Fat and synovial tissue remodeling in joint osteoarthritis

关节骨关节炎中的脂肪和滑膜组织重塑

基本信息

批准号：
10308923
负责人：
Ling Qin
金额：
$ 39.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308923
关键词：
Address Adipocytes Adult Aging Animal Model Attention Automobile Driving Biology Cartilage Cell Lineage Cell Nucleus Cells Degenerative polyarthritis Development Dipeptidyl Peptidases Disease Exhibits Extracellular Matrix Fatty acid glycerol esters Fibroblasts Fibrosis Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Human Immune Immunofluorescence Immunologic In Situ Hybridization In Vitro Inflammation Inflammatory Injury Joints Knee Knee Osteoarthritis Knee joint Knock-in Mouse Knowledge Maintenance Mesenchymal Mesenchymal Stem Cells Molecular Morbidity - disease rate Mus Obesity Operative Surgical Procedures Pathogenesis Pathologic Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Population Process Production Proliferating Property Role Signal Transduction Source Synovial Fluid Synovial Membrane Tamoxifen Techniques Tissue-Specific Gene Expression Tissues Transforming Growth Factor beta arthropathies articular cartilage base bone cell type clinical predictors cytokine design in silico in vivo insight interest joint mobilization macrophage mouse model neglect novel therapeutic intervention pain relief progenitor response soft tissue subcutaneous transcriptome sequencing

项目摘要

Project Summary Osteoarthritis(OA) is a major cause of morbidity and physical limitation in adults.OA results from the erosion of protective cartilage at the ends of bones because of injury, obesity and ageing. The past decade has witnessed significant advances in deciphering the basic mechanisms by which OA develops. However, to date, there are no disease-modifying drugs and available treatments primarily focus on pain relief. Diverse cell types and tissues within joints contribute to OA development and progression. Of particular interest are the synovium and infrapatellar fat pad (IFP), two major soft tissues in knee joints that have received relatively little attention. The synovium secretes lubricating synovial fluid to facilitate joint movement, while functions of the IFP are unclear. OA is associated with marked fibrosis and inflammation in the IFP and synovium. However, the cellular dynamics and molecular pathways that underlie the fibro-inflammatory remodeling of joint tissues are poorly understood. Our preliminary studies suggest that the synovium and IFP comprise an integrated functional unit. Lineage tracing studies show that the synovium and IFP, but not fat tissues immediately outside the joint, develop from a common pool of mesenchymal cells. Single cell gene profiling analyses of IFP/Synovium from OA patients identified several distinct mesenchymal cell populations, including a presumptive population of mesenchymal progenitor cells (MPCs), specifically marked by expression of dipeptidyl peptidase-4 (DPP4). These DPP4- expressing cells displayed high transcriptional similarity to a population of multipotent mesenchymal cells that we recently identified in subcutaneous fat tissue. Cell trajectory analysis predicts that MPCs in the joint give rise to synovial-lining layer fibroblasts and IFP adipocytes. Pathway analysis of genes enriched in MPC from OA joints identified extracellular matrix-related processes and TGFβ-signaling, a well-known inducer of fibrosis responses. Based on these observations, we hypothesize that as an integrated unit, the joint fat pad and synovium exhibit dynamic subpopulations of mesenchymal cells with a common MPC population whose dysregulation drives OA pathogenesis such as fibrosis and inflammation. Our specific aims are: 1) determine the effects of OA on mesenchymal cell programming in the joint IFP/synovium. We will profile gene expression in single cells and nuclei from healthy and osteoarthritic knee joints of mice and human, identify the cell type- specific effects of OA, and localize mesenchymal cell types/states in healthy and OA joints; 2) determine the fate and role of DPP4+ MPCs in OA. We will use a newly generated mouse model to evaluate the differentiation potential and immune cell-modulatory activity of MPCs, study the in vivo fate of MPCs, and investigate the role of DPP4+ MPCs in OA pathogenesis. The synovium and IFP changes are often used as clinical predictors of OA progression. This project will provide critical new insights into the role of mesenchymal cells within the synovium/IFP for coordinating joint tissue maintenance and disease, and will potentially reveal new treatment avenues for OA.

项目概要骨关节炎 (OA) 是成人发病和身体限制的主要原因。OA 是由侵蚀引起的由于受伤、肥胖和衰老，骨骼末端的保护性软骨会消失。在破译 OA 发展的基本机制方面取得了重大进展。然而，迄今为止，已经取得了一些进展。没有缓解疾病的药物，现有的治疗方法主要集中于缓解不同的细胞类型和组织。关节内有助于 OA 发生和进展的部分特别令人感兴趣的是滑膜和关节。髌下脂肪垫（IFP）是膝关节中的两种主要软组织，但受到的关注相对较少。滑膜分泌润滑滑液以促进关节运动，但 IFP 的功能尚不清楚。 OA 与 IFP 和滑膜中的明显纤维化和炎症有关，但细胞动力学却不同。人们对关节组织纤维炎症重塑的分子途径知之甚少。我们的初步研究表明滑膜和 IFP 构成一个完整的功能单元。追踪研究表明，滑膜和 IFP，而不是紧邻关节外部的脂肪组织，是由对 OA 患者的 IFP/滑膜进行单细胞基因分析。鉴定了几种不同的间充质细胞群，包括假定的间充质细胞群祖细胞 (MPC)，特别以二肽基肽酶 4 (DPP4) 的表达为标志。表达细胞与多能间充质细胞群表现出高度的转录相似性，我们最近在皮下脂肪组织中发现，细胞轨迹分析预测关节中的 MPC 会产生。 OA 中富含 MPC 的基因对滑膜内层成纤维细胞和 IFP 脂肪细胞的通路分析。关节识别出细胞外基质相关过程和 TGFβ 信号传导（众所周知的纤维化诱导剂）根据这些观察，我们将其作为一个整体单元，即关节脂肪垫和滑膜表现出动态的间充质细胞亚群，具有共同的 MPC 群，其失调会导致纤维化和炎症等 OA 发病机制。我们的具体目标是：1) 确定。 OA 对 IFP/滑膜联合间充质细胞编程的影响我们将分析基因表达。在小鼠和人类健康膝关节和骨关节炎膝关节的单细胞和细胞核中，识别细胞类型- OA 的具体影响，并定位健康关节和 OA 关节中的间充质细胞类型/状态 2) 决定命运；以及 DPP4+ MPC 在 OA 中的作用我们将使用新生成的小鼠模型来评估分化。 MPCs 的潜力和免疫细胞调节活性，研究 MPCs 的体内命运，并研究其作用 DPP4+ MPCs 在 OA 发病机制中的作用滑膜和 IFP 的变化经常被用作 OA 发病机制的临床预测因子。该项目将为间充质细胞在骨关节炎中的作用提供重要的新见解。滑膜/IFP用于协调关节组织维护和疾病，并有可能揭示新的治疗方法 OA 的途径。