Inflammation comprises the detection and response to injury and pathogens, the accumulation and intervention of cells that eliminate invading microorganisms and infected host cells, and the repair of tissues that are damaged by the initial insult, trauma or the responses of the host.
Numerous effector proteins regulate and coordinate repair, leukocyte recruitment, and immunity, and the activity of many of these effectors is controlled by limited proteolysis. So, proteinases provide an important control that regulates the varied cellular processes defining inflammation.
Matrix metalloproteinases (MMPs) constitute a family of 24 mammalian extracellular or membrane-bound proteinases that function in wound repair, mucosal defence, inflammation and acquired immunity. MMPs accomplish these varied tasks by acting on a variety of protein substrates, such as antimicrobial peptides, adhesion proteins, receptors, cytokines, chemokines and extracellular-matrix proteins.
In particular, several MMPs regulate the activity of chemokines, either directly or indirectly, thereby controlling many aspects of inflammation and immunity. Many chemokines are directly cleaved by MMPs, thereby resulting in enhancement, inactivation or antagonism of chemokine activities. By contrast, others chemokines are regulated by MMP cleavage of substrates that bind, retain and concentrate the chemotactic molecules in particular locations: that is, they establish chemokine gradients. This results in a coordinated influx of immune effector cells, including neutrophils, monocytes and eosinophils. So, MMPs actively participate in the evolution and outcome of the inflammatory response.
MMP7 is used as an example of an MMP that has diverse functions in the innate immune response. In the gut, MMP7 participates in the barrier function of the epithelium by activating antimicrobial peptides. In response to epithelial injury, MMP7 is expressed by cells at the wound edge, and its activity is required for re-epithelialization. This is thought to occur through the shedding of epithelial (E)-cadherin ectodomains, which loosen cell–cell contacts. Furthermore, at the wound site, MMP7 sheds chemokine-bound syndecan-1, a transmembrane proteoglycan, which in turn guides the transepithelial influx of neutrophils.
As their name implies, matrix metalloproteinases are thought to be responsible for the turnover and degradation of the extracellular matrix. However, matrix degradation is neither the sole nor the main function of these proteinases. Indeed, as we discuss here, recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Velasco, G. et al. Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J. Biol. Chem. 274, 4570–4576 (1999).
Bode, W., Gomis-Ruth, F. X. & Stockler, W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. FEBS Lett. 331, 134–140 (1993).
Massova, I., Kotra, L. P., Fridman, R. & Mobashery, S. Matrix metalloproteinases: structures, evolution, and diversification. FASEB J. 12, 1075–1095 (1998).
Shapiro, S. D. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr. Opin. Cell Biol. 10, 602–608 (1998).
Van Wart, H. E. & Birkedal-Hansen, H. 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).
Strongin, A. Y. et al. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem. 270, 5331–5338 (1995).
Hernandez-Barrantes, S. et al. Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation. J. Biol. Chem. 275, 12080–12089 (2000).
Wang, Z., Juttermann, R. & Soloway, P. D. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J. Biol. Chem. 275, 26411–26415 (2000).
Caterina, J. J. et al. Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2 (Timp-2) gene alters proMMP-2 activation. J. Biol. Chem. 275, 26416–26422 (2000).
Yang, Z., Strickland, D. K. & Bornstein, P. Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J. Biol. Chem. 276, 8403–8408 (2001).
Barmina, O. Y. et al. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization. J. Biol. Chem. 274, 30087–30093 (1999).
Weiss, S. J., Peppin, G., Ortiz, X., Ragsdale, C. & Test, S. T. Oxidative autoactivation of latent collagenase by human neutrophils. Science 227, 747–749 (1985).
Peppin, G. J. & Weiss, S. J. Activation of the endogenous metalloproteinase, gelatinase, by triggered human neutrophils. Proc. Natl Acad. Sci. USA 83, 4322–4326 (1986).
Fu, X., Kassim, S. Y., Parks, W. C. & Heinecke, J. W. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J. Biol. Chem. 276, 41279–41287 (2001).
Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002).
Fu, X., Kassim, S. Y., Parks, W. C. & Heinecke, J. W. Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. J. Biol. Chem. 278, 28403–28409 (2003). References 12–16 show that reactive metabolites, often leukocyte-generated oxidants, can both activate and inactivate the catalytic activity of MMPs. Although these mechanisms have not yet been shown in vivo , they are probably important for the regulation of MMPs in inflammation.
Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).
Mackay, A. R., Hartzler, J. L., Pelina, M. D. & Thorgeirsson, U. P. Studies on the ability of 65-kDa and 92-kDa tumor cell gelatinases to degrade type IV collagen. J. Biol. Chem. 265, 21929–21934 (1990).
Halpert, I. et al. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc. Natl Acad. Sci. USA 93, 9748–9753 (1996).
Brooks, P. C. et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3 . Cell 85, 683–693 (1996).
Dumin, J. A. et al. Procollagenase-1 (matrix metalloproteinase-1) binds the integrin α2β1 upon release from keratinocytes migrating on type I collagen. J. Biol. Chem. 276, 29368–29374 (2001).
Stricker, T. P. et al. Structural analysis of the α2 integrin I domain/procollagenase-1 (matrix metalloproteinase-1) interaction. J. Biol. Chem. 276, 29375–29381 (2001).
Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).
Yu, W. H. & Woessner, J. F. Jr. Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J. Biol. Chem. 275, 4183–4191 (2000).
Yu, W. H., Woessner, J. F. Jr, McNeish, J. D. & Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev. 16, 307–323 (2002). This paper provides a good example of how a 'secreted' MMP is bound to and compartmentalized by a cell-surface molecule.
Gross, J. & Lapiere, C. M. Collagenolytic activity in amphipian tissues: a tissue culture assay. Proc. Natl Acad. Sci. USA 48, 1014–1022 (1962).
McQuibban, G. A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000). This paper shows how exosite scanning and yeast two-hybrid techniques can be used to identify novel MMP substrates: in this case, chemokines. Together with other studies by these investigators (references 54 and 55), this study provides evidence that MMP proteolysis directly regulates chemokine activity.
Guo, L. et al. A proteomic approach for the identification of cell-surface proteins shed by metalloproteases. Mol. Cell. Proteomics 1, 30–36 (2002).
Tam, E. M., Morrison, C. J., Wu, Y. I., Stack, M. S. & Overall, C. M. Membrane protease proteomics: isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc. Natl Acad. Sci. USA 101, 6917–6922 (2004). This paper describes a proteomics study using state-of-the-art technology to identify MMP substrates. This knowledge is essential for understanding the function of these enzymes in vivo.
McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: they're not just for matrix anymore! Curr. Opin. Cell Biol. 13, 534–540 (2001).
Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999).
Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000).
Hotary, K., Allen, E., Punturieri, A., Yana, I. & Weiss, S. J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149, 1309–1323 (2000).
Hotary, K. B. et al. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J. Exp. Med. 195, 295–308 (2002).
Filippov, S. et al. Matrilysin-dependent elastolysis by human macrophages. J. Exp. Med. 198, 925–935 (2003).
Opdenakker, G., Van den Steen, P. E. & Van Damme, J. Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol. 22, 571–579 (2001).
Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).
Lee, H. M. et al. Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. J. Periodontol. 75, 453–463 (2004).
Whelan, C. J. Metalloprotease inhibitors as anti-inflammatory agents: an evolving target? Curr. Opin. Investig. Drugs 5, 511–516 (2004).
Sierevogel, M. J., Pasterkamp, G., de Kleijn, D. P. & Strauss, B. H. Matrix metalloproteinases: a therapeutic target in cardiovascular disease. Curr. Pharm. Des. 9, 1033–1040 (2003).
Itoh, T. et al. The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. J. Immunol. 169, 2643–2647 (2002).
Mudgett, J. S. et al. Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum. 41, 110–121 (1998).
Parks, W. C. Matrix metalloproteinases in repair. Wound Repair Regen. 7, 423–432 (1999).
Pilcher, B. K. et al. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J. Cell Biol. 137, 1445–1457 (1997).
Dunsmore, S. E. et al. Matrilysin expression and function in airway epithelium. J. Clin. Invest. 102, 1321–1331 (1998).
McGuire, J. K., Li, Q. & Parks, W. C. Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am. J. Pathol. 162, 1831–1843 (2003).
Legrand, C. et al. Airway epithelial cell migration dynamics: MMP-9 role in cell–extracellular matrix remodeling. J. Cell Biol. 146, 517–529 (1999).
