Extracellular matrix -- from basic research to clinical significance. An overview with special consideration of matrix metalloproteinases

Abstract

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.