Cadherin 11在骨关节炎滑膜炎及关节软骨破坏中的作用机制

Primary osteoarthritis (OA) was a complex, multifactorial inflammatory disease of the whole joint. The synovium, bone and cartilage were each involved in pathological processes that lead to progressive joint degeneration. The presence of synovitis was associated with more severe pain, joint dysfunction and increased risk of radiographic evidence of disease progression. Cadherin-11, a newly specific marker expressed on fibroblast-like synoviocytes(FLS), was not only indispensable for the development of the normal synovium lining layer, but also was the crucial molecule in driving synovial inflammation and cartilage erosions in rheumatoid arthritis. Cadherin-11 deficient mice showed resistant to inflammatory arthritis and strongly protected against cartilage destruction. However, few studies about the correlation between OA synovitis and cadherin-11 expression have been published. Our prior studies showed that expression of cadherin-11 increased with the synovitis severity in osteoarthritis. In this study, we will investigate the molecular mechanism of cadherin-11 over expression in osteoarthritis; also with lentivirus transfection containing cadherin 11 shRNA, explore the role of cadherin 11 in migration or invasion capacity, production of MMPs and inflammatory mediators in OA FLS, and observe the effect of anti-cadherin 11 in collagenase induced osteoarthritis in C57 BL/6 mice,which might provide a potent candidate molecule for therapeutic target of OA.

骨关节炎（osteoarthritis, OA）是累及整个关节器官包括软骨、滑膜、软骨下骨等各种组织的病变；滑膜炎是造成OA疼痛、炎症和软骨破坏的主要原因，与OA病情进展密切相关。炎症可能成为OA病情控制新的靶点及病情评估的有效标志。Cadherin 11是滑膜衬里层形成的关键粘附分子，在类风湿滑膜炎中表达增多并参与软骨侵蚀进程，Cadherin 11敲除小鼠关节软骨破坏受到明显抑制。我们前期研究发现，OA滑膜组织中Cadherin 11增高，并与滑膜炎性程度密切相关。本课题拟分析OA滑膜组织Cadherin 11表达上调的分子机制，采用shRNA慢病毒转染技术，观察Cadherin 11在OA滑膜细胞侵袭和迁移，促进炎性因子的分泌和软骨破坏中的作用，在OA小鼠模型中验证抗Cadherin 11治疗对滑膜炎和软骨破坏的影响，为Cadherin 11作为骨关节炎新的分子治疗靶点提供实验证据。

本项课题研究探讨骨关节炎滑膜Cadherin-11表达与滑膜炎症及炎性细胞因子的相关性，对PI3K信号传导通路在骨关节炎滑膜组织中Cadherin 11表达增高的作用机制进行了分析；通过慢病毒转染分别过度或抑制Cadherin 11表达，观察OA FLS细胞迁移、侵袭等细胞行为改变和 MMPs分泌及体外组织形成中的作用；构建胶原酶诱导骨关节炎小鼠模型，观察了Cadherin 11抗体和PI3K抑制剂对胶原酶诱导小鼠骨关节炎(CIOA)模型软骨破坏的抑制作用；建立SCID小鼠RA FLS/关节软骨共移植模型，分析敲低Cadherin-11表达对RA FLS侵蚀软骨的影响。研究结果证实，骨关节炎滑膜组织中Cadherin-11的表达与滑膜炎症呈正相关，并且与炎性细胞因子刺激有关；PI3K/AKT抑制剂在TNF-A刺激骨关节炎滑膜组织的Cadherin 11表达中发挥重要作用；敲低Cadherin-11的表达后，OA FLS细胞迁移、侵袭能力降低，MMP-2和MMP-9分泌减少；在CIOA模型中Cadherin 11抗体和PI3K抑制剂对胶原酶诱导小鼠骨关节炎模型软骨破坏程度具有明显抑制作用；敲低Cadherin 11的表达抑制RA FLS的组织形成，在SCID小鼠模型中降低软骨侵蚀程度。