The mouse mast cell-restricted tetramer-forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis

Objective. Increased numbers of mast cells (MCs) that express β tryptases bound to heparin have been detected in the synovium of patients with rheumatoid arthritis (RA). The corresponding tryptases in mice are mouse MC protease 6 (mMCP-6) and mMCP-7. Although MCs have been implicated in RA and some animal models of arthritis, no direct evidence for a MC-restricted tryptase in the pathogenesis of inflammatory arthritis has been shown. We created transgenic mice that lack heparin and different combinations of mMCP-6 and mMCP-7, to evaluate the roles of MC-restricted tryptase-heparin complexes in an experimental model of arthritis. Methods. The methylated bovine serum albumin/interleukin-1β (mBSA/IL-1β) experimental protocol was used to induce inflammatory monarthritis in different mouse strains. Mice were killed at the time of peak disease on day 7, and histochemical methods were used to assess joint pathology. Results. Arthritis was induced in the knee joints of mBSA/IL-1β-treated mMCP-6⁺/mMCP-7^- and mMCP-6 ^-/mMCP-7⁺ C57BL/6 mice, and numerous activated MCs that had exocytosed the contents of their secretory granules were observed in the diseased mice. In contrast, arthritis was markedly reduced in heparin-deficient mice and in mMCP-6^-/mMCP-7^- C57BL/6 mice. Conclusion. MC-derived tryptase-heparin complexes play important roles in mBSA/IL-1β-induced arthritis. Because mMCP-6 and mMCP-7 can compensate for each other in this disease model, the elimination of both tryptases is necessary to reveal the prominent roles of these serine proteases in joint inflammation and destruction. Our data suggest that the inhibition of MC-restricted tryptases could have therapeutic potential in the treatment of RA.