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Matrix Metalloproteinases (MMPs): Multi-Faceted Family of Endopeptidases

Matrix metalloproteinases (MMPs, aka matrixins) are zinc-dependent endopeptidases that are members of the metzincin-superfamily of enzymes. The first MMP (MMP-1) was discovered in tadpoles during embryogenesis (1), hinting at the prominent role that MMPs play in growth and development. Indeed, MMPs are a collection of enzymes that are chiefly responsible for the physiological turnover of extracellular matrix (ECM) and connective tissues in embryogenesis, organogenesis, angiogenesis, and tissue repair/remodeling. While typically found in low amounts in healthy adult tissues, MMP activity can be upregulated in pathologies where turnover of connective tissues and ECM are a defining feature, such as: arthritis (2), chronic allergic asthma (3), cancer (4), nephritis (5), and fibrotic diseases (6). 

All MMPs share two domains: a propeptide domain and an N-terminal catalytic domain containing a Zn2+ ion critical for MMP proteinase activity. Most MMPs also possess a C-terminal hemopexin-like domain that is vital for binding to collagen fibers, although MMP-7, MMP-23, and MMP-26 lack this domain. MMPs released into the extracellular space are typically zymogens, latent enzymes that need to be activated by other enzyme activity. A cysteine residue in the propeptide domain blocks the active site by interacting with the Zn2+ at the active site, rendering the enzyme inactive. Chemical modification or proteolytic removal of the pro-peptide domain by other proteinases, including other MMPs, will activate the MMP molecule. This activation mechanism, called a cysteine switch, is common to almost all MMP molecules identified thus far (7).

A) Basic structure of inactive MMP, showing hemopexin-like domain, pro-domain, and catalytic domain. B) Activated MMP with the pro-domain proteolytically removed. C) TIMP-MMP Complex with the TIMP blocking the Zn2+ ion in the MMP catalytic site.

Figure 1. Typical tertiary structure of soluble MMP showing the A) Inactive pro-MMP (zymogen), containing the pro-domain, B) Active MMP (with the pro-domain enzymatically removed and the Zn2+ ion in the active site exposed), and C) andTIMP complexed with MMP (inactive). 
Image from: T. T. Nguyen, S. Mobashery, M. Chang, Roles of Matrix Metalloproteinases in Cutaneous Wound Healing, Wound Healing - New insights into Ancient Challenges, IntechOpen, DOI: 10.5772/64611

Traditionally, MMPs have been categorized based on their substrate specificities and their form. Membrane-type MMPs (MT-MMP) are incorporated into cell membranes by a transmembrane domain or tethered to cell membranes by a glycosylphosphatidylinositol (GPI)-anchor. Soluble MMPs (collagenases, gelatinases, stromelysins, matrilysins, macrophage elastase) can be found free in the ECM or in cell vesicles where they are stored until stimulated for release. These soluble MMP classifications are based on shared substrate specificities and similarities in their structures:

  • Collagenases (MMP-1, MMP-8, MMP-13) are MMPs with the ability to cleave interstitial collagen (native form, fibrillar collagen; type I, II, III). This collagenase cleavage results in an N-terminal ¾ length peptide and a C-terminal ¼ length peptide. 
  • Gelatinases (MMP-2, MMP-9) primarily degrade denatured collagen, collagen fragments (like those generated by collagenase cleavage), and non-fibrillar collagen (types IV, V).
  • Stromelysins (MMP-3, MMP-10, MMP-11) and matrilysins (MMP-7, MMP-26) exhibit a much wider substrate specificity, degrading many different ECM components: proteoglycans, fibronectin, laminin, gelatin and others.
  • Macrophage Metalloelastase (MMP-12) primarily degrades elastin, but also many other ECM constituents. 

However, MMPs appear to exhibit a much broader proteolytic activity (at least in vitro) than originally thought. Many MMPs have proteolytic activity against numerous ECM proteins, as well as non-ECM components, such as growth factor-binding proteins (8), cell surface growth factor receptors (8), as well as cytokines and chemokines (9). This ability to modulate inflammatory signaling and chemotactic signaling molecules intimates a wider regulatory role for MMPs than initially thought. However, proteolytic processing of cytokines and chemokines by MMP is a complicated pathway. Indeed, cleavage of cytokines and chemokines by various MMPS can lead to activation or inactivation of the signaling molecule, with either agonist or antagonist effector functions (9). More research is needed to determine the how MMP cleavage of cytokines and chemokines affects immune responses and disease progression.

The table below provides more information on the reported substrates of most MMPs, as well as the physiological functions associated with MMP activity.


