Synovial Pathophysiology and Pain in Knee Osteoarthritis
Abstract
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.