{"id":{"repo_id":"uwo","oai_identifier":"oai:uwo.scholaris.ca:20.500.14721/32813"},"canonical_url":"https://search.dev.ndltd.org/etd/uwo/oai:uwo.scholaris.ca:20.500.14721/32813","repository":{"repo_id":"uwo","name":"Western University","base_url":"https://uwo.scholaris.ca/server/oai/request"},"display":{"title":"Mechanisms of Impaired Efferocytosis of Synovial Macrophages in Knee Osteoarthritis","abstract":"Osteoarthritis (OA) is the most common form of arthritis, which affects hundreds of millions of people worldwide with no medical treatments that can stop joint damage. Tissues that line the interior of joints are essential for maintaining joint health, specifically the synovium. Previous research from the Appleton lab has shown that efferocytosis, the process for the clearance of dead and dying cells by macrophages, is impaired in OA patients. This project further explored the OA-specific mechanisms controlling efferocytosis in macrophages and investigated whether there was variation in different processes, gene expression, and pathways. We hypothesized that the macrophage receptors that are required for engaging dead and dying cells are decreased and that targeting these pathways can rescue the defect. To study the specific altered mechanisms, this study used macrophages differentiated in vitro from primary blood monocytes, which were treated with synovial fluid from patients with high levels of inflammation due to knee OA. By feeding labeled apoptotic cells to macrophages stimulated with synovial fluid and fixing the cells during the process of efferocytosis, we were able to identify the steps in the process that were impaired. We found from our studies that the engulfment stage of efferocytosis is impaired. Next, RNA sequencing was used to compare the healthy control versus the diseased sample to measure the differential gene expression of receptors and enrichment of physiologic pathways. We found that the defect is reversible with the treatment of IL-4. We also found that signs of cell stress, such as the unfolded protein response (UPR), were significantly enriched. Selective inhibitors were used to block the UPR pathway and there was a rescue effect. Overall, this study identified mechanisms contributing to impaired efferocytosis in OA and helped to inform treatments to improve efferocytosis and patient outcomes.","abstract_html":"Osteoarthritis (OA) is the most common form of arthritis, which affects hundreds of millions of people worldwide with no medical treatments that can stop joint damage. Tissues that line the interior of joints are essential for maintaining joint health, specifically the synovium. Previous research from the Appleton lab has shown that efferocytosis, the process for the clearance of dead and dying cells by macrophages, is impaired in OA patients. This project further explored the OA-specific mechanisms controlling efferocytosis in macrophages and investigated whether there was variation in different processes, gene expression, and pathways. We hypothesized that the macrophage receptors that are required for engaging dead and dying cells are decreased and that targeting these pathways can rescue the defect. To study the specific altered mechanisms, this study used macrophages differentiated in vitro from primary blood monocytes, which were treated with synovial fluid from patients with high levels of inflammation due to knee OA. By feeding labeled apoptotic cells to macrophages stimulated with synovial fluid and fixing the cells during the process of efferocytosis, we were able to identify the steps in the process that were impaired. We found from our studies that the engulfment stage of efferocytosis is impaired. Next, RNA sequencing was used to compare the healthy control versus the diseased sample to measure the differential gene expression of receptors and enrichment of physiologic pathways. We found that the defect is reversible with the treatment of IL-4. We also found that signs of cell stress, such as the unfolded protein response (UPR), were significantly enriched. Selective inhibitors were used to block the UPR pathway and there was a rescue effect. Overall, this study identified mechanisms contributing to impaired efferocytosis in OA and helped to inform treatments to improve efferocytosis and patient outcomes.","abstract_has_math":false,"creators":["Bashal, Jasika"],"institution":"The University of Western Ontario","degree_name":"M Sc","degree_level":null,"degree_discipline":"Physiology and Pharmacology","degree_department":null,"school":null,"contributors":[],"advisors":["Appleton, C. Thomas","Heit, Bryan"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-02-03","date_published":"2023-02-03","updated_at":"2026-07-27T21:55:56Z","subjects":["Knee Osteoarthritis","Efferocytosis","Synovial Inflammation","Apoptosis","Macrophages"],"languages":["en_ca"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.14721/32813","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Appleton, C. 