OBESITY, BIOMECHANICS, AND INFLAMMATION IN OSTEOARTHRITIS

描述（由申请人提供）：骨关节炎（OA）是一种滑膜关节疼痛和衰弱性疾病，在美国影响约2700万人。在过去的二十年里，肥胖的患病率急剧上升，我们现在知道肥胖可能是OA的主要可预防的危险因素。该项目的目标是研究膳食脂肪酸对小鼠肥胖相关OA的影响，并通过各种体内和体外模型研究它们与改变的生物力学和促炎细胞因子的相互作用。我们认为，低级别慢性全身性炎症——由肥胖或饮食中的促炎脂肪酸引起——与局部炎症细胞因子或损伤后改变的机械负荷协同作用，促进关节软骨的炎症状态和基质降解。我们将追求以下目标：在目的1中，我们将研究高脂肪猪油为基础的饮食在瘦素受体缺乏小鼠（db/db）中OA发展中的作用，我们还将测量高脂肪饮食中高饱和和单不饱和脂肪酸，或omega-3或omega-6多不饱和脂肪酸的饮食诱导的肥胖小鼠骨关节炎的变化。在Aim 2中，我们将在不稳定的小鼠OA内侧半月板模型中研究肥胖（通过高脂肪饮食或瘦素缺乏）和体重减轻对OA进展的影响。在Aim 3中，我们将使用软骨外植体负载的受控体外模型来检查机械应力与促炎细胞因子和脂肪酸结合对软骨细胞合成代谢和分解代谢活性的影响，通过生物标志物的产生、基因表达和II型胶原蛋白和聚集蛋白的蛋白质合成来测量。对特定生物力学因素、促炎介质和关节软骨组织代谢之间相互作用的详细研究将提高我们对OA病理的理解，特别是当它与体内“生物力学”因素（如肥胖、损伤或体重减轻）相关时。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，并最终可能导致利用物理，饮食和分子治疗来预防疾病的新治疗方法。

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 27 million people in the United States. As the prevalence of obesity has risen dramatically in the past two decades, we now know that obesity is likely to be the primary preventable risk factor for OA. 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 following injury 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) and weight loss 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 and fatty acids on the anabolic and catabolic activities of the chondrocytes, as measured by biomarker production, gene expression, 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 insight into key elements of the pathogenesis of OA, and ultimately could lead to new treatments that exploit physical, dietary, and molecular therapies to prevent disease.