Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells.

OBJECTIVE: Mast cells are hypothesized to play a role in the pathogenesis of rheumatoid arthritis (RA) by mechanisms requiring elucidation. Tryptase released from these cells can activate protease-activated receptor 2 (PAR-2), which was recently shown to have proinflammatory actions. The purpose of this study was to examine the relationship between synovial mast cells and PAR-2. Mast cell proximity to PAR-2-expressing cells was investigated in RA synovium. In murine studies, we assessed the capacity of mast cell tryptase to mediate synovial proinflammatory responses via PAR-2 and whether degranulating mast cells induced synovial hyperemia by PAR-2 activation. METHODS: RA synovial tissue was examined by immunohistochemistry. PAR-2(+/+) and PAR-2(-/-) C57BL/6J mice were used to investigate the PAR-2 dependence of compound 48/80-induced synovial hyperemia, as measured by laser Doppler imaging, and joint swelling and hyperemic responses to recombinant human beta-tryptase. RESULTS: Mast cells and synovial lining cells staining for PAR-2 were colocalized in RA articular tissue. Compound 48/80 administration resulted in vasodilatation in PAR-2(+/+) mice but not in PAR-2(-/-) mice, which showed a vasoconstrictor response. Eliminating the 5-hydroxytryptamine-mediated component of this response with methysergide unveiled an enhanced PAR-2-mediated vasodilatation to compound 48/80 in PAR-2(+/+) mice and ablated the vasoconstrictor response in PAR-2(-/-) mice. Treatment with beta-tryptase resulted in dose-dependent knee joint swelling and synovial vasodilatation in PAR-2(+/+) mice but not PAR-2(-/-) mice. CONCLUSION: This in vivo study is the first to explore the relationship between synovial mast cells and PAR-2. Our results support the hypothesis that mast cells contribute to the pathogenesis of inflammatory arthritis through PAR-2 activation via release of mast cell tryptase.

Strain dependence in murine models of monoarthritis.

OBJECTIVE AND DESIGN: This study explores the inflammatory response in various murine strains. Utilising several approaches, monoarthritis was induced in the knee, providing an inflammatory model relevant to arthritis. METHODS: Acute (carrageenan/kaolin; C/K) or chronic inflammatory models (Freund's complete adjuvant; FCA) or antigen-induced arthritis (AIA), were induced by peri- and/or intra-articular injection. RESULTS: C/K elicited an acute inflammatory response in various strains of mice, with significant (P < 0.005) phenotypic variation. FCA induction provided a chronic inflammatory response. The magnitude of the response in both acute and chronic models was strain dependent, with BalbC exhibiting the most resistance to swelling in all models. AIA produced only an acute response in three strains tested. CONCLUSIONS: The data presented, demonstrating variation in the magnitude of acute and chronic inflammatory responses in different mice strains, allows informed selection of appropriate strains and models for future experimental studies.