ROLE OF NEUTROPHIL ELASTASE AND PROTEINASE-ACTIVATED RECEPTOR-2 IN THE JOINT INFLAMMATION AND PAIN ASSOCIATED WITH EXPERIMENTAL ARTHRITIS
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Arthritis affects many people around the world; it is a leading cause of chronic joint pain, and physical disability. Currently available drug treatments are inadequate and associated with side-effects, so there is a need for new treatments with better efficacy and safety profiles. It has been suggested that synovial inflammation plays an important role in the development of arthritic symptoms. The focus of this thesis was to assess the contribution of neutrophil elastase and proteinase-activated receptor-2 (PAR2) to the development of experimental knee joint arthritis. To this end, we evaluated the effect of local administration of neutrophil elastase on joint inflammation and pain. The role of PAR2 in mediating neutrophil elastase-induced joint inflammation and pain was assessed. Additionally, the effect of endogenous neutrophil elastase inhibition or PAR2 blockade was investigated using preclinical models of knee arthritis. Local administration of neutrophil elastase caused pro-inflammatory (an increase in leukocyte-endothelial interactions and synovial blood flow) and pro-nociceptive (a decrease in the hindpaw withdrawal threshold) effects. These effects could be blocked by the neutrophil elastase inhibitors (sivelestat or serpinA1). Neutrophil elastase-induced joint inflammation and pain can be blocked by PAR2 antagonist and do not develop in PAR2 knockout mice. Inhibition of endogenous neutrophil elastase produced anti-inflammatory effect in the kaolin/carrageenan model of acute synovitis; however, the pain response was not improved. PAR2 knockouts prevented both joint inflammation and pain in the kaolin/carrageenan model. Prophylactic inhibition of endogenous neutrophil elastase reduced Freund’s complete adjuvant (FCA)-induced chronic joint inflammation at the end of the study. FCA-induced weight-bearing deficits and withdrawal threshold were ameliorated in the acute phase of the model. In monoiodoacetate (MIA)-induced experimental osteoarthritis, we observed increased proteolytic activity of neutrophil elastase during the acute inflammatory phase of the model. Inhibition of neutrophil elastase during this inflammatory phase prevented the development of joint inflammation, pain and late-stage neuropathy in the MIA model. Modulation of PAR2 prevented MIA-induced joint inflammation, pain and neuropathy. Collectively, our findings highlight the potential of neutrophil elastase and/or PAR2 as a therapeutic target for the treatment of joint inflammation and pain associated with arthritis.