Thesis Format

Monograph

Synovial Macrophage Mitochondrial Dysfunction in Knee Osteoarthritis

Author

Lynn Huong, Western UniversityFollow

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Appleton, C. Thomas

2nd Supervisor

Beier, Frank

Co-Supervisor

Abstract

In knee osteoarthritis (OA), chronic synovial inflammation (synovitis) plays a key role in disease pathogenesis and is associated with patient symptom severity. However, it is not known how inflammation affects synovial macrophage function and whether mitochondrial impairment in synovial macrophages contributes to synovitis and pain. The purpose of this thesis was to examine the impact of the OA joint environment on macrophage mitochondria and to explore associations between synovial macrophage mitochondrial function and disease activity in knee OA. Synovial-derived macrophages from late-stage knee OA patients with severe pain and inflammation exhibited transcriptomic and morphological features indicative of mitochondrial stress. Healthy blood-derived macrophages exposed to synovial fluids from OA patients showed oxidative stress responses and altered mitochondrial morphology/activity, regardless of disease severity. Treatment with mitochondria-protective drugs mitigated oxidative damage in OA-exposed macrophages. Our findings highlight the importance of mitochondrial function in the synovium and suggest that mitochondrial dysfunction in synovial macrophages may perpetuate pain and inflammation in OA.

Summary for Lay Audience

Osteoarthritis (OA) is the most common joint disease worldwide, yet there is no effective medical treatment to stop joint damage. Historically, OA was thought to be a “wear and tear” condition affecting the cartilage. However, it is now known that OA is a disease of the entire joint, with all tissues, especially the synovium (joint lining tissue), playing crucial roles in maintaining joint health. In OA, synovial inflammation is a major contributor to pain and future joint damage. To date, the biological processes in the synovium driving OA pain and inflammation are not well understood.

Known as the “powerhouses of the cell,” mitochondria generate the energy essential for cell survival and function. In diseases, when mitochondrial number or function is disrupted, tissues become dysregulated and inflamed. In this project, we investigated whether the OA tissue environment affects macrophage mitochondrial function and if synovial macrophage mitochondrial impairment is linked to the presence of knee inflammation and severe pain.

We obtained pieces of synovial tissue from patients undergoing surgery for severe knee OA. Mitochondrial function was assessed and compared with self-reported pain levels and ultrasound-graded inflammation. In patients with severe pain and inflammation, we observed characteristics of mitochondrial stress, such as fragmented structures and decreased activity, within specialized immune cells called synovial macrophages.

Next, we treated healthy macrophages with joint fluids from knee OA patients with varying disease activity levels. Regardless of pain and inflammation severity, macrophages treated with OA synovial fluid exhibited cellular stress and disrupted mitochondrial function. We also tested in-clinic candidate treatments known to improve mitochondrial function in other diseases. We found that treating the OA-stimulated macrophages with mitochondria-protective drugs reduced mitochondrial stress responses.

The studies reported in this thesis were the first to discover that poorer mitochondrial function in synovial macrophages was associated with worse OA outcomes, such as pain and joint inflammation. We also demonstrated that the OA tissue environment may cause mitochondrial impairment in healthy macrophages. Future studies should utilize animal models to evaluate treatments focused on restoring mitochondrial function in the synovium to treat pain and disease progression in knee OA.

Recommended Citation

Huong, Lynn, "Synovial Macrophage Mitochondrial Dysfunction in Knee Osteoarthritis" (2024). Electronic Thesis and Dissertation Repository. 10509.
https://ir.lib.uwo.ca/etd/10509