Matrix Metalloproteinases (MMPs) (2023)

First printed in R&D Systems' 1999 Catalog.

(Video) Matrix metalloproteinases


The MMP family of enzymes contributes to both normal and pathological tissue remodeling. MMPs play a key role in the migration of normal and malignant cells through the body. They also act as regulatory molecules, both by functioning in enzyme cascades and by processing matrix proteins, cytokines, growth factors and adhesion molecules to generate fragments with enhanced or reduced biological effects.

Domain Structure & Function

Matrix Metalloproteinases (MMPs) (1)
Figure 1. MMPs can facilitate tumor cell metastasis and angiogenesis. Adapted from Opdenakker, G. & J. Van Damme (1992) Cytokine 4:251.

The matrix metalloproteinases (MMPs) are members of a family of at least 15 Zn-dependent endopeptidases that function extracellularly (Table 1).1 The MMPs each contain a protease domain that has a conserved HExGHxxGxxHS/T sequence in which the three Histidine residues form a complex with a catalytic Zn atom. In addition, all MMPs contain a regulatory domain (pro-piece) with a conserved PRCGxPD motif that is responsible for maintaining latency in MMPs via binding of the cysteine residue to the active site Zn. The simplest MMP is MMP-7 (matrilysin), which consists of a pro-piece and catalytic domain only. The other MMPs maintain this basic unit but have a variable number of structural domains added. Although most MMPs are secreted proteins, the recently described membrane-type MMPs (MT-MMPs) are anchored to the cell membrane by a transmembrane and intracytoplasmic domain. X-ray crystallography has shown that the catalytic domains of the different MMPs have similar structure, but the topology of the active site clefts differs, accounting for some of the differences in substrate specificities. Differences in the other domains confers further substrate specificity, regulates binding to matrix proteins, and determines interactions with the Tissue Inhibitors of Metalloproteinases (TIMPs), the natural inhibitors of MMP activity.2

(Video) Effects of proteinases with metalloproteinase domains (MMPs, ADAMs) on tumour progression

Substrates & Nomenclature

Much of the early literature suggested that each MMP had its own particular substrate.1 This concept led to the use of substrate-focused nomenclature for MMPs such that the collagenases broke down intact fibrillar collagens, gelatinases degraded denatured collagen, and metalloelastase attacked elastin. It is now recognized that MMPs usually degrade multiple substrates, with considerable substrate overlap between individual MMPs. For example, interstitial collagenase (MMP-1) is capable of degrading casein, gelatin, a-1 antitrypsin, myelin basic protein, L-Selectin, pro-TNF and IL-1 beta and pro-MMP-2 and -9. 72-kDa gelatinase (MMP-2) can degrade fibrillar collagen, elastin, IGF-binding proteins, FGF receptor and can activate MMP-1, -9 and -13. MMP-12 is highly active against type IV collagen, gelatin, fibronectin, vitronectin and plasminogen, but it is not very effective at degrading elastin. See Table 1 for a list of substrates that can be cleaved by purified MMPs in vitro.

In an attempt to break the link between name and function, all MMPs are now given an MMP number, such that Interstitial collagenase is MMP-1, etc. (Table 1). There are holes in this system. There is no MMP-4, -5 or -6, as the activities could not be ascribed to a specific gene product, and MMP-18 is known only as a Xenopus enzyme. As with all other enzymes, MMPs have an EC classification, although this lags well behind the MMP designation.

