Biomechanics and Inflammation in Cartilage

骨关节炎(OA)是一种疼痛和衰弱的滑膜关节疾病，估计有21 美国有一百万人。越来越多的证据表明局部和全身炎症 细胞因子如白介素1(IL-1)和炎症介质如游离脂肪酸、一氧化氮或 前列腺素在骨性关节炎的发病机制和疼痛中起重要作用。此外，生物力学负荷还发挥着 在维持软骨细胞外基质的正常动态平衡方面起着重要作用 在异常情况下，机械应力可能是骨性关节炎发生发展的重要因素。 我们的主要假设是，肥胖通过饮食和全身的协同作用导致骨性关节炎 作用于软骨细胞的促炎介质、细胞因子和机械应力。这样做的目的是 项目是检查饮食脂肪酸对肥胖相关的小鼠骨性关节炎的影响，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 模特们。我们认为由肥胖或促炎引起的低度慢性全身炎症 饮食中的脂肪酸与局部炎症细胞因子或改变的机械负荷协同作用(由于 肥胖或关节不稳定)以促进关节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(以猪油为基础)饮食的作用 在瘦素受体缺陷小鼠(db/db)的骨性关节炎的发展中，我们还将测量 高饱和和单不饱和高脂饮食对饮食诱导肥胖小鼠骨关节炎的影响 脂肪酸，或omega-3或omega-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)对不稳定的内侧半月板骨性关节炎进展的影响 小鼠骨性关节炎模型。在目标3中，我们将使用软骨移植块加载的受控体外模型来检查 机械应激联合促炎细胞因子(如IL-1、瘦素、肿瘤坏死因子-α)的作用 和脂肪酸对软骨细胞合成代谢和分解代谢活性的影响 产生，实时定量聚合酶链式反应检测转录和蛋白质合成的II型和 阿格利坎。特定生物力学因素、促炎因素之间相互作用的详细研究 在关节软骨中的中介物和组织代谢将提高我们对关节软骨病理的理解。 尤其是在体内与肥胖、损伤或体重减轻等“生物力学”因素有关的情况下。这个 这项研究的结果将为了解骨性关节炎发病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、心理社会和生化疗法来预防 疾病。

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.