Schubert T, Denk A, Mägdefrau U, Kaufmann S, Bastone P, Lowin T, Schedel J, Bosserhoff A K
Institute of Pathology, University Hospital of Regensburg, Regensburg, Germany.
Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):715-22. doi: 10.1177/039463200902200317.
Changes in the expression of repellent factors, i.e., Netrins and their receptors, may be responsible for the invasive behavior of the synovial tissue cells in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). This study was carried out to analyze the expression of Netrins and their receptors in synovial cells of patients with RA, OA, and control subjects without synovial inflammation. Quantitative RT-PCR was performed to measure the expression of Netrin-1, -3, -4, Neogenin, DCC, UNC5A-D. The influence of Netrin-1 on synovial fibroblasts (SF) was analyzed by determining proliferation, migration, and their ability to organize collagen. SF expressed all repellent factors of the Netrin family. When comparing SF of healthy donors to patients with RA and OA, a stronger expression of UNC5B (4 fold) and UNC5C (769 fold) in RA and OA was found, whereas expression of the other molecules revealed no significant differences. Treating the SF-cells with recombinant Netrin-1 resulted in inhibition of migration of RA- and OA-SFs whereas control cells were not affected. The stronger expression of UNC5B and UNC5C receptors might contribute to the disordered phenotype of RA- and OA-SFs. Addition of Netrin-1 reduces the migratory ability of SFs, potentially by repulsion, as seen in neuronal cells in embryonic development. Due to its function, Netrin-1 may constitute a novel target in the treatment of OA and RA.
排斥因子，即Netrins及其受体表达的变化，可能是类风湿性关节炎（RA）和骨关节炎（OA）患者滑膜组织细胞侵袭行为的原因。本研究旨在分析Netrins及其受体在RA、OA患者以及无滑膜炎症的对照受试者滑膜细胞中的表达。采用定量逆转录聚合酶链反应（RT-PCR）检测Netrin-1、-3、-4、Neogenin、DCC、UNC5A-D的表达。通过测定增殖、迁移以及组织胶原蛋白的能力，分析Netrin-1对滑膜成纤维细胞（SF）的影响。SF表达Netrin家族的所有排斥因子。将健康供体的SF与RA和OA患者的SF进行比较时，发现RA和OA中UNC5B（4倍）和UNC5C（769倍）的表达更强，而其他分子的表达没有显著差异。用重组Netrin-1处理SF细胞可抑制RA和OA-SF的迁移，而对照细胞不受影响。UNC5B和UNC5C受体的更强表达可能导致RA和OA-SF的表型紊乱。添加Netrin-1可降低SF的迁移能力，这可能是通过排斥作用实现的，就像在胚胎发育中的神经元细胞中看到的那样。由于其功能，Netrin-1可能构成OA和RA治疗的新靶点。