Betsuyaku, T., Fukuda, Y., Parks, W. C., Shipley, J. M. & Senior, R. M. Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. Am. J. Pathol. 157, 525–535 (2000).
Saarialho-Kere, U. K., Crouch, E. C. & Parks, W. C. Matrix metalloproteinase matrilysin is constitutively expressed in human exocrine epithelium. J. Invest. Dermatol. 105, 190–196 (1995).
Ouellette, A. J. & Selsted, M. E. Paneth cell defensins: endogenous peptide components of intestinal host defense. FASEB J. 10, 1280–1289 (1996).
Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999). This study identifies α-defensins as a new class of substrates for MMPs and demonstrates a specific role for MMP7 in innate immunity.
Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998).
Powell, W. C., Fingleton, B., Wilson, C. L., Boothby, M. & Matrisian, L. M. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr. Biol. 9, 1441–1447 (1999). This study establishes that FASL is a substrate for MMP7. MMP-mediated apoptosis, through the activation of FASL, might provide a mechanism for bacterial clearance, as indicated in figure 4.
Hartzell, W. & Shapiro, S. D. Macrophage elastase prevents Gemella morbillorum infection and improves outcome following murine bone marrow transplantation. Chest 116, 31S–32S (1999).
López-Boado, Y. S. et al. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J. Cell Biol. 148, 1305–1315 (2000).
López-Boado, Y. S., Wilson, C. L. & Parks, W. C. Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin. J. Biol. Chem. 276, 41417–41423 (2001).
Wilson, C. L. & Matrisian, L. M. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int. J. Biochem. Cell Biol. 28, 123–136 (1996).
Kagnoff, M. F. & Eckmann, L. Epithelial cells as sensors for microbial infection. J. Clin. Invest. 100, 6–10 (1997).
Borish, L. C. & Steinke, J. W. Cytokines and chemokines. J. Allergy Clin. Immunol. 111, S460–S475 (2003).
McQuibban, G. A. et al. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100, 1160–1167 (2002).
McQuibban, G. A. et al. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J. Biol. Chem. 276, 43503–43508 (2001).
Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J. & Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood 96, 2673–2681 (2000).
Van Den Steen, P. E. et al. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. Eur. J. Biochem. 270, 3739–3749 (2003).
Corry, D. B. et al. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nature Immunol. 3, 347–353 (2002). One the first papers to show that MMPs establish chemokine gradients in vivo . Reference 71 is a follow-up to these studies.
Pruijt, J. F. et al. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc. Natl Acad. Sci. USA 96, 10863–10868 (1999).
Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002). This paper describes a mechanism in which three epithelial products — an MMP, a CXC-chemokine and a proteoglycan — interact to control and coordinate acute inflammation at sites of injury.
Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nature Neurosci. 6, 1064–1071 (2003). This interesting study shows that MMP2 secreted by HIV-infected macrophages cleaves CXCL12 to generate a potent neurotoxin.
Balbin, M. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet. 35, 252–257 (2003).
Khandaker, M. H. et al. Metalloproteinases are involved in lipopolysaccharide- and tumor necrosis factor-α-mediated regulation of CXCR1 and CXCR2 chemokine receptor expression. Blood 93, 2173–2185 (1999).
Li, X. Y., Donaldson, K., Brown, D. & Macnee, W. The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation. Am. J. Resp. Cell Mol. Biol. 13, 185–195 (1995).
Corry, D. B. et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J. 18, 995–997 (2004).
Haro, H. et al. Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. J. Clin. Invest. 105, 133–141 (2000). Together with reference 102, this paper shows that specific MMPs function as crucial components of an inflammatory network between different cell types, using a model of tissue resorption.
Hautamaki, R. D., Kobayashi, D. K., Senior, R. M. & Shapiro, S. D. Requirement for macrophage elastase for cigarette smoke-induced emphysema. Science 277, 2002–2004 (1997).
Nelissen, I. et al. Gelatinase B/matrix metalloproteinase-9 cleaves interferon-β and is a target for immunotherapy. Brain 126, 1371–1381 (2003).
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).
Suzuki, M., Raab, G., Moses, M. A., Fernandez, C. A. & Klagsbrun, M. Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J. Biol. Chem. 272, 31730–31737 (1997).
Levi, E. et al. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc. Natl Acad. Sci. USA 93, 7069–7074 (1996).
Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
Kulkarni, A. B. & Karlsson, S. Transforming growth factor-β 1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am. J. Pathol. 143, 3–9 (1993).
Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).
Maeda, S., Dean, D. D., Gomez, R., Schwartz, Z. & Boyan, B. D. The first stage of transforming growth factor β1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3). Calcif. Tissue Int. 70, 54–65 (2002).
Karsdal, M. A. et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 277, 44061–44067 (2002).
Fantuzzi, G. et al. Response to local inflammation of IL-1β-converting enzyme-deficient mice. J. Immunol. 158, 1818–1824 (1997).
Schonbeck, U., Mach, F. & Libby, P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J. Immunol. 161, 3340–3346 (1998).
Ito, A. et al. Degradation of interleukin 1β by matrix metalloproteinases. J. Biol. Chem. 271, 14657–14660 (1996).
Gearing, A. J. H. et al. Processing of tumour necrosis factor-α precursor by metalloproteinases. Nature 370, 555–557 (1994).
Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).
Moss, M. L. et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 385, 733–736 (1997).
Mohan, M. J. et al. The tumor necrosis factor-α converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Biochemistry 41, 9462–9469 (2002).
English, W. R. et al. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-α convertase activity but does not activate pro-MMP2. J. Biol. Chem. 275, 14046–14055 (2000).
Visse, R. & Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).
Qi, J. H. et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9, 407–415 (2003).
Seo, D. W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171–180 (2003).
Oh, J. et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789–800 (2001).
Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).
Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2, 657–672 (2002).
Mott, J. D. et al. Post-translational proteolytic processing of procollagen C-terminal proteinase enhancer releases a metalloproteinase inhibitor. J. Biol. Chem. 275, 1384–1390 (2000).
Belaaouaj, A. et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Med. 4, 615–618 (1998).
Liu, Z. et al. The serpin α1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 102, 647–655 (2000). Using an experimental model of blister formation, this paper shows that MMP9 contributes to inflammation-mediated tissue damage by cleaving and inactivating the serpin α1-antiproteinase (a potent inhibitor of neutrophil elastase).
Lochter, A. et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872 (1997).
Sympson, C. J. et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J. Cell Biol. 125, 681–693 (1994).
Haro, H. et al. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-α in a model of herniated disc resorption. J. Clin. Invest. 105, 143–150 (2000).
Asahi, M. et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001).
Lelongt, B. et al. Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J. Exp. Med. 193, 793–802 (2001).
Larsen, P. H., Wells, J. E., Stallcup, W. B., Opdenakker, G. & Yong, V. W. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135 (2003).
Churg, A. et al. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-α release. Am. J. Respir. Crit. Care Med. 167, 1083–1089 (2003).
Hotary, K. B. et al. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J. Exp. Med. 195, 295–308 (2002).
Endo, K. et al. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J. Biol. Chem. 278, 40764–40770 (2003).
Koshikawa, N. et al. Proteolytic processing of laminin-5 by MT1-MMP in tissues and its effects on epithelial cell morphology. FASEB J. 18, 364–366 (2004).
Caterina, J. J. et al. Enamelysin (matrix metalloproteinase 20)-deficient mice display an amelogenesis imperfecta phenotype. J. Biol. Chem. 277, 49598–49604 (2002).
Billinghurst, R. C. et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J. Clin. Invest. 99, 1534–1545 (1997).
Otterness, I. G. et al. Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody. Matrix Biol. 18, 331–341 (1999).
Wu, W. et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum. 46, 2087–2094 (2002).
Hotary, K. B. et al. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114, 33–45 (2003).
Balbin, M. et al. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J. Biol. Chem. 276, 10253–10262 (2001).
Cossins, J., Dudgeon, T. J., Catlin, G., Gearing, A. J. & Clements, J. M. Identification of MMP-18, a putative novel human matrix metalloproteinase. Biochem. Biophys. Res. Commun. 228, 494–498 (1996).
Stolow, M. A. et al. Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development. Mol. Biol. Cell 7, 1471–1483 (1996).
Clark, H. F. et al. The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. 13, 2265–2270 (2003).
Itoh, T. et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58, 1048–1051 (1998).
Kato, T. et al. Diminished corneal angiogenesis in gelatinase A-deficient mice. FEBS Lett. 508, 187–190 (2001).
