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

关节的力学功能取决于隔室边界的严格分离。关节隔室边界的跨越和软骨隔室的破坏见于炎性和退行性关节疾病，如类风湿关节炎和骨关节炎。我们假设在关节隔室边界有分子线索维持这些边界的完整性。这种功能的候选分子是排斥因子，在胎儿和成人滑膜组织和软骨中表达。第一个拨款期的主要目的是通过使用表达研究和功能研究，挑选出可能发挥建立和维持组织边界功能的候选排斥因子。研究的细胞类型是作为潜在入侵者的滑膜成纤维细胞和可能发挥排斥作用的软骨细胞。在体外不同的模型系统（迁移、软骨破坏、血管生成、增殖等）中研究了它们产生排斥因子的潜力和对排斥因子的反应。在第一阶段的研究过程中，我们主要发现了两个候选的驱避因子家族：Robo/Slit-和Netrin/UNC/DCC系统。这两个系统对滑膜和软骨细胞功能都有强烈的影响。在第二个阶段，我们的目标是了解功能变化背后的分子机制。此外，我们专注于一种方法来影响系统寻找潜在的治疗或预后意义。

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.