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

Abstract

BACKGROUND: 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 gly‐coproteins. Others not in these groups are matrilysin, metalloelastase and a recently cloned membrane‐bound metalloproteinase. MMPs are Zn2+‐ and Ca2+‐requiring endopeptidases and are secreted in a latent proform: activation involves the loss of a propeptide. Naturally occurring inhibitors, TlMPs (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‐I (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. BIOLOGICAL AND PSYCHOLOGICAL IMPLICATIONS: The expression of MMPs and TlMPs by cells is regulated by many cytokines (particularly interleukin‐I, IL‐I), growth factors and hormones, some of which are specific to cell type and others that are ubiquitous (eg transforming growth factor β, TGF‐β). 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 poly‐clonal 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.

Enhancement of gingival inflammation induced by synergism of IL-1^|^beta; and IL-6

“…The evidence for the role of MMPs in periodontal destruction has been reported, and it is now recognized that an imbalance between activated MMPs and their endogenous inhibitors, i.e. tissue inhibitors of MMPs (TIMPs) leads to pathologic breakdown of the extracellular matrix seen in periodontitis (22). Therefore, the imbalance induced by inflammatory cytokines should be important to understand the mechanism of tissue destruction.…”

Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

“…29 In hairless mouse, repetitive UVB exposure has been reported to escalate the degradation of collagens VII and IV by up-regulating MMP-2 and MMP-9 expression. 30,31 In addition to the alterations in the dermal compartment, the changes in several epithelial keratins have been well documented in photoaged skin. In healthy skin, keratins compose up to 85% of a fully differentiated keratinocyte and orderly form the epithelial-specific intermediate filament composed of acidic type I (K9 to K20)-basic type II (K1 to K8) coiled-coil heterodimer in healthy skin.…”

Interleukin-6 Released from Fibroblasts Is Essential for Up-regulation of Matrix Metalloproteinase-1 Expression by U937 Macrophages in Coculture

“…Matrix metalloproteinases (MMPs), 3 a family of proteolytic enzymes that degrade collagen and other matrix proteins including elastin, fibronectin, proteoglycan, and laminin, play an essential role in the periodontal tissue destruction (4,5). MMPs are expressed in inflamed periodontal tissue by inflammatory cells including monocytes, macrophages, lymphocytes, and polymorphonuclear cells and also by resident cells such as fibroblasts, epithelial cells, and endothelial cells (6,7). Lipopolysaccharide (LPS) derived from Gram-negative bacteria, the major pathogens involved in periodontal disease, is a potent stimulator for MMP expression (1).…”