Ohno-Matsui, K. et al. Reduced retinal angiogenesis in MMP-2-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 5370–5375 (2003).
Berglin, L. et al. Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 403–408 (2003).
Wang, M. et al. Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response. Proc. Natl Acad. Sci. USA 96, 6885–6889 (1999).
Warner, R. L. et al. Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am. J. Respir. Cell Mol. Biol. 24, 537–544 (2001).
Silence, J., Lupu, F., Collen, D. & Lijnen, H. R. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler. Thromb. Vasc. Biol. 21, 1440–1445 (2001).
Kure, T. et al. Corneal neovascularization after excimer keratectomy wounds in matrilysin-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 137–144 (2003).
Dubois, B. et al. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J. Clin. Invest. 104, 1507–1515 (1999).
Dubois, B. et al. Gelatinase B deficiency protects against endotoxin shock. Eur. J. Immunol. 32, 2163–2171 (2002).
Ratzinger, G. et al. Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin. J. Immunol. 168, 4361–4371 (2002).
Liu, Z. et al. Gelatinase B-deficient mice are resistant to experimental bullous pemphigoid. J. Exp. Med. 188, 475–482 (1998).
Vu, T. H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).
Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).
Johnson, C., Sung, H. J., Lessner, S. M., Fini, M. E. & Galis, Z. S. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. Circ. Res. 94, 262–268 (2004).
McMillan, S. J. et al. Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation. J. Immunol. 172, 2586–2594 (2004).
Cataldo, D. D. et al. Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am. J. Pathol. 161, 491–498 (2002).
Lanone, S. et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110, 463–474 (2002).
Luttun, A. et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109, 1408–1414 (2004).
Longo, G. M. et al. Matrix metalloproteinase 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110, 625–632 (2002).
Pyo, R. et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J. Clin. Invest. 105, 1641–1649 (2000).
Asahi, M. et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J. Cereb. Blood Flow Metab. 20, 1681–1689 (2000).
Lambert, V. et al. MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J. 17, 2290–2292 (2003).
Shipley, J. M., Wesselschmidt, R. L., Kobayashi, D. K., Ley, T. J. & Shapiro, S. D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl Acad. Sci. USA 93, 3942–3946 (1996).
Wells, J. E. et al. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J. Neurosci. 23, 10107–10115 (2003).
Warner, R. L. et al. The role of metalloelastase in immune complex-induced acute lung injury. Am. J. Pathol. 158, 2139–2144 (2001).
The authors declare no competing financial interests.
The matrix metalloproteinase (MMP) pro-peptide region (or pro-domain) contains ∼80 amino acids, typically with a hydrophobic residue at the amino terminus. It also contains the highly conserved sequence PRCXXPD, where X denotes any amino acid. The thiol group of the cysteine residue in this sequence ligates with the zinc ion that is held by the histidine residues in the catalytic domain of the MMP. In this state, the enzyme is stable and inactive and is known as a zymogen.
The typical matrix metalloproteinase catalytic domain contains ∼160–170 residues, including the binding sites for the structural (calcium and zinc) and catalytic (zinc) metal ions. The 50–54 residues at the carboxyl terminus of the catalytic domain include a highly conserved HEXXHXXGXXH sequence (where X denotes any amino acid), which includes a glutamic acid residue (E) that provides the nucleophile that severs peptide bonds and histidine residues that coordinate the zinc ions.
- MET TURN
On the carboxy side of the zinc active site, matrix metalloproteinases have a methionine residue that is always conserved. This residue is part of a 1,4-β-turn that loops the polypeptide chain beneath the catalytic zinc ion and forms a hydrophobic base for the zinc-binding site.
A disintegrin and metalloproteinase family of proteases. They contain disintegrin-like and metalloproteinase-like domains and are involved in the regulation of developmental processes, cell–cell interactions and protein processing, including ectodomain shedding.
The superfamily of metalloenzymes includes more than 200 members. It has been divided into eight clans based on the similarity of protein folding characteristics and ∼40 families according to evolutionary relationships. The matrix-metalloproteinase family belongs to clan MB, the members of which have three histidine residues as zinc-binding ligands in the consensus sequence HEXXHXXGXXH (where X denotes any amino acid).
- HINGE REGION
A domain that is typically ∼75 residues and links the catalytic domain to the hemopexin-like domain of most matrix metalloproteinases.
