The role of repellent factors in the maintenance of joint compartment border integrity

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The mechanical functions of joints depend on strict separation of the compartment borders. Crossing of the joint compartment boundaries and destruction of the cartilage compartment is found in inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis. We hypothesize that there are molecular cues at the joint compartment borders maintaining the integrity of these borders. Candidate molecules for this function are repellent factors, which are expressed in fetal and adult synovial tissue and cartilage. The principal purpose of the first grant period was to single out candidate repellent factors that may exert the function of establishing and maintaining tissue boundaries by the use of expression studies and functional studies. The cell types under scrutiny were synovial fibroblasts as potential invaders and chondrocytes as cells that may exert repellent activities. Their potential to produce repellent factors and react to repellent factors was studied in vitro in different model systems (migration, cartilage destruction, angiogenesis, proliferation etc.). We found primarily two candidate repellent factor families during the progress of the first period: the Robo/Slit- and the Netrin/UNC/DCC system. Both systems had strong impact on synovial and chondrocytic function. In the second period we aim to understand the molecular mechanisms behind the functional changes. Further, we focus on a way to influence the system looking for potential therapeutic or prognostic implication.