Fat and synovial tissue remodeling in joint osteoarthritis

项目摘要 骨性关节炎是成年人发病率和体能受限的主要原因。 由于受伤、肥胖和衰老，骨骼末端的保护性软骨被破坏。过去的十年见证了 在破译办公自动化发展的基本机制方面取得重大进展。然而，到目前为止，有 没有治疗疾病的药物和可用的治疗方法主要集中在缓解疼痛上。不同的细胞类型和组织 关节内有助于骨性关节炎的发展和进步。特别值得注意的是滑膜和 膝下脂肪垫(IFP)，膝关节中的两个主要软组织，相对较少受到关注。这个 滑膜分泌润滑性滑液以促进关节运动，而IFP的功能尚不清楚。 骨性关节炎与IFP和滑膜的显著纤维化和炎症有关。然而，细胞动力学 而支撑关节组织纤维炎症重塑的分子途径也知之甚少。 我们的初步研究表明，滑膜和IFP组成了一个完整的功能单位。世系 追踪研究表明，滑膜和IFP，而不是关节外的脂肪组织，是从 一个共同的间充质细胞池。骨性关节炎患者IFP/滑膜的单细胞基因图谱分析 鉴定了几个不同的间充质细胞群体，包括一个推定的间充质细胞群体 祖细胞(MPC)，以二肽基肽酶-4(DPP4)的表达为标志。这些DPP4- 表达细胞与多潜能间充质细胞群体显示出高度的转录相似性 我们最近在皮下脂肪组织中发现了。细胞轨迹分析预测关节中的MPC 滑膜衬里层成纤维细胞和IFP脂肪细胞。骨性关节炎患者富含MPC基因的通径分析 关节识别细胞外基质相关的过程和转化生长因子β信号转导，众所周知的纤维化诱因 回应。基于这些观察，我们假设作为一个整体，关节脂肪垫和 滑膜显示动态的间充质细胞亚群，具有共同的MPC群体，其 调节失调导致骨性关节炎的发病机制，如纤维化和炎症。我们的具体目标是：1)确定 骨性关节炎对关节滑膜间充质细胞编程的影响我们将对基因表达进行分析 在小鼠和人的健康和骨关节炎膝关节的单个细胞和核中，鉴定细胞类型- 骨性关节炎的特殊作用，以及在健康和骨性关节炎关节中间充质细胞类型/状态的定位；2)决定命运 DPP4+MPC在骨性关节炎中的作用。我们将使用新产生的小鼠模型来评估分化 MPC的潜能和免疫细胞调节活性，研究MPC在体内的去向，并探讨其作用 DPP4+MPC在骨性关节炎发病中的作用滑膜和IFP的变化常被用作临床预测指标 办公自动化进展。该项目将为间充质细胞在血管内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，并可能揭示新的治疗方法 办公自动化的途径。

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.