PROTEOGLYCAN METABOLISM IN OSTEOARTHRITIS

骨关节炎中的蛋白聚糖代谢

• 批准号: 3160729
• 负责人: BRUCE CATERSON
• 金额: $ 14.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-06 至 1995-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3160729
• 关键词: biomarker; chondroitin sulfates; cytokine; disease /disorder model; early diagnosis; enzyme linked immunosorbent assay; guinea pigs; human tissue; immunocytochemistry; immunologic techniques; monoclonal antibody; osteoarthritis; pathology; protein metabolism; proteoglycan; radioimmunoassay; remission /regression; western blottings

Osteoarthritis is a slowly progressive destructive disease of the joints which is widespread in man and other animal species. The underlying cause(s) of osteoarthritis have not been identified despite numerous histological, biochemical and biomechanical studies examining the changes that occur as the disease develops. In humans, osteoarthritis takes years to develop and at present the disease cannot be diagnosed until quite late in the degenerative process. Thus current medical treatment consists of mainly trying to reverse the later, inflammatory stage of the disease. At present there is a particular need for methods detecting the early stages of osteoarthritis so that factors lead to the cartilage destruction can be better understood. In this proposal we describe preliminary data identify- ing, in osteoarthritic cartilage proteoglycans, the occurrence of struc- tural "markers" that are indicative of the initial biochemical changes leading to the onset of osteoarthritis. These markers consist of atypical structures in the chondroitin sulfate (CS) glycosaminoglycans of osteoarth- ritic proteoglycans. The objectives of this proposal are to further investigate this novel finding. The specific aims to achieve this objec- tive will be: 1. To determine the relative occurrence of atypical CS structures in proteoglycans from normal and osteoarthritic human cartilage using monoclonal antibodies that specifically recognize these structures. 2. To perform similar studies in two animal models that mimic the onset of osteoarthritis in man, i.e., the development of spontaneous OA. 3. To further characterize the specificity of monoclonal antibodies that recog- nize atypical CS structures and develop immunoassay procedures to measure the expression of these atypical CS structures in cartilage, serum and/or synovial fluid. 4. To perform in vitro cell culture studies to inves- tigate the biosynthesis of proteoglycans containing these atypical struc- tures, and to see cytokines and growth factors modulate the expression of these structures. 5. To perform immunohistochemical studies on normal and osteoarthritic cartilage to establish if focal or general expression of the epitopes occur in OA. Overall, the studies outlined in this proposal should lead to a better understanding of factors involved in the onset of osteoarthritis and may lead to the development of means for halting or reversing the disease process.

骨性关节炎是一种缓慢发展的破坏性关节疾病。 它广泛存在于人类和其他动物物种中。潜在的 骨性关节炎的病因(S)尽管有许多种，但仍未确定 组织学、生化和生物力学研究检测这些变化 随着疾病的发展而发生。在人类中，骨关节炎需要数年时间。 发展到目前，直到很晚才能诊断出这种疾病 在退化的过程中。因此，目前的医疗包括 主要是试图逆转疾病的后期炎症阶段。在… 目前，特别需要检测早期阶段的方法 使骨性关节炎的因素导致软骨破坏即可 更好地理解。在这份提案中，我们描述了初步数据，确定- 在骨关节炎软骨蛋白多糖中，结构-多聚糖的出现。 指示初始生物化学变化的文化“标记” 导致骨性关节炎的发病。这些标记由非典型的 骨关节硫酸软骨素(CS)糖胺聚糖的结构 裂解蛋白多糖。这项提议的目标是进一步 调查这一新发现。实现这一目标的具体目标是- 结论如下：1.确定非典型CS的相对发生率 正常人和骨关节炎人软骨蛋白多糖的结构 使用能识别这些结构的单抗。 2.在两个模拟脑缺血发作的动物模型上进行类似的研究 人类的骨性关节炎，即自发性骨性关节炎的发展。3.至 进一步鉴定识别-1的单抗的特异性 使非典型的CS结构正常化，并开发免疫分析程序来测量 这些非典型CS结构在软骨、血清和/或软骨中的表达 滑液。4.进行体外细胞培养研究，以研究- 滴定含有这些非典型结构的蛋白多糖的生物合成- 培养，并观察细胞因子和生长因子对其表达的调节 这些结构。5.对正常组织和正常组织进行免疫组织化学研究 确定骨关节炎软骨是否有局灶性或全身性表达 抗原表位存在于OA中。总体而言，这项提案中概述的研究 应该有助于更好地了解与发病有关的因素 骨关节炎，并可能导致发展的手段，停止或 逆转疾病进程。