MMP9 explained

Matrix metalloproteinase-9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene[1] encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.[2]

Function

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, as well as in pathological processes, such as arthritis, intracerebral hemorrhage,[3] and metastasis.[4] Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens and other extracellular matrix proteins.[5] Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling.[1]

Thrombospondins, intervertebral disc proteins, regulate interaction with matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling.[6]

Neutrophil action

MMP9, along with elastase, appears to be a regulatory factor in neutrophil migration across the basement membrane.[7]

MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines.[8] In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in sepsis.[9]

Angiogenesis

MMP9 may play an important role in angiogenesis and neovascularization. For example, MMP9 appears to be involved in the remodeling associated with malignant glioma neovascularization.[10] It is also a key regulator of growth plate formation- both growth plate angiogenesis and the generation of hypertrophic chondrocytes. Knock-out models of MMP9 result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes.[11] Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis [12]

Wound repair

MMP9 is greatly upregulated during human respiratory epithelial healing.[13] Using a MMP9 deficient mouse model, it was seen that MMP9 coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing.[14] When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.[15]

Structure

MMP9 is synthesized as preproenzyme of 707 amino-acid residues, including a 19 amino acid signal peptide and secreted as an inactive pro-MMP. The human MMP9 proenzyme consists of five domains. The amino-terminal propeptide, the zinc-binding catalytic domain and the carboxyl-terminal hemopexin-like domain are conserved. Its primary structure comprises several domain motifs. The propeptide domain is characterized by a conserved PRCGVPD sequence. The Cys within this sequence is known as the “cysteine switch”. It ligates the catalytic zinc to maintain the enzyme in an inactive state.[2] Activation is achieved through an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin generates active MMP-3 from its zymogen. Active MMP-3 cleaves the propeptide from the 92-kDa pro-MMP-9, yielding an 82-kDa enzymatically active enzyme.[16] In the active enzyme a substrate, or a fluorogenic activity probe.,[17] replaces the propeptide in the enzyme active site where it is cleaved. The catalytic domain contains two zinc and three calcium atoms. The catalytic zinc is coordinated by three histidines from the conserved HEXXHXXGXXH binding motif. The other zinc atom and the three calcium atoms are structural. A conserved methionine, which forms a unique “Met-turn” structure categorizes MMP9 as a metzincin.[18] Three type II fibronectin repeats are inserted in the catalytic domain, although these domains are omitted in most crystallographic structures of MMP9 in complex with inhibitors. The active form of MMP9 also contains a C-terminal hemopexin-like domain. This domain is ellipsoidal in shape, formed by four β-propeller blades and an α-helix. Each blade consists of four antiparallel β-strands arranged around a funnel-like tunnel that contains two calcium and two chloride ions.[19] The hemopexin domain is important to facilitate the cleavage of triple helical interstitial collagens..

Clinical significance

MMP9 has been found to be associated with numerous pathological processes, including cancer, placental malaria, immunologic and cardiovascular diseases.

Arthritis

Elevated MMP9 levels can be found in the cases of rheumatoid arthritis[20] and focal brain ischemia.[21]

Cancer

One of MMP9's most widely associated pathologies is the relationship to cancer, due to its role in extracellular matrix remodeling and angiogenesis. For example, its increased expression was seen in a metastatic mammary cancer cell line.[22] Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis.[23] However, because of its physiologic function, it may be difficult to leverage Gelatinase B inhibition into cancer therapy modalities. However, Gelatinase B has been investigated in tumor metastasis diagnosis- Complexes of Gelatinase B/Tissue Inhibitors of Metalloproteinases are seen to be increased in gastrointestinal cancer and gynecologic malignancies [24]

MMPs such as MMP9 can be involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis.[25]

Cardiovascular

MMP9 levels increase with the progression of idiopathic atrial fibrillation.[26]

MMP9 has been found to be associated with the development of aortic aneurysms,[27] and its disruption prevents the development of aortic aneurysms.[28] Doxycycline suppresses the growth of aortic aneurysms in animal models through its inhibition of MMP9 reduces aortic inflammation in humans.[29]

Pregnancy-associated malaria (Placental malaria)

A study on Ghanaian population showed that MMP-9 single nucleotide polymorphism 1562 C > T (rs3918242) was protective against placental malaria which suggests a possible role of MMP-9 in susceptibility to malaria.[30]

Dry eye

Dry eye patients, especially with meibomian gland dysfunction exhibit higher levels of MMP-9.[31]