Also Known As



Physiological Functions


Collagenase 1
Interstitial Collagenase
Fibroblast Collagenase


Aggrecan, Versican, Perlecan, Nidogen, Serpins, Tenascin C, Native Collagen, CXCL12, CCL7, CCL2, CCL13



Gelatinase A
72-kDa Gelatinase
Type IV Collagenase
Neutrophil Gelatinase


Gelatin, Collagen (I, IV, V), Elastin, Vitronectin, IL-1β, TGF-β, CXCL12, CX3CL1, CCL7

Angiogenesis, Inflammatory signaling regulation; Ectodomain shedding


Stromelysin 1
Transin 1


Fibronectin, Gelatin, Laminin, Proteoglycans, Globular Type IV, IL-1β, TGF-β, CXCL12, CCL2, CCL7, CCL8, CCL13

MMP activation; Wound healing; Involution


Matrilysin 1
PUMP-1 protease
Uterine Metalloproteinase


Fibronectin, Gelatin, Laminin, Elastin,

proMMP-2, proMMP-9

Endometrial involution;
Mucosal immunity; Wound repair


Collagenase 2
Neutrophil Collagenase


Collagen (I, II, III, V, VII, VIII, X), Gelatin, Aggrecan, Fibronectin, CXCL5, CXCL8, CXCL9, CCL2, CXCL5

Embryogenesis; Uterine tissue


Gelatinase B
92-kDa type IV Collagenase


Collagen (IV), IL-8, IL-1β, TGF-β, IFN-β CXCL12, CXCL4, CXCL1, CTAPIII, CXCL5, CXCL8, CXCL9

Neovascularization; Immune
cell migration; Endometrial tissue remodeling; Embryo implantation


Stromelysin 2


Collagen (III, IV, V), Gelatin, Aggrecan

Bone Remodeling, Ossification;
Wound healing; Cell migration


Stromelysin 3


Casein, Fibronectin, Vitronectin, Laminin, Entactin, Proteoglycans, Fibrinogen, Fibrin, Plasminogen



Macrophage Elastase


Elastin, Plasminogen



Collagenase 3


Collagen (I, II, III, IV, IX, XIV), Gelatin, Aggrecan, Perlecan, Fibronectin, Tenascin-C,


Bone Development;




Collagen (I, II, III), Fibronectin, Vitronectin, Tenascin, Nidogen, Aggrecan, Fibrin, Fibrinogen, Laminin-5, proMMP-2, proMMP-13, proMMP-8, TGF-β, CXCL12, CCL7

Angiogenesis; Endothelial cell




Collagen (I, II, III), Fibronectin, Vitronectin, Tenascin, Nidogen, Aggrecan, Fibrin, Fibrinogen, Laminin-5, proMMP-2, proMMP-13, proMMP-9

Ovulation (follicle rupture)









Gelatin, Fibrin, Fibrinogen






Tooth enamel turnover




Gelatin, Fibrin, Fibrinogen, Fibronectin, Collagen (IV), Proteoglycans, proMMP-2



Matrilysin 2


Fibronectin, proMMP-2, proMMP-9










































Table 1. Common MMPs, their alternative names, classifications, known substrates, and studied physiological functions.
Table compiled based on information provided by: 
1. T. Klein, R. Bischoff, Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 41, (2):271-290 (2011). doi:10.1007/s00726-010-0689-x. 
2. P. Van Lint, and C. Libert, Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. Journal of Leukocyte Biology 82, 1375-1381 (2007).


The ability of MMPs to influence immune cell behavior and inflammatory reactions makes regulation of MMP activity key for maintaining homeostasis. Transcription (expression) level regulation and the cysteine switch activation method described above are the primary regulatory mechanisms. However, endogenous Tissue Inhibitors of MetalloProteinases (TIMPs), a group of four broad-spectrum inhibitors (TIMP-1, TIMP-2, TIMP-3, TIMP-4) with varying affinities for different metalloproteinases, also play important roles in managing MMP activity (10). Dysregulation of MMP activity can be a driving force in diseases where collagen degradation and tissue remodeling are prominent features (osteaoarthritis, rheumatoid arthritis, cancer, asthma). Compounds that can specifically inhibit MMPs associated with disease pathologies could be key therapeutic targets for improving treatment options.



  1. J. Gross, C. M. Lapiere, Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA 48, 1014-1022 (1962).
  2. B. J. Rose, D. L. Kooyman, A Tale of Two Joints: The Role of Matrix Metalloproteases in Cartilage Biology. Dis Markers 4895050 (2016).
  3. H. Ohbayashi, K. Shimokata, Matrix metalloproteinase-9 and airway remodeling in asthma. Curr Drug Targets Inflamm Allergy 4, 177-181 (2005).
  4. K. Kessenbrock, V. Plaks, Z. Werb, Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52-67 (2010).
  5. Z. Jiang, T. Sui, B. Wang, Relationships between MMP-2, MMP-9, TIMP-1 and TIMP-2 levels and their pathogenesis in patients with lupus nephritis. Rheumatol Int 30, 1219-1226 (2010).
  6. M. Giannandrea, W. C. Parks, Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 7, 193-203 (2014).
  7. H. E. Van Wart, H. Birkedal-Hansen, The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87, 5578-5582 (1990).
  8. N. Reunanen, V. M. Kähäri, Matrix Metalloproteinases in Cancer Cell Invasion. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.
  9. P. Van Lint, C. Libert, Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol 82, 1375-1381 (2007).
  10. K. Brew, H. Nagase, The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803, 55-71 (2010).