Extrazelluläre Matrix - von der Grundlagenforschung zur klinischen Bedeutung

Zusammenfassung

Matrix Metalloproteinasen (MMPs) hydrolysieren nahezu alle Komponenten der extrazellulären Matrix (ECM). Diese Proteinasen spielen eine zentrale Rolle in vielen biologischen Prozessen wie der Embryogenese, dem „Tissue remodeling”, der Wundheilung und der Angiogenese. Bisher sind die Gene von 26 MMPs identifiziert. Die meisten sind zinkbindende Endopeptidasen aus mehreren Domänen. Neue Erkenntnisse über die dreidimensionale Struktur verbessern das Verständnis über die funktionellen Eigenschaften der MMPs. Im gesunden Gewebe ist die proteolytische Aktivität der MMPs zum Erhalt der Homöostase innerhalb der ECM unter anderem durch endogene MMP-Inhibitoren (TIMPs) reguliert. Eine Störung dieser Balance ist mit schweren Erkrankungen wie Fibrose, Arthritis und malignen Tumoren assoziiert. Zahlreiche Studien der letzten Jahre haben die Bedeutung der MMPs für Tumorentstehung, -wachstum, -migration, -Angiogenese sowie Invasion und Metastasierung belegt. Bestimmte MMPs wie die Gelatinasen (MMP-2 und MMP-9) haben spezielle Mechanismen, die eine Expression an der Tumorinvasionsfront ermöglichen. MMPs können nicht länger als reine Destruktoren der ECM betrachtet werden, sondern sind Teil eines komplizierten Kommunikationssystems, durch das Epithelzellen und Tumorzellen mit dem Stroma interagieren.

Summary

Matrix metalloproteinases (MMPs) hydrolyze most components of the extracellular matrix (ECM). These proteinases play a central role in many biological processes such as normal tissue remodeling, embryogenesis, wound healing and angiogenesis. Currently about 26 MMP genes have been identified, and most are multidomain zinc endopeptidases. Knowledge of their tertiary structure is crucial for the understanding of the functional properties of MMPs. In healthy tissue a strict regulation of MMPs is critical in order to maintain proper ECM homeostasis. Among other levels of regulation, MMPs are precisely regulated by their main endogenous protein inhibitors (TIMPs). Disruption of this balance results in serious diseases such as fibrosis, arthritis, and tumour growth. Several studies have documented the importance of MMP-mediated ECM destruction for tumour initiation, growth, migration, angiogenesis, invasion and metastasis. Certain MMPs such as gelatinases (MMP-2, MMP-9) have special mechanisms to localize at leading edges in tumour tissue. MMPs can no longer be thought of solely as ECM destructionists, but as part of an elegant communication system through which epithelial and tumor cells interact with the stroma.

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