Matrix metalloproteinase-8 (MMP-8; called also neutrophil collagenase or collagenase 2) is a member of matrix metalloproteinase family of zinc- and calcium-dependent endo-peptidases responsible for degradation of extracellular matrix. Matrix metalloproteinases (MMPs) possess catalytic properties responsible for tissue remodeling and degradation of structural components of the extracellular matrix (ECM) including collagens, elastins, gelatin, matrix glycoprotein, and proteoglycans.
MMP-8 was first described (as neutrophil collagenase) in 1990 when it was cloned from neutrophils obtained from a patient with granulocytic leukemia. Later observations found MMP-8 mRNA expression in chondrocytes as well as in human rheumatoid synovial fibroblasts, activated macrophages, smooth muscle cells and endothelial cells. The human MMP-8 gene is located on chromosome 11q22.3, residing in a gene cluster that contains several MMP genes. Its expression is inducible and upregulated by various inflammatory cytokines, such as interleukin-1β, tumour necrosis factor-α, and CD40 ligand. The MMP-8 protein consists of a signal peptide, a propeptide, a catalytic domain, a hinge region, and a hemopexin-like C-terminal domain. The mature MMP-8 enzyme is 64 kDa in size, with glycosylation increasing the size to 75 kDa. Autoproteolytic degradation has been described, yielding a 40-kDa fragment, which retains catalytic activity but does not cleave fibrillar collagen. MMP-8 can be proteolytically activated also by stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and by matrilysin-1 (MMP-7).
PMN-derived MMP-8 is expressed during the myelocyte stage of development of polymorphonuclear (PMN) precursors in the bone marrow, and it is stored as a latent enzyme (pro-MMP-8) within the specific granules of polymorphonuclear cells. Pro-MMP-8 is rapidly released from activated PMN undergoing degranulation, and is then activated via the cysteine switch mechanism to yield the active form of the enzyme to ensure rapid availability at inflammatory sites. The endogenous MMP inhibitors, TIMPs, can inhibit MMP-8. Therefore, the activity of MMP-8 in a tissue at a given time would be dependent on the relative amounts of its transcriptional stimuli, zymogen activators and enzymatic inhibitors that are present in that tissue at the time.
The best-known substrates of MMP-8 are interstitial collagens (types I-III), the major
structural components of the extracellular matrix, among which MMP-8 has higher proteolytic
activity on types I and III than type II. In addition, MMP-8 can also cleave nonmatrix
proteins such as serpins, bradykinin, angiotensin I, fibrinogen and many other.
As a result of its known catalytic activities, MMP-8 is believed to be involved in wound healing
and tissue remodeling during inflammation. In addition, MMP-8 has been implicated in the
pathogenesis of several chronic inflammatory diseases characterized by excessive influx
and activation of polymorphonuclear cell (PMN), including cystic fibrosis, rheumatoid arthritis,
chronic skin wounds and periodontal disease.
The number of publications investigating the role of MMPs in periodontal disease has been still growing. The imbalance between MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) is considered to trigger the degradation of extracellular matrix, basement membrane, and alveolar bone, and thus to initiate periodontal disease. MMP-8 was found to be the most prevalent MMP in diseased periodontal tissue, oral fluid, gingival
crevicular fluid (GCF) and saliva. Moreover, MMP-8 activity correlates with disease severity . Reduction of MMP activity was shown to reduce periodontitis progression. MMP-8 is apparently a major mediator of this aggressive tissue destruction, although one report indicates a protective role for MMP-8 during periodontal infection.
- References to MMP-8 (Matrix metalloproteinase-8)