Further reading

External links

Notes and References

  1. Web site: Matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) .
  2. Nagase H, Woessner JF . Matrix metalloproteinases . The Journal of Biological Chemistry . 274 . 31 . 21491–4 . July 1999 . 10419448 . 10.1074/jbc.274.31.21491 . free .
  3. Wang J, Tsirka SE . Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage . Brain . 128 . Pt 7 . 1622–33 . July 2005 . 15800021 . 10.1093/brain/awh489 . free .
  4. Vandooren J, Van den Steen PE, Opdenakker G . Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade . Critical Reviews in Biochemistry and Molecular Biology . 48 . 3 . 222–72 . 2013 . 23547785 . 10.3109/10409238.2013.770819 . 33781725 .
  5. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G . Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9) . Critical Reviews in Biochemistry and Molecular Biology . 37 . 6 . 375–536 . December 2002 . 12540195 . 10.1080/10409230290771546 . 35833950 .
  6. Hirose Y, Chiba K, Karasugi T, Nakajima M, Kawaguchi Y, Mikami Y, Furuichi T, Mio F, Miyake A, Miyamoto T, Ozaki K, Takahashi A, Mizuta H, Kubo T, Kimura T, Tanaka T, Toyama Y, Ikegawa S . A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation . American Journal of Human Genetics . 82 . 5 . 1122–9 . May 2008 . 18455130 . 2427305 . 10.1016/j.ajhg.2008.03.013 .
  7. Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A . Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane . American Journal of Respiratory Cell and Molecular Biology . 14 . 3 . 288–95 . March 1996 . 8845180 . 10.1165/ajrcmb.14.3.8845180 .
  8. Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, Proost P, Van Damme J . Gelatinase B functions as regulator and effector in leukocyte biology . Journal of Leukocyte Biology . 69 . 6 . 851–9 . June 2001 . 10.1189/jlb.69.6.851 . 11404367 . 15851048 . free .
  9. Dubois B, Starckx S, Pagenstecher A, ((Oord Jv)), Arnold B, Opdenakker G . Gelatinase B deficiency protects against endotoxin shock . European Journal of Immunology . 32 . 8 . 2163–71 . August 2002 . 12209628 . 10.1002/1521-4141(200208)32:8<2163::AID-IMMU2163>3.0.CO;2-Q . free .
  10. Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR . Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas . British Journal of Cancer . 79 . 11–12 . 1828–35 . April 1999 . 10206300 . 2362801 . 10.1038/sj.bjc.6690291 .
  11. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z . MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes . Cell . 93 . 3 . 411–22 . May 1998 . 9590175 . 2839071 . 10.1016/s0092-8674(00)81169-1 .
  12. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S . Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand . Cell . 109 . 5 . 625–37 . May 2002 . 12062105 . 2826110 . 10.1016/s0092-8674(02)00754-7 .
  13. Buisson AC, Zahm JM, Polette M, Pierrot D, Bellon G, Puchelle E, Birembaut P, Tournier JM . Gelatinase B is involved in the in vitro wound repair of human respiratory epithelium . Journal of Cellular Physiology . 166 . 2 . 413–26 . February 1996 . 8592002 . 10.1002/(sici)1097-4652(199602)166:2<413::aid-jcp20>3.0.co;2-a . 24996115 .
  14. Mohan R, Chintala SK, Jung JC, Villar WV, McCabe F, Russo LA, Lee Y, McCarthy BE, Wollenberg KR, Jester JV, Wang M, Welgus HG, Shipley JM, Senior RM, Fini ME . Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration . The Journal of Biological Chemistry . 277 . 3 . 2065–72 . January 2002 . 11689563 . 10.1074/jbc.m107611200 . free .
  15. Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, Wen FQ, Abe S, Wang X, Atkinson JJ, Shipley JM, Senior RM, Rennard SI . Matrix metalloproteinase-9 activates TGF-β and stimulates fibroblast contraction of collagen gels . American Journal of Physiology. Lung Cellular and Molecular Physiology . 306 . 11 . L1006-15 . June 2014 . 24705725 . 10.1152/ajplung.00015.2014 . 4042193 .
  16. Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP . Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion . The Journal of Biological Chemistry . 274 . 19 . 13066–76 . May 1999 . 10224058 . 10.1074/jbc.274.19.13066 . free .
