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Matrix Metalloproteinases and Cellular Fibrinolytic Activity
Abstract
Several molecular interactions between the matrix metalloproteinase (MMP) and the plasminogen/plasmin (fibrinolytic) system may affect cellular fibrinolysis. MMP-3 (stromelysin-1) specifically hydrolyzes urokinase (u-PA), yielding a 17 kD NH2-terminal fragment containing the functionally intact receptor (u-PAR)-binding sequence and a 32 kD COOH-terminal fragment containing the intact serine proteinase domain. MMP-3 generates an angiostatin-like fragment (containing kringles 1-4 with the cellular binding domains) from plasminogen. Treatment with MMP-3 of monocytoid THP-1 cells saturated with bound plasminogen, resulted in a dose-dependent reduction of the amount of u-PA-activatible plasminogen. Treatment with MMP-3 of cell-bound u-PA, in contrast, did not alter cell-associated u-PA activity. These data thus indicate that MMP-3 may downregulate cell-associated plasmin activity by decreasing the amount of activatible plasminogen, without affecting cell-bound u-PA activity. MMP-3 also specifically interacts with the main inhibitors of the fibrinolytic system. Thus, MMP-3 specifically hydrolyzes human alpha2-antiplasmin (alpha2-AP), the main physiological plasmin inhibitor. alpha2-AP cleaved by MMP-3 no longer forms a stable complex with plasmin and no longer interacts with plasminogen. Cleavage and inactivation of alpha2-AP by MMP-3 may constitute a mechanism favoring local plasmin-mediated proteolysis. Furthermore, MMP-3 specifically hydrolyzes and inactivates human plasminogen activator inhibitor-1 (PAI-1). Stable PAI-1 bound to vitronectin is cleaved and inactivated by MMP-3 in a comparable manner as free PAI-1; the cleaved protein, however, does not bind to vitronectin. Cleavage and inactivation of PAI-1 by MMP-3 may thus constitute a mechanism decreasing the antiproteolytic activity of PAI-1 and impairing the potential inhibitory effect of vitronectin-bound PAI-1 on cell adhesion and/or migration. These molecular interactions of MMP-3 with enzymes, substrates and inhibitors of the fibrinolytic system may thus play a role in the regulation of (cellular) fibrinolysis. Furthermore, the temporal and topographic expression pattern of MMP components, as well as studies in gene-deficient mice, suggest a functional role in neointima formation after vascular injury.
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“On the other hand, ECM biomaterials are recognized by surrounding cells, and, gradually degraded by proteolytic enzymes, mainly matrix metalloproteinases (i.e., MMP-1, MMP-8, MMP-3, MMP-9) [55,56].”
From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [56]
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Metadata
- Authors
- Lijnen, H. R.
- Affiliations
- KU Leuven (BE)
- Corresponding author
- Lijnen, H. R.
- Venue
- Biochemistry (Moscow)
- Published
- 2002-01
- Volume
- 67
- Issue
- 1
- Pages
- 92-98
- ISSN
- 0006-2979 (ISSN-L)
- 1608-3040
- OpenAlex
- W2133896679
- Cited by
- 167
- References
- 49
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 6
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemistry (Moscow) (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- matrix metalloproteinases, MMP-3, stromelysin-1, fibrinolysis, plasminogen, urokinase, angiostatin, alpha2-antiplasmin, plasminogen activator inhibitor-1, vitronectin, plasminogen activation, plasmin, cell adhesion, cell migration, matrix metalloproteinase inhibitors
- MeSH terms
- Animals, alpha-2-Antiplasmin, Cell Movement, Dose-Response Relationship, Drug, Fibrinolysis, Humans, Hydrolysis, Models, Biological, Muscle, Smooth, Plasminogen, Down-Regulation, Plasminogen Activator Inhibitor 1, Protein Structure, Tertiary, Vitronectin, Matrix Metalloproteinase 3, Matrix Metalloproteinases
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