Novel OA-markers by integrating basic biology and clinic

描述（申请人提供）： 像骨关节炎这样的关节疾病影响着很大比例的人群，大约10%，伴随着运动丧失、疼痛和功能障碍以及日常活动质量受损。对任何疾病组来说，社会成本都是最高的。目前的治疗方法非常有限，主要依赖于关节置换。开发新疗法的先决条件是描述进行性关节破坏的机制以及新的诊断程序，这些程序可以识别活动性疾病患者并评估改变疾病进展的疗法。本研究旨在开发新的诊断程序，提供骨关节炎发展机制的见解，从而促进治疗的新进展，并提供识别风险患者和监测治疗效果的方法。具体目标是：1）通过监测软骨和骨成分的释放来确定骨关节炎发展过程中关节软骨和骨中的过程; 2）鉴定新分子，所述新分子在关节中的关节软骨、半月板和骨中显示出独特的分布，并且具有作为影响这些结构的过程的分子标志物的潜力; 3）通过鉴定由在软骨破坏中有活性的特异性蛋白酶形成的新表位来定义特异性蛋白水解切割。开发的特异性抗体将用于组织中导致特异性片段的蛋白水解释放的过程的测定; 4）寻找实现靶分子的特异性蛋白水解的酶的身份; 5）通过关注含有识别骨细胞上的特异性配体的活性结构域的生物活性标记物来鉴定疾病机制，软骨和滑膜和/或可结合滑液中存在的其它因子。将开发活性片段的测定方法，并研究其在关节过程中的作用; 6）开发用于退行性关节疾病关节软骨中改变的已鉴定蛋白质的定量免疫测定法; 7）通过分析明确的人类患者队列以及有或无特定干预的动物模型来评估新开发的测定法。

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.