  17. Tranchant I, Vera L, Czarny B, Amoura M, Cassar E, Beau F, Stura EA, Dive V . Halogen bonding controls selectivity of FRET substrate probes for MMP-9 . Chemistry & Biology . 21 . 3 . 408–13 . March 2014 . 24583051 . 10.1016/j.chembiol.2014.01.008 .
  18. Bode W, Gomis-Rüth FX, Stöckler 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 Letters . 331 . 1–2 . 134–40 . September 1993 . 8405391 . 10.1016/0014-5793(93)80312-I . 27244239 .
  19. Gomis-Rüth FX, Gohlke U, Betz M, Knäuper V, Murphy G, López-Otín C, Bode W . The helping hand of collagenase-3 (MMP-13): 2.7 A crystal structure of its C-terminal haemopexin-like domain . Journal of Molecular Biology . 264 . 3 . 556–66 . December 1996 . 8969305 . 10.1006/jmbi.1996.0661 .
  20. Gruber BL, Sorbi D, French DL, Marchese MJ, Nuovo GJ, Kew RR, Arbeit LA . Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker . Clinical Immunology and Immunopathology . 78 . 2 . 161–71 . February 1996 . 8625558 . 10.1006/clin.1996.0025 .
  21. Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR . Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia . Neuroscience Letters . 238 . 1–2 . 53–6 . November 1997 . 9464653 . 10.1016/s0304-3940(97)00859-8 . 916260 .
  22. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, Noonan DM, Natali PG, Albini A . The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity . International Journal of Cancer . 87 . 3 . 336–42 . August 2000 . 10897037 . 10.1002/1097-0215(20000801)87:3<336::aid-ijc5>3.3.co;2-v . free .
  23. Farina AR, Mackay AR . Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression . Cancers . 6 . 1 . 240–96 . January 2014 . 24473089 . 3980597 . 10.3390/cancers6010240 . free .
  24. Zucker S, Lysik RM, DiMassimo BI, Zarrabi HM, Moll UM, Grimson R, Tickle SP, Docherty AJ . Plasma assay of gelatinase B: tissue inhibitor of metalloproteinase complexes in cancer . Cancer . 76 . 4 . 700–8 . August 1995 . 8625169 . 10.1002/1097-0142(19950815)76:4<700::aid-cncr2820760426>3.0.co;2-5 . 41700819 .
  25. Groblewska M, Siewko M, Mroczko B, Szmitkowski M . The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer . Folia Histochemica et Cytobiologica . 50 . 1 . 12–9 . April 2012 . 22532131 . 10.5603/fhc.2012.0002. free .
  26. Li M, Yang G, Xie B, Babu K, Huang C . Changes in matrix metalloproteinase-9 levels during progression of atrial fibrillation . The Journal of International Medical Research . 42 . 1 . 224–30 . February 2014 . 24345823 . 10.1177/0300060513488514 . free .
  27. Newman KM, Ogata Y, Malon AM, Irizarry E, Gandhi RH, Nagase H, Tilson MD . Identification of matrix metalloproteinases 3 (stromelysin-1) and 9 (gelatinase B) in abdominal aortic aneurysm . Arteriosclerosis and Thrombosis . 14 . 8 . 1315–20 . August 1994 . 8049193 . 10.1161/01.atv.14.8.1315 . free .
  28. Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW . Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms . The Journal of Clinical Investigation . 105 . 11 . 1641–9 . June 2000 . 10841523 . 300851 . 10.1172/jci8931 .
  29. Lindeman JH, Abdul-Hussien H, van Bockel JH, Wolterbeek R, Kleemann R . Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells . Circulation . 119 . 16 . 2209–16 . April 2009 . 19364980 . 10.1161/CIRCULATIONAHA.108.806505 . free .
  30. Apoorv TS, Babu PP, Meese S, Gai PP, Bedu-Addo G, Mockenhaupt FP . Matrix metalloproteinase-9 polymorphism 1562 C > T (rs3918242) associated with protection against placental malaria . The American Journal of Tropical Medicine and Hygiene . 93 . 1 . 186–8 . July 2015 . 26013370 . 4497894 . 10.4269/ajtmh.14-0816 .
  31. Messmer . Elisabeth M. . von Lindenfels . Victoria . Garbe . Alexandra . Kampik . Anselm . Matrix Metalloproteinase 9 Testing in Dry Eye Disease Using a Commercially Available Point-of-Care Immunoassay . Ophthalmology . November 2016 . 123 . 11 . 2300–2308 . 10.1016/j.ophtha.2016.07.028 . 27665213 .

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