(Video) MMP & TIMPs in Skincare | Professional Skincare Training

Table 1. MMP Facts.
MMPAlternative NamesEC NumberChromosomeSubstrates
  • Collagenase
  • Fibroblast Collagenase
  • Interstitial Collagenase
EC3.4.24.711q22-q23Collagens (I, II, III, VII, VIII and X)17, 18; Gelatin; aggrecan19; hyaluronidase-treated versican20; proteoglycan link protein21; large tenascin-C22; a1-antitrypsin/a1-proteinase inhibitor (a1-AT)23-25; a1-antichymotrypsin (a1-ACHYM)24, 25; a2M; rat a1M; pregnancy zone protein; rat a1I3 (a1-inhibitor 3); ovostatin; entactin (nidogen)26; MBP27; GST-TNF/TNF peptide28; L-Selectin29; IL-1ß30; serum amyloid A; IGF-BP532; IGF-BP333; MMP-234; MMP-920
  • 72 kDa Gelatinase
  • Gelatinase A
  • Type IV Collagenase
  • Neutrophil Gelatinase
EC3.4.24.2416q13Collagens (I49, IV50, V, VII, X17, XI and XIV51); Gelatin; elastin50, 52; fibronectin; laminin-1, laminin-553; galectin-354; aggrecan45; decorin55; hyaluronidase-treated versican20; proteoglycan link protein21; osteonectin48; MBP27; GST-TNF/TNF peptide28; IL-1ß56; Aß1-4056, 57v; Ab10-2058; APP69559; a1-AT25; prolysyl oxidase fusion protein60; IGF-BP532; IGF-BP333; FGF R161; MMP-134; MMP-962; MMP-1363
  • Stromelysin-1
  • Transin
EC3.4.24.1711q23Collagens (III, IV50, V, IX); Gelatin; aggrecan19, 66; versican and hyaluronidase-treated versican20; perlecan46; decorin55; proteoglycan link protein21; large tenascin-C23; fibronectin; laminin; entactin26, 67; osteonectin48; elastin40; casein68; a1-AT23, 25; a1-ACHYM25; antithrombin-III2525; a2M; ovostatin; Substance P; MBP27; GST-TNF/TNF peptide28; IL-1ß30; serum amyloid A31; IGF-binding protein-333; fibrinogen and cross-linked fibrin69; plasminogen70; MMP-1 “superactivation”71; MMP-2/TIMP-2 complex72; MMP-773; MMP-874; MMP-975; MMP-1343
  • Matrilysin
  • PUMP
EC3.4.24.2311q21-q22Collagen IV82, 50 and X18; Gelatin82; aggrecan19; decorin55; proteoglycan link protein21; fibronectin and laminin82; insoluble fibronectin fibrils83; entactin26; large and small tenascin-C84; osteonectin48; ß4 intergrin85; elastin50; casein82; transferrin86; MBP27; a1-AT23; GST-TNF/TNF peptide28; plasminogen65; MMP-173; MMP-287; MMP-973, 35, 88; MMP-9/TIMP-1 complex88
  • Neutrophil Collagenase
  • Collagenase I
EC3.4.24.3411q21-q22Collagens (I, II, III, V36, VII, VIII and X); Gelatin; aggrecan37, 38; a1-AT39; a1-ACHYM16; a2-antiplasmin40; fibronectin41
  • 92 kDa Gelatinase
  • Gelatinase B
EC3.4.24.3520q11.2-q13.1Collagens (IV50, V36, VII, X17 and XIV51); Gelatin; elastin50, 52; galectin-354; aggrecan19; hyaluronidase-treated versican20; proteoglycan link protein21; fibronectin31; entactin26; osteonectin48; a1-AT23, 24; MBP27; GST-TNF/TNF peptide28; IL-1ß30; Aß1-4064; plasminogen65
  • Stromelysin-2
EC3.4.24.2211q22.3-q23Collagens (III76, IV77, 50 and V76); Gelatin74; casein68, 76; aggrecan66; elastin50; proteoglycan link protein21; MMP-168; MMP-877
  • Stromelysin-3
22q11.2Human enzyme: a1-AT78; a2M79; casein79; IGF-binding protein-180; Mouse enzyme: a1-AT78; casein, laminin, fibronectin, gelatin, collagen IV and carboxymethylated transferrin81
  • Macrophage Metalloelastase
11q22.2-q22.3Collagen IV89; Gelatin89; elastin and k-elastin60, 90; casein91; a1-AT89, 92; fibronectin89; vitronectin89; laminin89; entactin93; proteoglycan monomer89, 77, 94; GST-TNF89; MBP89; fibrinogen94; fibrin95; plasminogen96
  • Collagenase-3
11q22.3Collagens (I, II and III42, 43, IV, IX, X and XIV44); Gelatin, a1-ACHYM and plasminogen activator inhibitor 244; aggrecan45; perlecan46; large tenascin-C and fibronectin44; osteonectin47; MMP-948
  • MT-MMP-1
14q11-q12Collagen (I, II and III97, 98); Gelatin, casein, k-elastin, fibronectin, laminin, vitronectin and proteoglycans97-99; large tenascin-C, entactin98; a1-AT, a2M97; GST-TNF98; MMP-2100, 101; MMP-1363
  • MT-MMP-2
16q12.2-q21Fibronectin, large tenascin-C, entactin, laminin, aggrecan, perlecan98; GST-TNF98; MMP-2102, 103
  • MT-MMP-3
8q21Collagen III104; Gelatin, casein105; fibronectin; MMP-2102, 103
  • MT-MMP-4
MMP-19<12q14Gelatin107*, 108
  • Enamelysin
* assigned as MMP-18 in reference 107. MMP-18 has, however, subsequently been assigned as xenopus MMP