- HEMOPEXIN-LIKE DOMAIN
This matrix-metalloproteinase domain comprises ∼200 residues and contains four repeats that resemble hemopexin and vitronectin. It is not essential for catalytic activity but does modulate substrate specificity and binding to tissue inhibitors of metalloproteinases.
- GLYCOSYLPHOSPHAT- IDYLINOSITOL (GPI)-ANCHORING SIGNALS
A glycolipid modification that is usually located at the carboxyl terminus and anchors proteins to the external surface of the plasma membrane.
- GELATIN-BINDING DOMAINS
These domains contain three fibronectin-like modules (also known as fibronectin type II modules) and are present in the catalytic domain of both matrix metalloproteinase 2 and -9.
- CYSTEINE-SWITCH MECHANISM
The pro-peptide maintains a matrix metalloproteinase (MMP) in an inactive state. When the interaction between the conserved cysteine residue in the pro-domain and the active site zinc ion is disrupted (for example, by proteolytic removal of the pro-peptide or by the action of organomercurials and chaotropic agents on the thiol of the cysteine residue), the active site becomes accessible, and the MMP has been 'activated'. The pro-domain does not need to be removed for a proMMP to acquire activity; only disruption of the zinc–thiol interaction is absolutely required.
Tissue inhibitors of metalloproteinases. A family of four (TIMP1, -2, -3 and -4) endogenous matrix-metalloproteinase (MMP) inhibitors that bind the catalytic site in activated enzymes. TIMP1 and TIMP3 also bind the hemopexin-like domain of the MMP9 and MMP13 zymogens, whereas TIMP2, -3 and -4 can bind this domain in the MMP2 zymogen.
A family of structurally related, small glycoproteins (70–90 amino acids) that have potent leukocyte activation and/or chemotactic activity. They have pivotal roles in innate and acquired immunity. These molecules, of which there are more than 50, are classified into four subfamilies depending on the arrangement of the amino-terminal conserved cysteine residues: CC-, CXC-, C- and CX3C-chemokines (where X denotes any amino acid). In general, CC-chemokines attract monocytes, lymphocytes, basophils and eosinophils, whereas CXC-chemokines are chemotactic for neutrophils.
- INNATE IMMUNITY
The term generally refers to innate pathogen-recognition systems, as well as to antimicrobial peptides. Innate immunity comprises immediate responses that are generated without the requirement for memory of, or prior exposure to, the pathogen. It is mostly mediated by receptors that have broad specificity (such as Toll-like receptors): that is, receptors that recognize many related pathogen-associated molecular patterns.
A mechanism of repair that involves epithelial-cell proliferation and migration across a denuded surface to re-establish cell contact and close a wound. During re-epithelialization, cells receive and process cues from a new microenvironment (that is, the exposed wound) and coordinate various responses, including the induction of matrix metalloproteinases and pro-inflammatory mediators, and the activation and expression of integrins.
A class of antimicrobial peptides that have activity against Gram-positive and Gram-negative bacteria, fungi and viruses. Defensins are classified into two main categories on the basis of the position of conserved cysteine and hydrophobic residues and the linkages of disulphide bonds: α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells. A third category, the θ-defensins, arises from the splicing of two α-defensin-related peptides into a circular molecule; at present, these defensins have been detected only in the neutrophils of rhesus macaques.
- NEUTROPHIL TRANSEPITHELIAL MIGRATION
During bacterial infections at mucosal sites, neutrophils migrate from the vasculature through the interstitial compartment and across the epithelial barrier. The activation and migration of neutrophils into lungs also contributes to inflammatory tissue injury and remodelling of tissue architecture
About this article
Cite this article
Parks, W., Wilson, C. & López-Boado, Y. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4, 617–629 (2004). https://doi.org/10.1038/nri1418
Wiener klinische Wochenschrift (2021)
Microarray analysis reveals an inflammatory transcriptomic signature in peripheral blood for sciatica
BMC Neurology (2021)
Effects of exercise training on renal interstitial fibrosis and renin–angiotensin system in rats with chronic renal failure
Journal of Hypertension (2021)
Pathology International (2021)
Integrated traditional Chinese medicine alleviates sciatica while regulating gene expression in peripheral blood
Journal of Orthopaedic Surgery and Research (2021)