Regulation of synovial fibroblast function via Cadherin-11 cleavage

通过 Cadherin-11 裂解调节滑膜成纤维细胞功能

• 批准号: 8456137
• 负责人: Michael B. Brenner
• 金额: $ 35.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456137
• 关键词: 3-Dimensional; Adhesives; Arthralgia; Arthritis; Autoimmune Diseases; Autoimmunity; Automobile Driving; Basement membrane; Bathing; Behavior; Binding; Bone Marrow; Cadherin Domain; Cadherins; Cartilage; Cell Adhesion Molecules; Cell Line; Cell Lineage; Cell membrane; Cell physiology; Cells; Cleaved cell; Cost Measures; Cues; Cytoplasmic Protein; Degenerative polyarthritis; Desmosomes; Disease; Electrons; Epithelium; Extracellular Domain; Extracellular Matrix; Extracellular Space; Facies; Family; Fibroblasts; Functional disorder; Generations; Goals; Health; Human; Hyperplasia; Immune; Immune response; Immunoglobulins; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Investigation; Joints; Knockout Mice; Mediating; Mediator of activation protein; Mesenchymal; Microscopic; Modeling; Molecular; Mus; N-Cadherin; Nuclear Protein; Nutritional Support; Organ Culture Techniques; Osteoclasts; Pathogenesis; Pathologic; Pathway interactions; Patients; Perception; Physiology; Plasma; Play; Prevalence; Proteins; Publishing; Regulation; Rheumatoid Arthritis; Role; Science; Seminal; Series; Signal Transduction; Source; Structure; Swelling; Synovial Fluid; Synovial Membrane; System; Thick; Tight Junctions; Tissues; Work; angiogenesis; bone; cadherin-11; career; extracellular; insight; joint destruction; macrophage; member; mouse model; public health relevance; research study; response; therapeutic development

DESCRIPTION (provided by applicant): Diarthrodial joints are lined by a highly specialized tissue called the synovium. In health, the synovial tissue is thought to be the primary synthetic source of the viscous and lubricating synovial fluid that bathes the joint tissues. Further, it is thought to provide nutritional support for the avascular cartilage tissue. In the context of inflammatory arthritis, the synovial lining undergoes profound changes that include infiltration with bone marrow derived lineages, hyperplasia and formation of a pathologic extension, termed 'pannus', that is thought to contribute substantially to the destructive erosions evident in diseases such as rheumatoid arthritis (RA). Despite longstanding appreciation for these synovial functions in health and disease, there exists very little understanding of the molecular regulation of synovial tissue behavior. The PI has a primary career focus on understanding synovial physiology in health and pathophysiology in the context of arthritis. With a goal of gaining insight into the molecular regulation of synovial tissue, we have examined mechanisms by which a member of the cadherin family of homophilic adhesion molecules-cadherin-11-modulates behavior of the predominant mesenchymal lineage of synovial tissue, the synovial fibroblast (FLS). In initial collaborative studies, the expression and function of cad11 on primary human FLS was established. In recently published work (Science 315:1006-1010, 2007), the PI and his colleagues demonstrated that cad11 is expressed on ex vivo primary FLS (and not on bone marrow derived lineages) and functionally modulates adhesive, migratory and invasive capacities of these cells. He also demonstrated that healthy cad11-null mice display a hypoplastic synovial lining thereby providing prima facie evidence for the contribution of cad11 to regulation of FLS behavior in the synovial tissue. Examination of arthritic activity in a mouse model of inflammatory arthritis demonstrates an ameliorated inflammatory response in cad11 null mice thus illustrating a primary involvement of the FLS lineage in the overall pathophysiology of inflammatory arthritis. These studies also showed that cad11 null mice are significantly protected from synovial fibroblast mediated cartilage erosion via pannus tissue. In aggregate, these seminal analyses establish a new paradigm for our perception of the joint lining tissue in health and disease. Now, in ongoing studies of synovial fluid from patients with RA, we have discovered substantial quantities of soluble cad11 thereby implicating cleavage of cad11 as an active mechanism in RA disease physiology. In a 'bedside-to-benchtop' approach, we demonstrate that cad11 is cleaved on synovial fibroblasts to yield a secreted form as well as potentially bioactive cell-associated cad11 fragments. Guided by recently published studies of E- and N-cadherin in other tissues and cell lineages, we hypothesize that regulated cleavage may be directly involved in the molecular pathways regulating FLS (and by implication, synovial tissue) function. This submission proposes a series of investigations to dissect the regulation of cad11 cleavage and functional consequences of this cleavage in primary human synovial fibroblasts. It is anticipated that this translational activity will expand our understanding of disease mechanisms in rheumatoid arthritis as well as provide rationale and context for development of therapeutics directed at cad11 for patients with RA.

描述（由申请人提供）：腹泻关节被称为Synovium的高度专业的组织衬里。在健康中，滑膜组织被认为是沐浴关节组织的粘性和润滑滑液的主要合成来源。此外，人们认为它可以为血管软骨组织提供营养支持。 In the context of inflammatory arthritis, the synovial lining undergoes profound changes that include infiltration with bone marrow derived lineages, hyperplasia and formation of a pathologic extension, termed 'pannus', that is thought to contribute substantially to the destructive erosions evident in diseases such as rheumatoid arthritis (RA).尽管长期以来对健康和疾病中这些滑膜功能的理解，但对滑膜组织行为的分子调节的了解很少。 PI的主要职业专注于在关节炎的背景下了解健康和病理生理学的滑膜生理。为了深入了解流出组织的分子调节，我们检查了机制，通过这些机制，均应粘附分子 - 钙粘着蛋白111-修饰的钙粘蛋白家族的成员可以通过合质性层层层次层次的行为进行纤维纤维组织的主要间质谱系。在最初的协作研究中，建立了CAD11对原代人FL的表达和功能。在最近发表的工作（Science 315：1006-1010，2007）中，PI和他的同事表明，CAD11是在离体初级FL（而不是在骨髓衍生的谱系上）表达的，并在功能上调节了这些细胞的粘合性，迁移和侵入性能力。他还证明，健康的CAD11-NULL小鼠显示出低型滑膜衬里，从而为CAD11对滑膜组织中FLS行为的贡献提供了表面证据。在炎症性关节炎的小鼠模型中，关节炎活性的检查表明，CAD11 NULL小鼠的炎症反应得到了改善，因此说明了FLS谱系在炎症性关节炎的整体病理生理学中的主要参与。这些研究还表明，CAD11零小鼠受到通过Pannus组织的滑膜介导的软骨侵蚀的显着保护。总体而言，这些开创性分析为我们对健康和疾病中关节内膜组织的感知建立了一个新的范式。现在，在正在进行的RA患者滑动流体的研究中，我们发现了大量可溶性CAD11，从而暗示了CAD11的裂解是RA疾病生理学中的一种活性机制。在“床头到台式”方法中，我们证明了CAD11在滑膜成纤维细胞上裂解，以产生分泌的形式以及潜在的生物活性细胞相关的CAD11片段。在最近发表的其他组织和细胞谱系中的E-和N-钙粘着蛋白的研究的指导下，我们假设受调节的裂解可能直接参与调节FLS（以及暗示的滑膜组织）功能的分子途径。该提交提出了一系列研究，以剖析原代人滑膜成纤维细胞中这种裂解的CAD11裂解和功能后果。预计这种翻译活动将扩大我们对类风湿关节炎疾病机制的理解，并为针对RA患者的CAD11的治疗剂提供理由和背景。