Role in Physiology and Pathology

Although the link between single MMPs and individual substrates is not as direct as once thought, it is clear that as a family, the MMPs are capable of breaking down any extracellular matrix component (see Table 1). In normal physiology, MMPs produced by connective tissue are thought to contribute to tissue remodeling in development, in the menstrual cycle, and as part of repair processes following tissue damage. The obvious destructive capability of MMPs initially focused most research onto diseases that involve breakdown of the connective tissues (e.g., rheumatoid arthritis, cancer and periodontal disease). Leukocytes, particularly macrophages, are major sources of MMP production. MMPs released by leukocytes play vital roles in allowing leukocytes to extravasate and penetrate tissues, a key event in inflammatory disease. Opdenakker proposed that MMP action not only permits leukocyte emigration into tissues and causes tissue damage, it also generates immunogenic fragments of normal proteins that may escalate autoimmune disease. In an analogous way, metastatic cancer cells also use MMPs to get in and out of tissues and to establish a blood supply (Figure 1).4 Drug companies have synthesized low molecular weight MMP inhibitors that have shown efficacy in models of these diseases, reinforcing their central role in pathology.5

The MMP axis is highly regulated to avoid excessive tissue damage. Most MMPs, with the exception of 72 kDa gelatinase and the MT-MMPs, are not constitutively expressed in normal tissues. Inflammatory cytokines such as IL-1 and TNF, growth factors such as TGF-beta and noxious stimuli are required to initiate transcription. MMPs are also expressed as inactive zymogens (the pro-piece must be dissociated from the catalytic domain before the enzyme is activated). This dissociation can be achieved by autocatalysis or by the action of enzymes such as furin, plasmin or even other MMPs. For example, the activation of pro-MMP-2 occurs at the surface of many cells and is mediated by MT-MMPs. Once activated, MMPs are subject to inactivation by TIMPs and by binding to plasma proteins such as alpha-2 macroglobulin. It is thought that the local balance of MMP expression and activation versus the level of TIMP governs the level of destruction mediated by MMPs. This is of great significance when studying MMP involvement in disease processes.

(Video) Matrix metalloproteases

In order to implicate a particular MMP in a disease, several overlapping approaches have been taken. Each has its advantages and disadvantages (Table 2). Development of a comprehensive picture of MMP involvement in any tissue culture system or in vivo disease model likely would require several of these methods.

Table 2. Methods for studying the involvement of MMPs in desease
Quantitative PCR
  • MMP specific
  • Can measure changes in mRNA for multiple MMPs in small samples
  • High throughput
  • Primers easy to design and test
  • Does not measure protein or activity
  • Can be MMP specific
  • Can localize MMP expression
  • Antibodies can cross react with other MMPs
  • Does not discriminate active and inactive enzyme
  • Labor intensive
  • Low sensitivity
  • MMP specific
  • High throughput of samples
  • MMPs found in blood and tissue fluids
  • High sensitivity possible
  • May crossreact with other MMPs
  • May detect inactive or inhibitor -complexed MMPs
Activity assays
  • Can detect active MMP
  • Can be very sensitive
  • May not be specific for particular MMP
  • Subject to sample interference
Gene knock out in mice
  • MMP specific
  • Costly
  • Requires establishment of disease model in knock out strain
  • Knock out may be compensated for in development
MMP inhibitors in models
  • Direct relevance to therapy
  • MMP specific inhibitors have not yet been described

The MMP/Cytokine Connection

Matrix Metalloproteinases (MMPs) (2)
Figure 2. The MMP/Cytokine Connection

The MMP axis has several areas of overlap with the cytokine network. As described above, inflammatory cytokines or growth factors can regulate the expression of MMPs. Cytokine activation of cells can also lead to increased processing of MMPs from the inactive zymogens to the active enzymes. Cytokines and their receptors can also be substrates for MMP action (Figure 2). Pro-inflammatory cytokine IL-1 beta can be cleaved and inactivated by MMP-1, -2, -3, and -9.9 In addition, the degradation of matrix proteins such as decorin can liberate growth factors such as TGF-beta that are sequestered on the matrix.10 Many membrane-bound cytokines, receptors and adhesion molecules can be released from the cell surface by the action of metalloproteinases, referred to as sheddases or convertases.11, 12 This may down regulate cell surface signaling by removal of a receptor or extend the sphere of influence of a molecule by release of a soluble active form. The consequences of this will depend on the molecule. For example, soluble TNF cleaved from the cell surface is pro-inflammatory, whereas TNF receptors cleaved from a cell act as soluble TNF inhibitors. In contrast, the cleaved soluble IL-6 receptor acts to stabilize IL-6 and the complex acts as an IL-6 agonist.

