CHONDROPROTECTIVE EFFECTS OF SUPEROXIDE DISMUTASE

描述（申请人摘要）：关节软骨破坏 通过疾病过程如炎性关节炎和骨关节炎 会造成严重的疼痛和残疾合成代谢和 分解代谢过程被改变， 组件无法补偿在 了以下条件超氧化物歧化酶对关节软骨的影响 体内平衡尚未得到系统的研究。探索性研究使用 细胞外超氧化物歧化酶（EC-SOD）基因敲除和转基因小鼠最初开发用于评估肺纤维化的发病机制，以检查这些 提出了关系。 长期目标是探索EC-SOD的潜在软骨保护作用。工作假设是EC-SOD在以下方面发挥核心作用： 防止关节炎关节中的软骨退化。测试 假设EC-SOD在保护关节炎中起核心作用， 通过比较关节炎关节的结构和代谢， 酵母多糖诱导的膝关节炎后关节软骨的反应 不能产生EC-SOD的野生型、EC-SOD敲除小鼠和EC-SOD 产生过量EC-SOD的转基因小鼠。实验模型研究 关节炎涉及一氧化氮（NO）作为重要的致病因子。 EC-SOD可阻止NO与超氧阴离子反应生成过氧亚硝基阴离子， 强氧化剂，这可能是NO的一些破坏性作用的原因。 白细胞介素-I（IL-1）对蛋白聚糖合成的抑制已经与 NO的存在。为了检验预防过氧亚硝酸盐的假设， 形成是EC-SOD对抗IL-1抑制的一种机制， 大屠杀修复，我们计划比较NO生产，硝基酪氨酸 免疫反应性、基质金属蛋白酶和蛋白多糖合成 野生型、EC-SOD敲除和EC-SOD转基因小鼠关节内注射 注射IL-1。IL-1与软骨细胞的发育有关， 对胰岛素样生长因子-I（IGF）的合成代谢作用不敏感， 关节炎的体外和体内模型。与野生型小鼠相比， iNOS基因敲除小鼠在胰岛素样生长因子-1诱导下维持其合成代谢反应 关节注射IL-1。这意味着NO和NO衍生物，如 过氧亚硝基阴离子作为软骨细胞发育的关键因素 关节炎关节对IGF-1不敏感。为了验证这个假设， 过氧亚硝基阴离子是参与IL-1诱导的软骨细胞 对IGF-1的合成代谢作用无反应，我们计划比较NO 生产，硝基酪氨酸免疫反应性，和蛋白多糖的合成， 野生型EC-SOD基因敲除和EC-SOD转基因小鼠之间IGF-1的存在 在关节内注射IL-1后。拟议的研究将继续进行 EC-SOD在调节软骨中的作用的现有知识基础 关节炎关节的退化。这些研究也将有助于改善 了解NO和过氧亚硝酸盐在 关节炎的病理生理学

DESCRIPTION (applicant's abstract): Destruction of articular cartilage through disease processes such as inflammatory arthritis and osteoarthritis causes significant pain and disability. The normal balance between anabolic and catabolic processes is altered so that chondrocyte synthesis of matrix components cannot compensate for the increased rates of degradation found in these conditions. The effects of superoxide dismutase on articular cartilage homeostasis has not been systematically studied. Exploratory studies using extracelluar superoxide dismutase (EC-SOD) knock-out and transgenic mice originally developed for evaluating the pathogenesis of pulmonary fibrosis to examine these relationships are proposed. The long term goal is to explore the potential chondroprotective effects of EC-SOD. The working hypothesis is that EC-SOD plays a central role in protecting against cartilage degradation in the arthritic joint. To test the hypothesis that EC-SOD plays a central role in protecting against articular cartilage loss in the arthritic joint by comparing the structural and metabolic responses of articular cartilage following zymosan induced gonarthritis between wild-type, EC-SOD knockout mice which cannot produce EC-SOD, and EC-SOD transgenic mice which produce excess EC-SOD. Studies in experimental models of arthritis have implicated nitric oxide (NO) as an important pathogenic factor. EC-SOD may prevent the reaction of NO with superoxide to form peroxynitrite, a potent oxidant which may account for some of the damaging effects of NO. Interleukin-l (IL-l) inhibition of proteoglycan synthesis has been linked to the presence of NO. To test the hypothesis that prevention of peroxynitrite formation is one mechanism by which EC-SOD protects against IL-1 inhibition of carnage repair, we plan to compare NO production, nitrotyrosine immunoreactivity, matrix metalloproteinases, and proteoglycan synthesis between wild-type, EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. IL-l has been associated with development of chondrocyte insensitivity to the anabolic actions of Insulin-like Growth Factor-I (IGF) in both in vitro and in vivo models of arthritis. In contrast to wild-type mice, iNOS knockout mice maintain their anabolic response to IGF-1 following intra articular injection of IL-1. This implicates NO and NO derivatives such as peroxynitrite as critical, factors in the development of chondrocyte insensitivity to IGF-1 in the arthritic joint. To test the hypothesis that peroxynitrite is the reactive species involved in IL-1 induced chondrocyte unresponsiveness to the anabolic effects of IGF-1, we plan to compare NO production, nitrotyrosine immunoreactivity, and proteoglycan synthesis in the presence of IGF-1 between wild-type EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. The proposed studies will advance the current knowledge base on the effects of EC-SOD in modulating cartilage degradation in the arthritic joint. These studies will also serve to improve understanding of the relative roles of NO and peroxynitrite on the pathophysiology of arthritis.