Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Master of Science


Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research


Appleton, Tom

2nd Supervisor

Birmingham, Trevor



Synovial inflammation and biomechanical loading are independent risk factors for knee osteoarthritis (OA). However, the relationship between inflammatory and biomechanical factors, specifically if increased biomechanical loading causes synovial inflammation in OA (mechanoinflammation), is not well understood. The purpose of this thesis was to explore the associations of knee load during walking with features of synovial inflammation in knee OA. The knee adduction moment magnitude was associated with increased synovial vascularization and perivascular edema. Synovial fluid from OA patients with high knee adduction moments promoted endothelial cell migration in vitro. Late-stage knee OA synovial fluid caused endothelial monolayer hyperpermeability in vitro regardless of the patient’s knee adduction moment magnitude. We identified placental growth factor as a synovial fluid cytokine associated with increased knee adduction moment magnitude. Our findings support the mechanoinflammatory hypothesis of knee OA and suggest that increased knee loading contributes to synovial microvascular dysfunction in knee OA.

Summary for Lay Audience

Historically, doctors and scientists recognized osteoarthritis (OA) as non-inflammatory arthritis. However, inflammation of the joint lining (synovium) is now understood to occur in most OA patients. OA is a mechanically driven disease, but the link between increased knee load during walking and synovial inflammation is not well understood. We investigated how joint overloading contributes to synovial inflammation in knees with OA.

We studied patients undergoing surgery for the treatment of severe knee OA. Before surgery, study patients underwent gait testing to estimate their knee joint loads during walking. At the time of surgery, a surgeon collected synovial fluid and a piece of synovium from the affected knee. We then analyzed this synovial fluid and synovium for features of inflammation, which were then compared with the magnitude of knee joint loads experienced during walking.

The synovium from patients with increased knee loading had more blood vessels and evidence of blood vessel leak, which are both signs of inflammation. Treating endothelial cells with OA synovial fluid from patients with increased knee loading promoted cell migration, a key feature of new blood vessel formation. Endothelial cells treated with OA synovial fluid, regardless of joint loading magnitude, caused endothelial cell leak. We also found the synovial fluid from patients with increased knee loading had higher amounts of placental growth factor, a molecule known to cause new blood vessel formation and tissue inflammation.

The studies reported in this thesis were the first to explore the relationship between knee loading and synovial tissue inflammation in humans with knee OA. We demonstrated increased knee loading is related to features of synovial inflammation, including undesirable changes to synovial blood vessels. We also identified a candidate molecule, placental growth factor, that may mediate the effects of increased knee load on synovial inflammation. No current treatments can stop or reverse OA progression; therefore, novel therapies are needed. Future research should explore treatments that reduce knee loading and/or prevent synovial blood vessel formation in patients with knee OA. Future research should also attempt to identify the mechanisms driving the association between increased knee load and synovial blood vessel pathology.

Available for download on Sunday, March 31, 2024

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