(Video) Effects of proteinases with metalloproteinase domains (MMPs, ADAMs) on tumour progression HD

Although classical MMPs can process many of these cell surface molecules, members of the reprolysin or adamalysin clan of metalloenzymes may contribute much of the sheddase or convertase activity at the cell membrane. These enzymes have a catalytic site similar to that of the MMPs, but they have a different domain structure. The best characterized enzyme is the TNF-alpha converting enzyme (TACE or ADAM-17).13-14 This enzyme was initially isolated from cell membranes using a TNF substrate assay to follow purification. Combined inhibitors of MMP and sheddase activity have been produced. They are active in models of inflammatory diseases, such as multiple sclerosis, where a cytokine drive has been implicated.15


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(Video) MMPs - A surprising ingredient in healthy wound repair


What is a normal MMP-9 level? ›

The normal range of plasma MMP-9 concentration was determined to be 11.4–59.4 ng/ml.

What does high MMP mean? ›

Notably, high levels of MMP-9 have been associated with plaque progression, destability and rupture. These various effects exaggerate the inflammatory process, promoting atherosclerosis and increasing the risk of atherothrombosis and cardiovascular (CV) events.

What can trigger high levels of matrix metalloproteinases? ›

Serum levels of MMPs are known to be altered in many human pathologic conditions. Elevated serum levels of MMPs have been reported in, for example, polycystic kidney disease (19), systemic sclerosis (20), rheumatoid arthritis (21), and cancer.

What does matrix metalloproteinases do to the skin? ›

UV radiation increases the expression of matrix metalloproteinases (MMPs) in human skin. MMPs are responsible for degrading the extracellular matrix (ECM) proteins such as collagen, fibronectin, elastin, and proteoglycans, contributing to photoaging [3,4].

What is MMP in inflammation? ›

Matrix metalloproteinases (MMPs), well-known inflammatory mediators are a family of zinc-dependent proteolytic enzymes that degrade various components of ECM and non-ECM molecules mediating tissue remodeling in both physiological and pathological processes.

What is MMP in rheumatoid arthritis? ›

Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce matrix-degrading enzymes, including MMPs, which facilitate cartilage destruction in the affected joints in RA.

How do I lower my MMP-9? ›

In the present study, we demonstrated that EPA and DHA were able to decrease MMP-9 protein levels and activity at relatively low concentrations. Incubation of PBMC from healthy controls with DHA and EPA at 50 μg/mL reduced MMP-9 levels to non-detectable levels and reduced MMP-9 activity by 51% and 69%, respectively.

How do I inhibit MMP? ›

One mechanism to inhibit MMP activity is by dislodging the enzymes from their receptors. Gold salts bind to a heavy metal site distinct form the zinc-containing active center, which inhibits their activity. MMP activity can be decreased by binding to the cleavage site on the substrate e.g. catechin.

What inhibits matrix metalloproteinases? ›

Batimastat (BB-94) and marimastat (BB-2516) are synthetic, low-molecular weight MMP inhibitors. They have a collagen-mimicking hydroxamate structure, which facilitates chelation of the zinc ion in the active site of the MMPs. These compounds inhibit MMPs potently and specifically.

What does MMP do to collagen? ›

MMP-2 digests solubilized monomers of collagens I, II, and III [13–15]. MMP-9 digests solubilized collagen I and III monomers [16].

What is MMP in wound healing? ›

Significance: Matrix metalloproteinases (MMPs) are present in both acute and chronic wounds. They play a pivotal role, with their inhibitors, in regulating extracellular matrix degradation and deposition that is essential for wound reepithelialization.

What does matrix do to your body? ›

The Matrix is the buffer zone for all types of stress including physical stress, chemical stress, electromagnetic stress and psychological stress. It can protect the body from the toxic effects of stress if it is not already full of toxins. An overburdened matrix becomes deregulated and inflamed.

Is MMP a tumor suppressor? ›

Functional analysis of the identified mutations has confirmed that all of them lead to the loss-of-function of MMP8 and enhance the progression of melanoma, thus providing definitive evidence that MMP8 is a tumor-suppressor gene.

