CHONDROPROTECTIVE EFFECTS OF SUPEROXIDE DISMUTASE

描述(申请人摘要)：关节软骨破坏 通过炎症性关节炎和骨关节炎等疾病过程 会导致严重的疼痛和残疾。正常平衡的合成代谢和 分解代谢过程改变，使软骨细胞合成基质 组件不能弥补在 这些条件。超氧化物歧化酶对关节软骨的影响 动态平衡还没有得到系统的研究。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是为评估肺纤维化的发病机制而开发的，以检测这些 提出了建立关系的建议。长期目标是探索EC-SOD潜在的软骨保护作用。工作假说是EC-SOD在 防止关节炎关节软骨退化。要测试 EC-SOD在预防关节病变中起中心作用的假说 关节软骨结构与代谢的比较研究 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和EC-SOD的野生型EC-SOD基因敲除小鼠 产生过量EC-SOD的转基因小鼠。生物力学实验模型的研究 一氧化氮(NO)是关节炎的重要致病因素之一。 EC-SOD可阻止NO与超氧化物反应生成过氧亚硝酸根， 强大的氧化剂，这可能解释了NO的一些破坏性影响。 白介素L(IL-L)抑制蛋白多糖合成与 NO的存在。来检验预防过氧亚硝酸盐的假设 形成是EC-SOD对抗IL-1抑制的机制之一 大屠杀修复，我们计划比较没有生产，硝基酪氨酸 免疫反应性、基质金属蛋白酶和蛋白多糖的合成 野生型EC-SOD基因敲除和EC-SOD转基因小鼠关节腔内注射 注射IL-1。IL-L与软骨细胞的发育有关 胰岛素样生长因子-I(IGF)的合成代谢作用不敏感 无论是体外还是体内的关节炎模型。与野生型小鼠相比， INOS基因敲除小鼠在INT后维持对IGF-1的合成代谢反应 关节内注射IL-1。这意味着没有也没有衍生品，如 过氧亚硝酸盐作为软骨细胞发育的关键因素 关节炎关节对IGF-1不敏感。来检验这一假设 过氧亚硝酸盐是参与IL-1诱导软骨细胞分化的活性物质 对IGF-1的合成代谢作用无反应，我们计划比较NO 产生，硝基酪氨酸免疫反应性和蛋白多糖的合成 野生型EC-SOD基因敲除小鼠和EC-SOD转基因小鼠体内IGF-1的表达 关节腔内注射IL-1后。拟议的研究将会取得进展 EC-SOD对软骨调节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进 了解NO和过氧亚硝酸根在细胞周期中的相对作用 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.