Collagenases and tissue inhibitors of metalloproteinases: a functional balance in tissue degradation

Abstract

Members of the family of matrix metalloproteinases (MMPs; also called collagenases or matrixins) are key enzymes in matrix degradation. They function at neutral pH and can digest synergistically all the matrix macromolecules. Biochemical and clonal studies indicate that there are three major groups: the specific collagenases cleave interstitial collagens; the gelatinases degrade types IV, V, VII and XI collagens and act synergistically with collagenases by degrading denatured collagens (gelatins); and the stromelysins have broader specificity and can degrade basement membrane collagens as well as proteoglycans and matrix glycoproteins. Others not in these groups are matrilysin, metalloelastase and a recently cloned membrane-bound metalloproteinase. MMPs are Zn(2+)- and Ca(2+)-requiring endopeptidases and are secreted in a latent proform: activation involves the loss of a propeptide. Naturally occurring inhibitors, TIMPs (Tissue Inhibitors of MetalloProteinases), are important controlling factors in the actions of MMPs, and tissue destruction in disease processes often correlates with an imbalance of MMPs over TIMPs. The major inhibitor is TIMP-1 (or TIMP), a 30-kDa glycoprotein that is synthesised by most cells. A second unglycosylated inhibitor, TIMP-2, which is less abundant, has the interesting property of binding to the proform of gelatinase A and is involved in controlling its activation. The expression of MMPs and TIMPs by cells is regulated by many cytokines (particularly interleukin-1, IL-1), growth factors and hormones, some of which are specific to cell type and others that are ubiquitous (eg transforming growth factor beta, TGF-beta). Many of these factors are products of monocytes/macrophages and their production in inflammatory situations is therefore part of the chain of events leading to tissue degradation. From many recent studies it seems that tissue destruction, both physiological and pathological, is correlated with an imbalance of inhibitors over proteinases. We proposed that one way in which pathogenic organisms might mediate tissue degradation in periodontal diseases is through the ability of cell wall antigens to stimulate cytokine production by circulating mononuclear cells. These would then induce MMP synthesis by resident gingival cells (or by the mononuclear cells themselves), thereby initiating degradative events. We have identified MMPs in human gingival biopsy specimens by using specific polyclonal antibodies and indirect immunofluorescence. Their distributions are extremely variable, both in the connective tissue and the epithelium, but the results indicate that host cell production of MMPs may contribute to tissue degradation in periodontal disease. TIMP could also be found in some situations and could be a limiting factor.