What is the difference between PMR and rheumatoid arthritis? ›

Classically, RA involves the small joints of the hands and feet but also frequently involves the knees, wrists, and ankles. PMR typically involves the neck, shoulders, and hips and never involves the feet.

Does MMP-13 enzyme cause neuropathy? ›

We previously reported that MMP-13 activity also underlies paclitaxel(chemotherapy)-induced peripheral neuropathy where it is upregulated specifically in the epidermis.

Does MMP degrade collagen? ›

The main group of enzymes responsible for the collagen and other protein degradation in extracellular matrix (ECM) are matrix metalloproteinases (MMPs).

Is MMP-9 Pro inflammatory? ›

MMP9 is a known mediator of inflammation and plays a role in fracture repair [3, 29]. The profile of inflammatory cell recruitment differed between Mmp9-/- and wild type mice and changes were mostly observed for macrophages and CD4 T cells between genotypes (p<0.001).

What activates MMP-9? ›

Activation of MMP-9 requires a disruption of the cysteine interaction with the zinc atom thus exposing the catalytic site [13]. The most studied mechanism of MMP-9 activation is enzyme proteolysis of the pro-domain.

How can I reduce MMP-13 naturally? ›

Both of curcumin and rosmarinic acid exhibited excellent MMP-13 inhibitory activity (IC50: 3.6 and 2.9 μM, respectively). The results indicate that curcumin and rosmarinic acid might be potent MMP-13 natural inhibitors.

Does doxycycline inhibit MMPs? ›

Background/aims: Doxycycline is a broad spectrum anti- biotic that chelates metal ions and is frequently used as part of the treatment of ocular surface diseases. Its therapeutic value has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and IL-1 synthesis.

What activates matrix metalloproteinases? ›

The MMP activation by reactive oxygen is driven through preferential oxidation of the thiol–zinc interaction and autocatalytic cleavage, followed by enzyme inactivation with extended exposure by modification of amino acids critical for catalytic activity, as shown in vitro for MMP-7 [30].

Do malignant cells produce metalloproteinases? ›

MMPs are mainly produced by nonmalignant stromal cells in malignant tumors. Tumor cells also secrete factors, such as extracellular MMP inducer (EMMPRIN), which enhance the expression of MMPs by stromal fibroblasts (see Toole, in this book).

What is the role of MMPs in periodontitis? ›

MMPs participate in morphogenesis, physiological tissue turnover, and pathological tissue destruction. Alterations in the regulation of MMP activity are implicated in the manifestation of oral diseases, and MMPs comprise the most important pathway in tissue destruction associated with periodontal disease.

Where are MMPs secreted? ›

MMPs are produced by multiple tissues and cells (Table 1). MMPs are secreted by connective tissue, pro-inflammatory, and uteroplacental cells including fibroblasts, osteoblasts, endothelial cells, vascular smooth muscle (VSM), macrophages, neutrophils, lymphocytes, and cytotrophoblasts.

How long does it take to see results after starting a collagen supplement? ›

As such, no matter your goal for using collagen, it will take at least 8 weeks to experience noticeable results ( 6 ). Most studies use a minimum of 8 weeks to assess collagen's effects on skin health and joint pain relief, but other studies use longer periods, such as 12 months, for bone health ( 9 , 14 , 22 ).

What accelerates collagen loss? ›

The collagen tissues support the formation of bones, tendons, and cartilage that form depending on the level of mineralization. However, an individual can lose collagen components in the body due to exposure to ultraviolet light, tobacco, excessive intake of sugar, and aging.

Does MSM increase collagen production? ›

Increased Collagen Production

MSM plays a major part in the body's ability to produce collagen. As an essential ingredient in tissue to hold the human body together, collagen provides structural support and impacts the flexibility and resilience of skin.

What does MMP-9 test for? ›

Additional Information. MMP-9 is a marker of inflammation, tissue remodeling, wound healing, and mobilization of tissue-bound growth factors and cytokines.

What is MMP-9 biomarker? ›

MMP-9 has been found to be a potential biomarker for several cancers [84,85,86,87,88]. It could be explored as a biomarker in fields, such as diagnosis, treatment efficacy monitoring and disease progression monitoring. Cancer biomarker represents one promising application of MMP-9 research.


1. Effects of proteinases with metalloproteinase domains (MMPs, ADAMs) on tumour progression HD
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5. Detection: Functional Matrix Metalloproteinases By Zymography l Protocol Preview
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6. Matrix Metalloproteinase vs Flower Power
(Dr. Grandel USA Northeast / VIVARI Corp)
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