Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Appleton, Christopher

Abstract

Non-resolving synovial inflammation is present in both human and animal models and plays a key role in the pathogenesis of knee osteoarthritis (OA). However, it is not known how inflammation affects synovial macrophage function and if this contributes to the loss of tissue homeostasis. The purpose of this thesis was to understand the role of efferocytosis in knee OA. There is an increased apoptotic cell burden within the synovium of patients with late-stage knee OA. Synovial-derived macrophages from these patients exhibited impaired efferocytosis. Healthy blood-derived macrophages exposed to synovial fluid from patients with knee OA recapitulated the defective efferocytosis. Impaired efferocytosis in a rat model of post-traumatic knee OA was associated with increased pain-related behaviours, joint damage, and synovial apoptotic cell burden. Our findings support the key functions of the synovium and emphasizes the importance of targeting synovial health in OA to improve outcomes.

Summary for Lay Audience

In the past, osteoarthritis (OA) was thought of as a “wear and tear” disease of the cartilage. However, it is now accepted that OA is a disease of the entire joint as all tissues that make up the joint, such as the synovium play important roles in maintaining its health.

In OA, the synovium becomes dysfunctional and is associated with disease progression and pain. However, it is not known how this tissue becomes dysfunctional. We investigated the relationship between synovial tissue function and the synovial cells that are responsible for tissue functionality in the setting of OA.

We obtained pieces of synovial tissue from healthy participants without knee OA and from patients with severe knee OA and analyzed different features of the samples. In patients with severe OA, there were greater amounts of dead cells accumulating in the synovium compared to healthy participants. Specialized cells known as macrophages that are responsible for clearing dead cells were also found to be dysfunctional within the synovium of patients with severe OA.

Next, we used an experimental rat model of OA to determine if impaired clearance of dead cells led to worse pain and joint damage. Over a period of 12 weeks, rats underwent surgery to induce OA and were injected in the right knee with DNA designed to block the function of clearing dead cells to recapitulate what we found in human samples. We found that impaired clearance of dead cells does lead to worse pain-related behaviours and joint damage.

The studies reported in this thesis were the first to discover a buildup of dead cells in synovial tissue from patients with severe OA and that impairment in clearing these cells was associated with worse OA outcomes such as pain and joint structure. Future research should explore treatments that focus on recovering the ability to clear dead cells in the synovium in patients with knee OA. Future research should also attempt to identify mechanisms driving the association between impaired clearance of dead cells and worse OA outcomes.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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