Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Appleton, C. Thomas G.

Abstract

In osteoarthritis (OA), synovitis is associated with symptom severity. As synovium secretes both catabolic and anabolic factors into the joint, the impact of synovitis in OA remains unclear. We developed a novel co-culture system using tissues from an established rat model of post-traumatic knee OA (PTOA) to study signaling between synovium and chondrocytes. We found that synovium from early stage but not later stage PTOA joints caused an overall protective effect in chondrocytes. We then selectively treated synovial macrophages with liposomal drugs causing depletion, STAT1 inhibition, or STAT6 inhibition in early PTOA joints. We found cartilage damage in vivo was not affected, but chondrocyte responses to treated synovium in vitro indicate that STAT1 inhibition could be protective, while STAT6 inhibition is potentially pro-inflammatory. Thus, we demonstrate that synovial signals affect chondrocyte physiology in the OA knee joint and that targeting synovial macrophages as a potential therapeutic strategy warrants further investigation.

Summary for Lay Audience

Osteoarthritis is a serious joint disease that causes pain and disability with no direct treatment. Patients manage symptoms with pain medication and exercise. We still do not completely understand the mechanisms behind osteoarthritis, but we do know that the disease involves the cells in cartilage on the ends of bones changing from their normal state to send out inflammatory signals and enzymes that destroy the tissue around them. The joint lining, or synovium, which wraps around the joint space, also changes by becoming inflamed. In my project, we investigated how the synovium signals to cartilage cells and how the condition of the synovium affects osteoarthritis in the joint.

Our experiments used young adult male rats following ethical guidelines. We surgically injured the rats’ knees to induce osteoarthritis. We collected cartilage and synovium and grew them in artificial conditions to isolate the signals exchanged between these tissues. Because inflamed synovium is correlated with human disease severity, we hypothesized that growing early osteoarthritic synovium with healthy cartilage cells would cause them to become inflammatory and destructive. To our surprise, we found a protective effect with indications of increased production of tissue molecules by cartilage cells. We then grew synovium from joints at a later stage of osteoarthritis with cartilage cells and found that this protective effect was completely absent. From this, we concluded that the synovium undergoes a change over time, which has implications for our understanding of osteoarthritis, although these findings need to be confirmed in humans.

We then investigated the impact of macrophages in the synovium in osteoarthritis. Macrophages are a diverse immune cell population with important roles in the joint, especially signaling. We packaged different drugs into small lipid particles and injected them into pre-osteoarthritic knees, where only macrophages could consume the drugs. For the three drugs we tested, we found different patterns of reduced inflammation in the synovium and mixed effects in cartilage cells grown with the synovium, but no differences in cartilage damage or pain. Our future work will use knees at a later stage of osteoarthritis, where we expect to see significant results in osteoarthritis-related outcomes.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Monday, August 01, 2022

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