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.