Novel OA-markers by integrating basic biology and clinic

描述(由申请人提供)： 关节疾病，如骨关节炎，影响了很大比例的人口，约占10%，表现为运动障碍、疼痛和功能障碍，以及日常活动质量受损。在所有疾病群体中，社会成本是最高的之一。现有的治疗方法非常有限，很大程度上依赖于关节置换。开发新的治疗方法的前提是描述进行性关节破坏的机制，以及能够识别活动性疾病患者和评估改变疾病进展的治疗的新的诊断程序。这项研究旨在开发新的诊断程序，为骨关节炎的发生机制提供见解，从而促进治疗的新进展，并为识别处于危险中的患者和监测治疗效果提供手段。其具体目的是：1)通过监测软骨和骨成分的释放来确定关节软骨和骨中的过程；2)确定在关节软骨、半月板和骨中表现出独特分布的新分子，并有可能作为影响这些结构的过程的分子标志物；3)通过鉴定在软骨破坏中活跃的特定蛋白水解酶形成的新表位来确定特定的蛋白水解性切割。开发的特定抗体将用于分析组织中导致特定片段蛋白分解的过程；4)搜索完成靶分子特定蛋白分解的酶的特性；5)通过重点研究包含识别骨、软骨和滑膜细胞上的特定配体和/或能够与滑液中存在的其他因子相结合的活性结构域的生物活性标志物，确定疾病机制。将开发活性片段的分析方法，并研究它们在关节病变过程中的作用；6)为确定的退行性关节疾病关节软骨中改变的蛋白质开发定量免疫分析方法；7)通过分析明确的人类患者队列以及在有或没有特定干预的动物模型中对新开发的分析方法进行评估。

DESCRIPTION(Provided by Applicant): Joint disease like osteoarthritis affects a very large proportion of the population, in the order of 10%, with loss of motion, pain and dysfunction and impaired quality of daily activities. The cost to society rank among the highest for any disease group. Therapy existing today is very limited and largely rely on joint replacement. A prerequisite for development of novel therapy is to delineate mechanisms in the progressive joint destruction as well as novel diagnostic procedures that can identify patients with active disease and evaluate therapy that modifies disease progression. This study is to develop new diagnostic procedures that provide insights in mechanisms in osteoarthritis development and thereby facilitate new advances in therapy as well as provide means for identifying patients at risk and for monitoring therapeutic effects. The specific aims are: 1 ) To define processes in the articular cartilage and bone during development of osteoarthritis by monitoring for release of cartilage and bone constituents; 2) To identify new molecules that show a unique distribution to articular cartilage, meniscus and bone in the joint and have potential as molecular markers of processes affecting these structures; 3) To define specific proteolytic cleavage by the identification of neoepitopes formed by specific proteinases active in cartilage destruction. Specific antibodies developed will be used for assays of processes in the tissue leading to proteolytic release of specific fragments; 4) To search for the identity of enzymes accomplishing specific proteolysis of target molecules; 5) To identify disease mechanisms by focusing on bioactive markers that contain active domains that recognize specific ligands on cells of bone, cartilage and synovium and/or can bind to other factors present in the synovial fluid. Assays will be developed for active fragments and their role in the process in the joint will be investigated; 6) To develop quantitative immunoassays for identified proteins that are altered in articular cartilage of degenerative joint disease; 7) To evaluate newly developed assays by analyses of well defined human patient cohorts as well as animal models with or without specific intervention.