Regulation of matrix biology by matrix metalloproteinases
Introduction
The extracellular matrix (ECM) is composed of a complex mixture of insoluble molecules including collagens, laminins, fibronectin, entactin/nidogen and heparan sulfate proteoglycans. The ECM not only provides a solid-state support for cells, it also acts a reservoir for embedded cytokines and growth factors and harbors cryptic information within molecules that make up the ECM network. ECM receptors at the cell surface provide outside-in signals for cells to sense their microenvironment and react to stimuli 1., 2., 3., 4.. Thus, the state of macromolecules within the ECM is of critical importance and proteolysis is a major factor leading to changes in the ECM. Proteolysis can affect the adherence of cells to the ECM as well as releasing bioactive fragments, sequestered growth factors and cytokines 5., 6.•, 7..
Because matrix metalloproteinases (MMPs) degrade all the components of the ECM, they have been extensively studied in the context of modulating matrix function. MMPs belong to the metzincin superfamily of metalloproteinases, which also includes astacins, ADAMs (a protein with a disintegrin and metalloprotease domain) and ADAM-TS (an ADAM with a thrombospondin-like motif) proteases [8]. Because of the similarity in their metalloproteinase domains, there is potential for functional overlap within the MMP family as well as overlap between other metalloproteinase families. The importance of MMP in the regulation of ECM homeostasis in humans has been demonstrated by the discovery of mutations in the MMP-2 (gelatinase A) gene [9]. Individuals with these mutations manifest a disorder involving characteristic facial features, lytic bone lesions, arthritis and subcutaneous nodules. Interestingly, these features are not present in the MMP-2-null mouse; however, some of the same features are observed in the membrane type 1 MMP (MT1-MMP)-null mouse. MT1-MMP is a known activator of MMP-2, suggesting that in different species a deficiency in either of these enzymes can lead to a common pathology. The specific biochemical and physiological mechanisms of this disorder are not clear. However, it has been postulated that the balance of MMP activity has been tipped in such a way as to interfere with the release of growth factors or disrupt ECM maintenance [10]. Thus, it is important to expand our knowledge of how MMP activity regulates matrix biology and cellular behavior. This review highlights some specific instances where MMPs have been shown to participate in the regulation of matrix biology.
Section snippets
MMPs release cryptic fragments and neo-epitopes from ECM macromolecules
Fragments of ECM molecules have been studied for some time. In some instances this has been for practical reasons associated with the large insoluble nature of the molecules. However, ECM fragments were found to have bioactivities that the parent molecules do not. Furthermore, the presence of some of these fragments in medium conditioned by cells or in bodily fluids suggests that they have physiological and/or pathological functions and that they are released by ECM proteolysis in vivo. Because
MMPs release growth factors
Not only does the ECM contain cryptic information released by proteolysis, it also acts as a reservoir for latent growth factors and cytokines (Figure 2). Release and activation of the embedded growth factors depends on proteolysis. Vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGFβ) represent two examples of such factors that are stored within the ECM and can be released by MMP proteolysis.
VEGF is an important factor in the process of angiogenesis because it
MMPs modify the cell–ECM interface
Even though ADAMs are considered the major sheddases, MMPs also cleave molecules present at the cell–ECM interface that can alter cellular attachment to the ECM. Dystroglycan is the core protein of the dystrophin–glycoprotein complex and links the intracellular cytoskeleton to the ECM. β-Dystroglycan is the transmembrane component that interacts with cytoskeletal proteins and anchors α-dystroglycan to the cell surface. α-Dystroglycan binds the extracellular region of β-dystroglycan and ECM
New tools of the trade
For a complete understanding of MMP regulation of the ECM, new reagents will be required. Mouse models that exploit the deletion or over-expression of MMPs or their inhibitors have been indispensable for the characterization of MMP function in specific tissues and during pathological challenges. However, novel tools will be invaluable for understanding mechanisms of MMP regulation of ECM biology. For example a transgenic mouse carrying a mutated collagen α1 gene coding for resistance to
Conclusions
The ECM is no longer thought of as just a passive physical support for cells. Rather, it is now realized that the ECM contains cryptic information that influences cellular behavior. Furthermore, MMPs specifically cleave both ECM and non-ECM molecules in order to release this hidden information from the ECM in a functional manner. MMPs also assist in maintaining ECM molecules in their appropriate condition. A recently published study illustrates this concept. Although levels of the mRNA for
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from the NIH (AR46238, DE13058 and CA88858).
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