AGING AND OBESITY IN OSTEOARTHRITIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肥胖增加了负重关节(如膝盖和髋关节)和非负重关节(如手)患骨性关节炎的风险，这表明系统性因素介导了疾病的发生。从脂肪组织中释放的可溶性介质可能是这一关键环节。脂肪组织曾经被认为是一个简单的能量储存库，现在被理解为一个动态的内分泌样器官，随着肥胖的发展增加促炎细胞因子的释放。炎症介质的慢性产生，如白细胞介素1和一氧化氮，可能通过损害线粒体电子传递链功能和产生活性氧来刺激关节软骨的分解代谢过程。 我们假设，随着年龄的增长和肥胖加速的轻度慢性炎症损害了软骨细胞中线粒体介导的氧化还原调节系统，从而增加了它们对急性炎症诱导的氧化损伤、细胞死亡和基质分解代谢的易感性。在初步研究中，饮食诱导 肥胖小鼠患膝骨性关节炎与身体脂肪增加成正比。为了能够直接测量软骨细胞线粒体功能和氧化还原调节，我们建议研究F344BN大鼠膝关节骨关节炎的发育。我们将研究年龄和饮食诱导的肥胖对全身和局部(即关节)脂肪组织和炎症介质水平的影响，并确定年龄和高脂饮食如何改变软骨细胞电子传递链功能、细胞氧化还原电位和蛋白质氧化。然后，我们建议确定这些机制是如何在喂食正常和高脂肪食物的老年大鼠接受局部细胞因子攻击后调节膝骨性关节炎的发展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity increases the risk of osteoarthritis (OA) in both weight-bearing (e.g., knee and hip) and non-weight bearing (e.g., hand) joints, suggesting that a systemic factor mediates the onset of the disease. Soluble mediators released from adipose tissue may be this critical link. Once considered simply an energy storage depot, adipose tissue is now understood to be a dynamic endocrine-like organ, increasing the release of proinflammatory cytokines with the development of obesity. Chronic production of inflammatory mediators, such as interleukin-1¿ and nitric oxide, may stimulate catabolic processes in articular cartilage by impairing mitochondrial electron transport chain function and producing reactive oxygen species. We hypothesize that mild, chronic inflammation that accrues with aging and is accelerated by obesity impairs mitochondrial-mediated redox regulatory systems in chondrocytes thereby increasing their susceptibility to acute inflammatory-induced oxidative damage, cell death, and matrix catabolism. In preliminary studies, dietinduced obese mice developed knee OA in proportion to body fat gain. To be able to make direct measurements of chondrocyte mitochondrial function and redox regulation, we propose to study the development of knee OA in F344BN rats. We will investigate the effect of age and diet-induced obesity on systemic and local (i.e., joint) levels of adipose tissue and inflammatory mediators, and we will determine how age and a high-fat diet modify chondrocyte electron transport chain function, cellular redox potentials, and protein oxidation. We then propose to determine how these mechanisms regulate the development of knee OA following a local cytokine challenge in aged rats fed normal and high-fat chow.