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。的 滑膜衬里显示成纤维细胞样滑膜细胞（FLS）和巨噬细胞的细胞致密化 在有序的细胞外基质中。在炎性关节炎中，这层膜表现出明显的增生， 血管翳形成，并在功能上获得迁移、附着和侵蚀到相邻血管的能力。 软骨和骨骼。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的生理和结构， 炎症性关节炎中的异常滑膜。我们发现钙粘蛋白家族的蛋白质， 钙粘蛋白-11在FLS上表达，是FLS细胞粘附、迁移和侵袭的主要因子 以及滑膜衬里的形成。引人注目的是，在钙粘蛋白-11缺乏的小鼠中， 此外，滑膜缺乏在炎性关节炎中观察到的典型变化。 在cadherin-11基因敲除的小鼠中，关节炎的炎症反应减弱，而滑膜不 附着或侵入软骨。这项建议的具体目标是着重阐述以下方面的作用： 钙粘蛋白-11在基质产生和滑膜细胞增殖中的作用（目的1），FLS的能力， 迁移、附着和侵蚀软骨（目标2），以及它们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并相互作用（目的3）。那就 确定钙粘蛋白-11是否可以作为体内炎性关节炎的新治疗靶点， 无论是单独或联合抗TNF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机制，了解滑膜炎， 并指出潜在的治疗方法，针对FLS在炎症性关节炎的基础上， cadherin-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.