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In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."]},{"key":"dc:description.abstract","label":"Abstract","values":["Osteoarthritis (OA) is the most common form of arthritis, which affects hundreds of millions of people worldwide with no medical treatments that can stop joint damage. Tissues that line the interior of joints are essential for maintaining joint health, specifically the synovium. Previous research from the Appleton lab has shown that efferocytosis, the process for the clearance of dead and dying cells by macrophages, is impaired in OA patients. This project further explored the OA-specific mechanisms controlling efferocytosis in macrophages and investigated whether there was variation in different processes, gene expression, and pathways. We hypothesized that the macrophage receptors that are required for engaging dead and dying cells are decreased and that targeting these pathways can rescue the defect. To study the specific altered mechanisms, this study used macrophages differentiated in vitro from primary blood monocytes, which were treated with synovial fluid from patients with high levels of inflammation due to knee OA. By feeding labeled apoptotic cells to macrophages stimulated with synovial fluid and fixing the cells during the process of efferocytosis, we were able to identify the steps in the process that were impaired. We found from our studies that the engulfment stage of efferocytosis is impaired. Next, RNA sequencing was used to compare the healthy control versus the diseased sample to measure the differential gene expression of receptors and enrichment of physiologic pathways. We found that the defect is reversible with the treatment of IL-4. We also found that signs of cell stress, such as the unfolded protein response (UPR), were significantly enriched. Selective inhibitors were used to block the UPR pathway and there was a rescue effect. Overall, this study identified mechanisms contributing to impaired efferocytosis in OA and helped to inform treatments to improve efferocytosis and patient outcomes."]},{"key":"dc:title","label":"Title","values":["Mechanisms of Impaired Efferocytosis of Synovial Macrophages in Knee Osteoarthritis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Appleton, C. Thomas","Heit, Bryan"],"dc:creator":["Bashal, Jasika"],"dc:date.accessioned":["2025-07-10T19:37:02Z"],"dc:date.available":["2025-07-10T19:37:02Z"],"dc:date.issued":["2023-02-03"],"dc:description":["Collaborative Specialization: Musculoskeletal Health Research","The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."],"dc:description.abstract":["Osteoarthritis (OA) is the most common form of arthritis, which affects hundreds of millions of people worldwide with no medical treatments that can stop joint damage. Tissues that line the interior of joints are essential for maintaining joint health, specifically the synovium. Previous research from the Appleton lab has shown that efferocytosis, the process for the clearance of dead and dying cells by macrophages, is impaired in OA patients. This project further explored the OA-specific mechanisms controlling efferocytosis in macrophages and investigated whether there was variation in different processes, gene expression, and pathways. We hypothesized that the macrophage receptors that are required for engaging dead and dying cells are decreased and that targeting these pathways can rescue the defect. To study the specific altered mechanisms, this study used macrophages differentiated in vitro from primary blood monocytes, which were treated with synovial fluid from patients with high levels of inflammation due to knee OA. By feeding labeled apoptotic cells to macrophages stimulated with synovial fluid and fixing the cells during the process of efferocytosis, we were able to identify the steps in the process that were impaired. We found from our studies that the engulfment stage of efferocytosis is impaired. Next, RNA sequencing was used to compare the healthy control versus the diseased sample to measure the differential gene expression of receptors and enrichment of physiologic pathways. We found that the defect is reversible with the treatment of IL-4. We also found that signs of cell stress, such as the unfolded protein response (UPR), were significantly enriched. Selective inhibitors were used to block the UPR pathway and there was a rescue effect. Overall, this study identified mechanisms contributing to impaired efferocytosis in OA and helped to inform treatments to improve efferocytosis and patient outcomes."],"dc:identifier.uri":["https://hdl.handle.net/20.500.14721/32813"],"dc:language.iso":["en_ca"],"dc:publisher":["The University of Western Ontario"],"dc:subject":["Knee Osteoarthritis","Efferocytosis","Synovial Inflammation","Apoptosis","Macrophages"],"dc:title":["Mechanisms of Impaired Efferocytosis of Synovial Macrophages in Knee Osteoarthritis"],"dc:type":["thesis"],"thesis:degree_discipline":["Physiology and Pharmacology"],"thesis:degree_name":["M Sc"]},"updated_at":"2026-07-27T21:55:56Z"}