Gelatinase B

Gelatinase B (EC 3.4.24.35, 92-kDa gelatinase, matrix metalloproteinase 9, type V collagenase, 92-kDa type IV collagenase, macrophage gelatinase, 95 kDa type IV collagenase/gelatinase, collagenase IV, collagenase type IV, gelatinase MMP 9, MMP 9, type IV collagen metalloproteinase) is an enzyme.[1][2][3] This enzyme catalyses the following chemical reaction

Cleavage of gelatin types I and V and collagen types IV and V
Gelatinase B
Identifiers
EC no.3.4.24.35
CAS no.146480-36-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
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PMCarticles
PubMedarticles
NCBIproteins

This enzyme is similar to gelatinase A, but possesses a further domain. Regarding its structure, Gelatinase B has domains which can bind with gelatin, laminin, and collagens type I and IV- collagenases do not possess these binding domains.[4]

Function

Due to its role in cleaving collagen in the extracellular matrix, gelatinase B has multiple functional roles in normal physiology.

Neutrophil action

Gelatinase B, along with elastase, appears to be a regulatory factor in neutrophil migration across the basement membrane.[5] Gelatinase B plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines.[6] In a mouse model, Gelatinase B deficiency resulted in resistance to endotoxin shock, suggesting that Gelatinase B is important in sepsis.[7]

Angiogenesis

Gelatinase B may play an important role in angiogenesis and neovascularization. For example, gelatinase B appears to be involved in the remodeling associated with malignant glioma neovascularization.[8] It is also a key regulator of growth plate formation—both growth plate angiogenesis and the generation of hypertrophic chondrocytes. Knock-out models of Gelatinase B result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes.[9] Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis [10]

Wound repair

In in vitro experiments, it has been demonstrated that gelatinase B is greatly upregulated during human respiratory epithelial healing.[11] Using a gelatinase B deficient mouse model, it was seen that gelatinase B coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing.[12] When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.[13]

Pathology

Gelatinase B has been found to be associated with numerous pathological processes, including immunologic and vascular diseases. For example, it has been implicated in the development of aortic aneurysms,[14] and its disruption prevents the development of aortic aneurysms.[15] Elevated gelatinase B levels can also be found in the cases of rheumatoid arthritis[16] and focal brain ischemia.[17]

However, one of its most widely studied associated pathology is the relationship between Gelatinase B and 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.[18] A.R. Farina and others have argued that Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis.[19] 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 [20]

See also

References
  1. Hibbs MS, Hoidal JR, Kang AH (Dec 1987). "Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages". The Journal of Clinical Investigation. 80 (6): 1644–50. doi:10.1172/jci113253. PMC 442435. PMID 3680518.
  2. Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI (Oct 1989). "SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages". The Journal of Biological Chemistry. 264 (29): 17213–21. PMID 2551898.
  3. Mainardi CL, Hasty KA (May 1990). "Secretion and glycosylation of rabbit macrophage type V collagenase". Matrix. 10 (2): 84–90. doi:10.1016/s0934-8832(11)80174-5. PMID 2165210.
  4. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (Dec 2002). "Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9)". Critical Reviews in Biochemistry and Molecular Biology. 37 (6): 375–536. doi:10.1080/10409230290771546. PMID 12540195.
  5. Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A (Mar 1996). "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. doi:10.1165/ajrcmb.14.3.8845180. PMID 8845180.
  6. Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, Proost P, Van Damme J (Jun 2001). "Gelatinase B functions as regulator and effector in leukocyte biology". Journal of Leukocyte Biology. 69 (6): 851–9. PMID 11404367.
  7. Dubois B, Starckx S, Pagenstecher A, Oord JV, Arnold B, Opdenakker G (Aug 2002). "Gelatinase B deficiency protects against endotoxin shock". European Journal of Immunology. 32 (8): 2163–71. doi:10.1002/1521-4141(200208)32:8<2163::aid-immu2163>3.0.co;2-q. PMID 12209628.
  8. Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR (Apr 1999). "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. doi:10.1038/sj.bjc.6690291. PMC 2362801. PMID 10206300.
  9. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z (May 1998). "MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes". Cell. 93 (3): 411–22. doi:10.1016/s0092-8674(00)81169-1. PMC 2839071. PMID 9590175.
  10. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S (May 2002). "Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand". Cell. 109 (5): 625–37. doi:10.1016/s0092-8674(02)00754-7. PMC 2826110. PMID 12062105.
  11. Buisson AC, Zahm JM, Polette M, Pierrot D, Bellon G, Puchelle E, Birembaut P, Tournier JM (Feb 1996). "Gelatinase B is involved in the in vitro wound repair of human respiratory epithelium". Journal of Cellular Physiology. 166 (2): 413–26. doi:10.1002/(sici)1097-4652(199602)166:2<413::aid-jcp20>3.0.co;2-a. PMID 8592002.
  12. 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 (Jan 2002). "Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration". The Journal of Biological Chemistry. 277 (3): 2065–72. doi:10.1074/jbc.m107611200. PMID 11689563.
  13. 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 (Jun 2014). "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. doi:10.1152/ajplung.00015.2014. PMC 4042193. PMID 24705725.
  14. Newman KM, Ogata Y, Malon AM, Irizarry E, Gandhi RH, Nagase H, Tilson MD (Aug 1994). "Identification of matrix metalloproteinases 3 (stromelysin-1) and 9 (gelatinase B) in abdominal aortic aneurysm". Arteriosclerosis and Thrombosis. 14 (8): 1315–20. doi:10.1161/01.atv.14.8.1315. PMID 8049193.
  15. Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW (Jun 2000). "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. doi:10.1172/jci8931. PMC 300851. PMID 10841523.
  16. Gruber BL, Sorbi D, French DL, Marchese MJ, Nuovo GJ, Kew RR, Arbeit LA (Feb 1996). "Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker". Clinical Immunology and Immunopathology. 78 (2): 161–71. doi:10.1006/clin.1996.0025. PMID 8625558.
  17. Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR (Nov 1997). "Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia". Neuroscience Letters. 238 (1–2): 53–6. doi:10.1016/s0304-3940(97)00859-8. PMID 9464653.
  18. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, Noonan DM, Natali PG, Albini A (Aug 2000). "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. doi:10.1002/1097-0215(20000801)87:3<336::aid-ijc5>3.3.co;2-v. PMID 10897037.
  19. Farina AR, Mackay AR (2014). "Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression". Cancers. 6 (1): 240–96. doi:10.3390/cancers6010240. PMC 3980597. PMID 24473089.
  20. Zucker S, Lysik RM, DiMassimo BI, Zarrabi HM, Moll UM, Grimson R, Tickle SP, Docherty AJ (Aug 1995). "Plasma assay of gelatinase B: tissue inhibitor of metalloproteinase complexes in cancer". Cancer. 76 (4): 700–8. doi:10.1002/1097-0142(19950815)76:4<700::aid-cncr2820760426>3.0.co;2-5. PMID 8625169.
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