Biomechanics and Inflammation in Cartilage

软骨的生物力学和炎症

• 批准号: 8379995
• 负责人: Farshid Guilak
• 金额: $ 32.97万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8379995
• 关键词: Affect; Biochemical; Biological Markers; Biomechanics; Body Weight decreased; Body fat; Cartilage; Characteristics; Chondrocytes; Chronic; Collagen; Degenerative polyarthritis; Development; Diet; Dietary Fatty Acid; Disease; Elements; Equilibrium; Exhibits; Extracellular Matrix; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Genetic Transcription; Goals; Homeostasis; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Joint Instability; Joints; Knee Osteoarthritis; Lead; Leptin; Leptin deficiency; Link; Maintenance; Measurement; Measures; Mechanical Stress; Mechanics; Medial meniscus structure; Mediator of activation protein; Messenger RNA; Metabolic; Metabolism; Monounsaturated Fatty Acids; Morbid Obesity; Mus; Nitric Oxide; Nonesterified Fatty Acids; Obese Mice; Obesity; Omega-3 Fatty Acids; Osteoarthrosis Deformans; Pain; Pathogenesis; Pathology; Play; Production; Prostaglandins; Protein Biosynthesis; Risk Factors; Role; Severities; Signal Transduction; TNF gene; Time; Tissues; United States; Unsaturated Fatty Acids; aggrecan; articular cartilage; base; cytokine; db/db mouse; feeding; improved; in vitro Model; in vivo; insight; joint loading; lard; leptin receptor; mouse model; prevent; psychosocial

Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 21 million people in the United States. There is increasing evidence that local and systemic inflammatory cytokines such as interleukin 1 (IL-1) and inflammatory mediators such as free fatty acids, nitric oxide, or prostaglandins play a major role in OA pathogenesis and pain. Additionally, biomechanical loading plays an important role in the normal homeostatic maintenance of the cartilage extracellular matrix, and under abnormal conditions, mechanical stress may be a significant factor in the initiation and progression of OA. Our governing hypothesis is that obesity causes OA through synergistic interactions of dietary and systemic pro-inflammatory mediators, cytokines, and mechanical stress acting on the chondrocytes. The goal of this project is to examine the influence of dietary fatty acids on obesity-associated OA in mice, and to examine their interaction with altered biomechanical and pro-inflammatory cytokines using various in vivo and in vitro models. We propose that low-grade chronic systemic inflammation ¿ due to obesity or pro-inflammatory fatty acids in the diet ¿ acts in synergy with local inflammatory cytokines or altered mechanical loading (due to obesity or joint instability) to promote a state of inflammation and matrix degradation in the articular cartilage. We will pursue the following aims: In Aim 1, we will examine the role of a high-fat (lard-based) diet in the development of OA in a leptin-receptor deficient mouse (db/db), and we will also measure osteoarthritic changes in diet-induced obese mice fed high-fat diets high in saturated and monounsaturated fatty acids, or omega-3 or omega-6 poly-unsaturated fatty acids. In Aim 2, we will examine the effects of obesity (via high-fat diet or leptin deficiency) on the progression of OA in a destabilized medial meniscus model of mouse OA. In Aim 3, we will use controlled in vitro models of cartilage explant loading to examine the effects of mechanical stress in combination with pro-inflammatory cytokines (e.g., IL-1, leptin, TNF-a) and fatty acids on the anabolic and catabolic activities of the chondrocytes, as measured by biomarker production, real-time PCR measurements of mRNA transcription, and protein synthesis of collagen II and aggrecan. Detailed studies of the interactions between specific biomechanical factors, pro-inflammatory mediators, and tissue metabolism in articular cartilage will improve our understanding of the pathology of the OA, particularly as it relates in vivo to "biomechanical" factors such as obesity, injury, or weight loss. The results of this study will provide new insights into key elements of the pathogenesis of OA, and ultimately could lead to new treatments that exploit mechanical, psychosocial, and biochemical therapies to prevent disease.

骨关节炎（OA）是一种疼痛和使人虚弱的滑膜关节疾病，估计影响21 在美国的百万人。越来越多的证据表明，局部和全身炎症 细胞因子如白细胞介素1（IL-1）和炎症介质如游离脂肪酸、一氧化氮或 胡枝子素在OA发病机制和疼痛中起主要作用。此外，生物力学负荷起着 在软骨细胞外基质的正常稳态维持中起重要作用， 在异常情况下，机械应力可能是OA发生和发展的重要因素。 我们的主要假设是肥胖通过饮食和全身性的协同作用引起OA。 促炎介质、细胞因子和作用于软骨细胞的机械应力。这个目标 项目是检查膳食脂肪酸对小鼠肥胖相关OA的影响，并检查 它们与改变的生物力学和促炎细胞因子的相互作用， 模型我们认为，由于肥胖或促炎性疾病引起的低度慢性全身性炎症 饮食中的脂肪酸与局部炎性细胞因子或改变的机械负荷（由于 肥胖或关节不稳定）以促进关节中的炎症和基质降解状态 软骨我们将追求以下目标：在目标1中，我们将研究高脂肪（猪油为基础）饮食的作用 在瘦素受体缺陷小鼠（db/db）中OA的发展中，我们还将测量 饮食诱导的肥胖小鼠中的骨关节炎变化 脂肪酸或ω-3或ω-6多不饱和脂肪酸。在目标2中，我们将研究 肥胖（通过高脂饮食或瘦素缺乏）对不稳定内侧半月板OA进展的影响 小鼠OA模型。在目标3中，我们将使用受控的软骨外植体加载体外模型来检查 机械应力与促炎细胞因子（例如，IL-1、瘦素、TNF-α） 和脂肪酸对软骨细胞的合成代谢和分解代谢活性的影响，如通过生物标志物测量的 mRNA转录的实时PCR测量和胶原II的蛋白质合成， 聚集蛋白聚糖。详细研究了特定生物力学因素、促炎因子和炎症因子之间的相互作用， 介质，和组织代谢的关节软骨将提高我们的理解的病理， OA，特别是因为它在体内与肥胖、受伤或体重减轻等“生物力学”因素有关。的 这项研究的结果将为OA发病机制的关键因素提供新的见解，并最终 可能导致新的治疗方法，利用机械，心理和生化疗法，以防止 疾病