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* Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Department of Pediatric Rheumatology, Children’s Hospital, Boston, MA 02115;
The Case Center for Proteomics, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
Department of Rheumatology, Liverpool Hospital and South Western Sydney Clinical School, University of New South Wales, Sydney, Australia; and
¶ Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center and Center for Lung Inflammation and Infection, Institute for Biosciences and Technology, Houston, TX 77030
Although mast cells (MCs) often are abundant in the synovial tissues of patients with rheumatoid arthritis, the contribution of MCs to joint inflammation and cartilage loss remains poorly understood. MC-restricted tryptase/heparin complexes have proinflammatory activity, and significant amounts of human tryptase β (hTryptase-β) are present in rheumatoid arthritis synovial fluid. Mouse MC protease-6 (mMCP-6) is the ortholog of hTryptase-β, and this serine protease is abundant in the synovium of arthritic mice. We now report that C57BL/6 (B6) mice lacking their tryptase/heparin complexes have attenuated arthritic responses, with mMCP-6 as the dominant tryptase responsible for augmenting neutrophil infiltration in the K/BxN mouse serum-transfer arthritis model. While inflammation in this experimental arthritis model was not dependent on protease-activated receptor-2, it was dependent on the chemokine receptor CXCR2. In support of the latter data, exposure of synovial fibroblasts to hTryptase-β/heparin or mMCP-6/heparin complexes resulted in expression of the neutrophil chemotactic factors CXCL1/KC, CXCL5/LIX, and CXCL8/IL-8. Our proteomics, histochemistry, and immunohistochemistry data also revealed substantial loss of cartilage-derived aggrecan proteoglycans in the arthritic joints of wild-type B6 mice but not mMCP-6-null B6 mice. These observations demonstrate the functional contribution of MC-restricted tryptase/heparin complexes in the K/BxN mouse arthritis model and connect our mouse findings with rheumatoid arthritis pathophysiology.
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1 This work was supported by the American Arthritis Foundation (to K.S.); the Australian Research Council and Arthritis Australia (to H.P.M.); the University of Texas M. D. Anderson Cancer Center Physician Scientist Program (to R.A.); the Cogan Family Foundation (to D.M.L.); and the National Institutes of Health Grants AI054950 (to R.L.S.), AI059746 (to D.M.L.), AI031599 (to M.F.G.), AR051321 (to P.A.N.), and HL036110 (to R.L.S.).
2 Address correspondence and reprint requests to Dr. David Lee, Brigham and Women’s Hospital, Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Smith Building, Room 552B, 1 Jimmy Fund Way, Boston, MA 02115. E-mail address: dlee{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; B6, C57BL/6; FLS, fibroblast-like synoviocytes; HA, hyaluronan; hTryptase-β, human tryptase β; MC, mast cell; mMCP, mouse MC protease; 6+/7–, mMCP-6+/+/mMCP-7–/–; 6–/7+, mMCP-6–/–/mMCP-7+/+; 6–/7–, mMCP-6–/–/mMCP-7–/–; MS/MS, tandem mass spectroscopy; NDST-2, N-deacetylase/N-sulfotransferase-2; PAR-2, protease-activated receptor-2; WT, wild type; W/Wv, WBB6F1-KitW/KitW-v.
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