Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies.

Tetlow, Lesley; Woolley, David

doi:10.1136/ard.54.11.896

Cited by 133 publications

(114 citation statements)

References 47 publications

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“…An involvement of mast cells in rheumatoid arthritis has been suggested by numerous studies (33)(34)(35)(36)(37) and was recently supported by a study using mast cell-deficient mice (38). However, the mechanisms underlying the contribution of mast cells to the ECM destruction observed in these cases are not elucidated.…”

Section: Figurementioning

confidence: 85%

Human Mast Cell β-Tryptase Is a Gelatinase

Fajardo

Pejler

2003

The Journal of Immunology

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Remodeling of extracellular matrix is an important component in a variety of inflammatory disorders as well as in normal physiological processes such as wound healing and angiogenesis. Previous investigations have identified the various matrix metalloproteases, e.g., gelatinases A and B, as key players in the degradation of extracellular matrix under such conditions. Here we show that an additional enzyme, human mast cell β-tryptase, has potent gelatin-degrading properties, indicating a potential contribution of this protease to matrix degradation. Human β-tryptase was shown to degrade gelatin both in solution and during gelatin zymographic analysis. Further, β-tryptase was shown to degrade partially denatured collagen type I. β-Tryptase bound strongly to gelatin, forming high molecular weight complexes that were stable during SDS-PAGE. Mast cells store large amounts of preformed, active tryptase in their secretory granules. Considering the location of mast cells in connective tissues and the recently recognized role of mast cells in disorders in which connective tissue degradation is a key event, e.g., rheumatoid arthritis, it is thus likely that tryptase may contribute to extracellular matrix-degrading processes in vivo.

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Section: Figurementioning

confidence: 85%

Human Mast Cell β-Tryptase Is a Gelatinase

Fajardo

Pejler

2003

The Journal of Immunology

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“…There is considerable circumstantial evidence implicating mast cells in the pathogenesis of human rheumatoid arthritis (RA). These include the production of inflammatory (13,14) and tissue destructive (15,16) mediators. Moreover, a significant increase in mast cell numbers has been documented in human synovial tissue derived from patients with RA (8,9).…”

Section: Ast Cells Are Derived From Hemopoietic Progenitor Cells Thmentioning

confidence: 99%

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

Girolamo

Indoh

Jackson

et al. 2006

The Journal of Immunology

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Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-α significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-γ inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-α significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-γ, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.

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“…Numerous cellular participants of innate and adaptive immunity contribute to the pronounced inflammatory processes seen in rheumatoid synovitis. Our group (1)(2)(3)(4) and many other investigators (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) have obtained data implicating a prominent involvement of mast cells (MCs) and their mediators in RA and some animal models of this autoimmune disorder. On a weight basis, tetramer-forming ␤ tryptases (15)(16)(17)(18)(19) are the most abundant proteins present in the secretory granules of human MCs.…”

mentioning

confidence: 99%

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

McNeil

Shin

Campbell

et al. 2008

Arthritis & Rheumatism

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Objective. Increased numbers of mast cells (MCs) that express ␤ 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 MCrestricted tryptase-heparin complexes in an experimental model of arthritis.Methods. The methylated bovine serum albumin/ interleukin-1␤ (mBSA/IL-1␤) 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-1␤-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 heparindeficient mice and in mMCP-6 ؊ /mMCP-7 ؊ C57BL/6 mice.Conclusion. MC-derived tryptase-heparin complexes play important roles in mBSA/IL-1␤-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.Rheumatoid arthritis (RA) is an inflammatory disorder of synovial joints characterized by damage to articular structures due to chronic inflammation of the synovium. Numerous cellular participants of innate and adaptive immunity contribute to the pronounced inflammatory processes seen in rheumatoid synovitis. Our group (1-4) and many other investigators (5-14) have obtained data implicating a prominent involvement of mast cells (MCs) and their mediators in RA and some animal models of this autoimmune disorder. On a weight basis, tetramer-forming ␤ tryptases (15)(16)(17)(18)(19) are the most abundant proteins present in the secretory granules of human MCs. Three ␤ tryptase complementary DNAs (designated hTryptase ␤1, ␤2, and ␤3) have been cloned.

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Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies.

Abstract: Objectives-To examine the distribution and activation of mast cells (MCs)

Cited by 133 publications

References 47 publications

Human Mast Cell β-Tryptase Is a Gelatinase

Human Mast Cell β-Tryptase Is a Gelatinase

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

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

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