Fat and synovial tissue remodeling in joint osteoarthritis

项目摘要 骨关节炎（OA）是成年人发病和身体限制的主要原因。 由于受伤、肥胖和衰老，骨骼末端的保护性软骨会减少。在过去十年有 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， 没有改善疾病的药物，可用的治疗主要集中在疼痛缓解上。多种细胞类型和组织 在关节内有助于OA的发展和进展。特别感兴趣的是滑膜， 髌下脂肪垫（IFP）是膝关节中的两个主要软组织，相对较少受到关注。的 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。 OA与IFP和滑膜中的显著纤维化和炎症相关。然而，细胞动力学 并且对关节组织的纤维炎性重塑的分子途径知之甚少。 我们的初步研究表明，滑膜和IFP包括一个完整的功能单位。谱系 追踪研究表明，滑膜和IFP，而不是直接在关节外的脂肪组织， 一个共同的间充质细胞池骨关节炎患者IFP/滑膜单细胞基因谱分析 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），通过表达二肽基肽酶-4（DPP 4）特异性标记。这些DPP 4- 表达细胞显示出与多能间充质细胞群体的高转录相似性， 我们最近在皮下脂肪组织中发现的。细胞轨迹分析预测，关节中的MPCs引起了 滑膜衬里层成纤维细胞和IFP脂肪细胞。骨关节炎MPC富集基因的通路分析 关节鉴定了细胞外基质相关过程和TGFβ信号传导，一种众所周知的纤维化诱导剂 应答基于这些观察，我们假设，作为一个完整的单位，关节脂肪垫和 滑膜表现出间充质细胞的动态亚群，具有共同的MPC群， 调节异常驱动OA发病机制，如纤维化和炎症。我们的具体目标是：1）确定 OA对关节IFP/滑膜中间充质细胞编程的影响。我们将分析基因表达 在来自小鼠和人的健康和骨关节炎膝关节的单细胞和细胞核中，鉴定细胞类型- OA的特异性作用，并在健康和OA关节中定位间充质细胞类型/状态; 2）确定命运 以及DPP 4 + MPC在OA中的作用。我们将使用一个新产生的小鼠模型来评估分化 MPCs的潜在和免疫细胞调节活性，研究MPCs的体内命运，并研究MPCs的作用。 DPP 4 + MPCs在OA发病机制中的作用。滑膜和IFP的变化通常被用作临床预测因子， OA进展。该项目将提供关键的新见解间充质细胞的作用， 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 OA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.