Figure 1.
Extracellular matrix (ECM) remodeling upon oxidative stress and DNA damage. (A) The ECM is composed of various molecules, such as extracellular glycoproteins (e.g., collagens, fibronectin, and laminins), elastins, proteoglycans, and hyaluronan. These components are in close communication with the cell via transmembrane proteins (e.g., integrins, syndecans, and dystroglycan) that anchor different ECM components to the cell, activating various signal transduction cascades. Specific tissues have specialized ECMs and cell surface receptors, as can be observed for skeletal muscle, where the dystrophin-glycoprotein complex anchors laminins and links them to the actin cytoskeleton via dystrophin. ECM remodeling is carried out through the action of metalloproteinases (MMPs) and lysyl oxidase (LOX). (B) ECM remodeling can be promoted by oxidative stress. In the presence of increased reactive oxygen species (ROS) levels [e.g., diabetes, high H2O2, hypochlorous acid (HOCl), or HOCl-modified fibronectin], some ECM genes become more highly expressed, such as fibronectin (FN1), collagen α1 chain (COL1A1), and laminin α1 chain (LAMA1), while others show decreased expression, as observed for laminin β2 chain (LAMB2). The exact mechanism(s) by which oxidative stress induces expression of ECM genes remains to be fully uncovered. The role of oxidative stress is also revealed by treatment with antioxidants where reduction in the levels of ROS normalizes ECM composition. (C) DNA damage (represented as a yellow electric ray symbol on top of double stranded DNA) is another insult that triggers changes in the ECM. The DNA damage responsive protein p53 has been implicated in the downregulation of FN1 expression, promoting cell motility and suppressing apoptosis. Another important player in this context is p21. This negative regulator of the cell cycle has been shown to induce COL1A1 expression and consequently lead to collagen deposition and fibrosis. The transcription factor p73, a p53 family member, is also a key protein in ECM remodeling in the response to DNA damage. Upon activation, p73 has been demonstrated to directly promote the transcription of ITGB4, encoding integrin β4, and consequently promoting cell adhesion. For simplicity, not all ECM components are shown in the figures, just the ones that are relevant to illustrate the phenomenon being highlighted.