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Collagenase in synovitis of rheumatoid arthritis
T Sorsa1, Y T Konttinen, O Lindy
1Department of Anatomy, Helsinki University, Finland.
Abstract:
There are two types of collagenases, products of two distinct genes, called MMP-1 (matrix metalloproteinase 1 or "fibroblast-type collagenase") and MMP-8 ("neutrophil collagenase"). In synovial fluid, MMP-8 is stored as latent proenzyme in polymorphonuclear neutrophils. MMP-8 is activated by hypochlorous acid produced by myeloperoxidase from hydrogen peroxide and chloride ion and by the hydroxyl radical produced in Haber Weiss reaction fed by superoxide produced by, eg, NADPH (reduced nicotinamide adenine dinucleotide) oxidase and xanthine oxidase. In addition to activation upon secretion, oxidatively modified MMP-8 is susceptible to a subsequent proteolytic attack and activation by cathepsin G. The authors suggest that activation of neutrophil-derived MMP-8 involves oxidative, nonproteolytic activation upon secretion and a more slowly progressive proteolytic activation by cathepsin G (or chymases and tryptases), and that these oxidative and proteolytic activation mechanisms act in concert. In contrast to MMP-8, MMP-1 is synthesized de novo and secreted immediately after synthesis by fibroblasts, macrophages, and some epithelial cells. Human rheumatoid synovial tissue contains mainly fibroblast-type MMP-1 collagenase as assessed by collagenase extracted from synovial tissue and by MMP-1 and MMP-8 immunostaining. It is suggested that in vivo, MMP-1 in synovitis tissue is activated by a plasminogen activator/plasminogen/prostromelysin (alternatively tryptases)/proMMP-1 cascade. In conclusion, MMP-8 and MMP-1 show type-specific compartmentalization and modes of activation in rheumatoid synovial fluid and tissue.
Insights
Matrix metalloproteinase-8 (MMP-8) and matrix metalloproteinase-1 (MMP-1) collagenases exhibit distinct activation pathways and compartmentalization in rheumatoid synovial fluid and tissue. Understanding these differences is key to targeting collagenase activity in inflammatory joint diseases.
Area of Science:
- Biochemistry
- Immunology
- Rheumatology
Background:
- Collagenases, specifically matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-8 (MMP-8), are crucial enzymes involved in extracellular matrix degradation.
- MMP-1, or fibroblast-type collagenase, is synthesized by fibroblasts, macrophages, and some epithelial cells.
- MMP-8, or neutrophil collagenase, is stored as a latent proenzyme in neutrophils.
Purpose of the Study:
- To elucidate the distinct activation mechanisms and tissue-specific distribution of MMP-1 and MMP-8 in rheumatoid synovial fluid and tissue.
- To differentiate the roles of oxidative and proteolytic pathways in MMP-8 activation.
- To understand the in vivo activation cascade of MMP-1 in synovitis.
Main Methods:
- Analysis of collagenase activity in synovial fluid and tissue extracts.
- Immunohistochemical staining for MMP-1 and MMP-8 in human rheumatoid synovial tissue.
- Investigation of MMP-8 activation by reactive oxygen species (hypochlorous acid, hydroxyl radical) and proteolytic enzymes (cathepsin G).
- Examination of MMP-1 activation pathways involving the plasminogen/plasmin system.
Main Results:
- MMP-8 activation in synovial fluid involves oxidative, non-proteolytic mechanisms upon secretion, followed by slower proteolytic activation by cathepsin G.
- Oxidative activation of MMP-8 is facilitated by reactive oxygen species generated through myeloperoxidase and NADPH oxidase.
- Human rheumatoid synovial tissue predominantly contains fibroblast-type MMP-1, activated via a plasminogen activator/plasmin cascade.
Conclusions:
- MMP-8 and MMP-1 display type-specific compartmentalization within rheumatoid joints.
- Distinct activation mechanisms, including oxidative and proteolytic pathways for MMP-8 and a plasmin-dependent cascade for MMP-1, are operative in vivo.
- These findings highlight the differential regulation of collagenases in the rheumatoid synovium, offering insights into targeted therapeutic strategies.