它们的作用致病性下调加剧了软骨变性抑制和分解代谢刺激。三提出了具体目的来检验这一假设。目标1是定义Sox8和Sox9在成人中的作用在健康条件下的关节软骨细胞。任何一个或两个基因都会在人类原发性中被击倒关节软骨细胞并有条件地在成年小鼠的关节软骨细胞中灭活，后果将被评估。目标2是测试Sox8和Sox9抑制是否会影响OA的发展。 Sox8和 Sox9的表达和活动将检查与人类OA严重程度的相关性。另外，OA将会将分析成年小鼠的诱导以及Sox8/Sox9失活对疾病发展的影响机械解剖。 AIM 3是测试Sox8或Sox9的强迫表达以及如何有助于在OA条件下保持关节软骨细胞正常状态。 Sox蛋白将过表达主要来自正常和OA膝盖的人类关节软骨细胞及其对细胞行为的影响。老鼠会有条件地被迫表达关节软骨细胞中的Sox蛋白，并将测试软骨在正常和OA条件下的命运。由专家调查员和临床医生组成的团队已组装确保成功实现项目。新颖的发现有望改变电流了解决定关节软骨细胞规范和健康活动的关键机制疾病，从而激发新的想法，以设计数百万的急需有效治疗世界各地患有OA和其他联合退行性疾病的患者。