The matrix metalloproteinases (MMP) are a group of zinc dependent enzymes (endopeptidases) which degrade varying components of the extracellular matrix in both normal and diseased tissue. Some of the functions are summarized in the table below.
ROLE OF MMP IN PHYSIOLOGIC AND PATHOLOGIC PROCESS CHARACTERIZATION Embryogenesis and development Controlled proteolytic activity and extracellular matrix remodelling occurs during implantation and normal embryonic development Acute wound healing
MMP1 and MMP10 are expressed by basal keratinocytes at the migrating wound front
MMP3 is expressed by distinct group of keratinocytes behind this migrating front
Cancer and metastasis
MMP7 may play a role in tumor progression and has been demonstrated in cancers of the colon, pancreas, transitional cell carcinomas of the kidney, and small cell carcinomas of the lung
MMP may contribute to tumor growth by facilitating development of angiogenesis allowing extravasation of tumor cells-may involve MMP1, 2, 9, and MT1-MMP with serine proteases
In basal cell carcinoma, MMP1, 2, 9, 11 protein and mRNA have been demonstrated in stromal cells adjacent to the tumor
Invasive squamous cell carcinomas are associated with expression of MMP 1 and 10
J Biol Chem 1999;274:21056-21062
Melanoma has been associated with MMP-2 with expression associated with the degree of cellular atypia-also highly invasive melanoma cell lines produce significantly lower amounts of TIMP-2 than do lesser invasive ones, suggesting more proteolytic activity in the invasive cells
Chronic wounds MMP 1 and 3 are in higher levels Bullous diseases Bullous pemphigoid shows distinct expression profile with MMP9 mRNA limited to eosinophils and capable of cleaving the extracellular portion of the 180 kd BP autoantigen Noninfectious granulomatous disease Sarcoidosis, granuloma annulare, and necrobiosis lipoidica show similar profile of MMP9 and 12
MMP2 localized to stromal fibroblasts
Photodamage Increased MMP1,3,7,9, and 12 have been found in sun-exposed skin Contact hypersensitivity MMP 3 necessary for initiation of the response and MMP 9 required to clear the eruption
The families of MMP are continually being catalogued. The following compilation is the most recent classification.
MMP OTHER NAMES 1 Collagenase 1, interstitial collagenase 2 Gelatinase A, 72kD gelatinase 3 Stromelysin 1 7 Matrilysin, PUMP 8 Collagenase 2, neutropil collagenase 9 Gelatinase B, 92kD gelatinase 10 Stromelysin 2 11 Stromelysin 3 12 Macrophage metalloelastase 13 Collagenase 3 14 MT1-MMP 15 MT2-MMP 16 MT3-MMP 17 MT4-MMP 18 Collagenase 4 19 No other name 20 Enamelysin 21 XMMP 22 CMMP 23 No other name
MPPs are not constitutively expressed. The activity of MMP is regulated by the following:
Gene expression via cytokines, growth factors, and cell-cell and cell-matrix interactions
Activation of the proenzyme or zymogen form
Natural inhibitors including tissue metalloproteinase inhibitors (TIMPs)
There is a tightly regulated balance between these enzymes and inhibitors. Disease processes result when this balance goes awry. Recently synthetic inhibitors are in clinical trials as possible anti-cancer agents.
TISSUE INHIBITORS OF METALLOPROTEINASES CHARACTERIZATION TIMP-1 TIMP-2 TIMP-3 750 kd protein 16.5 kd protein Marimastat (BP-2516) Synthetic inhibitor
Currently in trial as an anti-angiogenic agent
Primomastat (AG3340) Synthetic inhibitor
Specific inhibitor of MMP2, 13, and MT-MMP
Adv Dermatol 2000;16:185-208
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