Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy


Health and Rehabilitation Sciences

Collaborative Specialization

Musculoskeletal Health Research


Appleton, C. Thomas

2nd Supervisor

Birmingham, Trevor B.



Purpose: The overall purpose of this dissertation was to investigate the role of synovial pathophysiology in knee osteoarthritis (OA) pain.

Methods: This dissertation includes four studies. Participants were recruited as part of the on-going Western Ontario Registry for Early Osteoarthritis (WOREO) Knee Study, which is a prospective cohort study designed to investigate clinical, biomechanical, and pathophysiological features of early- and late-stages of knee OA, including those undergoing total knee arthroplasty (TKA). Patient-reported outcome measures of pain were collected. Several methodologies were used to characterize synovial pathophysiology including musculoskeletal ultrasound (US), histopathology, high throughput ‘omics’ technologies (i.e., spatial profiling, single-cell RNA sequencing), and cell-based functional assays.

Results: Moderate/severe US-synovitis was associated with worse intermittent and constant pain in patients with radiographic early-stage OA. However, no associations were identified in patients with late-stage knee OA. Histopathological features of synovial tissue damage, microvascular pathology, and inflammation are present in the synovium from late-stage knee OA patients. Higher US measures of synovitis were associated with higher histopathological scores for inflammation, while lower US measures were associated with higher scores for synovial tissue damage. Worse pain was characterized by increased synovial tissue damage (particularly microvascular pathology), immune exhaustion, and neurovascular remodeling. Histopathological measures of synovial microvascular pathology were associated with decreased response to TKA.

Conclusions: Novel insights were uncovered regarding the role of synovial microvascular pathology in pain cross-sectionally, and longitudinally after TKA. Importantly, we identified a link between synovial immune cell exhaustion, aberrant neurovascular remodeling, and OA pain. These findings suggest that restoring the homeostatic function of the synovium may be key to improving outcomes for patients living with knee OA.

Summary for Lay Audience

Knee osteoarthritis (OA) is the most common joint disease with nearly 520 million people affected worldwide. OA impacts all joint tissues, which results in chronic pain, poor function, and disability. In fact, pain is the number one reason for people living with OA to seek healthcare. The synovium (joint lining tissue) is an important tissue for keeping the joint healthy, but in OA is a major contributor to pain and disease severity. To date, the biological processes in the synovium responsible for OA pain are not well understood. The purpose of this thesis was to further investigate how the synovium contributes to OA pain. Patients with early- and late-stage knee OA, and those having knee replacement surgery were included. Pain experiences for each participant were measured using a self-reported questionnaire. The health of the synovium was measured in different ways including ultrasound imaging, histopathology (assessed using a microscope), and by measuring cell function. In patients with early-stage knee OA, synovial inflammation was related to worse pain. However, in patients with late-stage knee OA, we found that abnormal changes to the blood vessels and nerves in the synovium were related to worse pain and to worse outcomes after knee replacement surgery. Future studies should assess treatments that restore normal synovial blood vessel and nerve function to treat pain and disease progression more effectively in knee OA.

Available for download on Monday, July 22, 2024

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