Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix.

The extracellular matrix is often viewed as the scaffolding that supports the cellular elements of various tissues. It is now recognized that in addition to their structural functions, the components of the extracellular matrix serve as modulators of cell growth and tissue differentiation.1,2 As these processes occur they in turn can influence matrix composition, and may lead to the formation of specialized extracellular matrix structures such as basement membranes. Tissue differentiation results in a changing dynamic between the cellular and stromal matrix elements. Changes in matrix composition requires the removal of the previous extracellular components. This is accomplished through the action of proteases, which selectively degrade matrix macromolecules and may alter cell-matrix attachments.3 The components of the new matrix are organized and assembled as this process proceeds. Both matrix removal and synthesis occur simultaneously in an orderly and progressive fashion. The end stage of differentiation is a homeostasis between new matrix formation and matrix turnover. Again, this occurs in a balanced fashion such that there is preservation of matrix function and no gross change in matrix composition. Tissue involvement with various pathological conditions results in alterations of both the cellular and matrix elements. In the pathological state the normal homeostasis between the cellular elements and the surrounding stromal matrix is disrupted. This may cause alterations in the distribution, composition, and function of the extracellular matrix that are evident in many pathological conditions. Frequently, the dynamic nature of this balance in the pathological state is not appreciated. Where there is either tissue fibrosis or tissue destruction, we tend to view these disease processes as either excessive production of matrix components or enhanced proteolytic turnover of normal stromal matrix proteins. The study by Gunja-Smith and colleagues4 in the current issue of TheAmerican Journal ofPathology addresses some of these concepts by providing evidence that changes in the myocardium associated with idiopathic dilated cardiomyopathy consist of both enhanced collagen content as well as an increase in the activity of matrix-degrading proteases, and that both may contribute to subtle changes in matrix composition. Together these changes have a devastating effect on matrix function that results in cardiac failure. The results of their studies support the view that pathological changes in the extracellular matrix are a disturbance in the dynamic balance of matrix synthesis and turnover. To facilitate a full appreciation of these findings, will provide a brief overview of stromal matrix turnover as mediated by neutral metalloproteinases known as matrix metalloproteinases and discuss the findings of Gunja-Smith et al in relation to the dynamics of extracellular matrix remodeling. Turnover of the extracellular matrix is a unique biological problem because of the high collagen content of most extracellular matrix structures and the resistance of these triple helical molecules to the action of most proteases. We now know that connective tissue remodeling, either physiological or pathological, is in most cases a highly organized process that involves the selective action of a group of related proteases that are active at neutral pH and collectively can degrade most, if not all, components of the extracellular matrix. These proteases are known as