Fat and synovial tissue remodeling in joint osteoarthritis

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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.