Cadherin-11 Regulation of Murine Synoviocytes

在这里，我们研究调节滑膜组织结构和功能的分子机制。这个 滑膜衬里显示成纤维样滑膜细胞(FLS)和巨噬细胞的细胞致密 在有序的细胞外基质中。在炎症性关节炎中，衬里表现出明显的增生和 血管疙瘩的形成和功能获得了迁移、附着和侵蚀到邻近血管的能力 软骨和骨头。滑膜衬里的主要间充质细胞FLS被认为是 密切参与调节正常滑膜和滑膜的生理和结构 炎症性关节炎滑膜异常。我们发现钙粘蛋白家族的蛋白质，特别是 钙粘蛋白-11在FLS上表达，是FLS细胞黏附、迁移和侵袭的主要因素 形成滑膜衬里。令人惊讶的是，在钙粘蛋白-11缺乏的小鼠中，滑膜衬里是 基线期滑膜发育不良，滑膜缺乏炎症性关节炎的典型改变。 在钙粘蛋白11基因缺失的小鼠中，关节炎的炎症反应减弱，而滑膜没有 附着或侵入软骨。这项提案的具体目标集中在阐述 钙粘蛋白-11在基质的产生和滑膜细胞的增殖(AIM 1)中，FLS对 迁移、附着和侵蚀软骨(目标2)及其参与炎症反应的能力 在体外模型中与滑膜中的巨噬细胞反应和相互作用(目标3)。那么，我们会 确定钙粘附素-11是否可能作为体内炎性关节炎的新治疗靶点，减少 单独或联合抗肿瘤坏死因子治疗的炎症反应和软骨损伤(目的 4)。总之，这些研究将揭示新发现的与理解滑膜炎相关的机制 并指出了以FLS为靶点治疗炎性关节炎的潜在治疗方法 钙粘附素-11的表达和功能。

Here we examine the molecular mechanisms regulating synovial tissue architecture and function. The synovial lining demonstrates cellular compaction of fibroblast-like synoviocytes (FLS) and macrophages within an ordered extracellular matrix. In inflammatory arthritis, this lining exhibits marked hyperplasia and pannus formation and functionally acquires the ability to migrate over, attach to, and erode into adjacent cartilage and bone. The major mesenchymal cells of the synovial lining, the FLS, are thought to be intimately involved in regulating the physiology and architecture of the normal synovial membrane and of the abnormal synovium in inflammatory arthritis. We found that the cadherin family of proteins, specifically cadherin-11, is expressed on FLS and is a major factor in their cellular adhesion, migration and invasion and in formation of the synovial lining. Strikingly, in cadherin-11 deficient mice, the synovial lining is hypoplastic at baseline and further, the synovium lacks the typical changes seen in inflammatory arthritis. In cadherin-11 null mice, the inflammatory response in arthritis is attenuated and the synovium does not attach to or invade cartilage. The specific aims of this proposal are focused on elaborating the role of cadherin-11 in the production of matrix and synovlocyte proliferation (Aim 1), the capacity of FLS to migrate, attach to, and erode cartilage (Aim 2) and on their ability to participate in the inflammatory reaction and interact with macrophages in the synovium in in vitro models (Aim 3). Then, we will determine if cadherin-11 might serve as a new therapeutic target for inflammatory arthritis in vivo, reducing both the inflammatory reaction and cartilage damage alone or in combination with anti-TNF therapy (Aim 4). Together, these studies will reveal newly identified mechanisms relevant to understanding synovitis as well as point to potential therapeutic approaches that target FLS in inflammatory arthritis based on the expression and function of cadherin-11.