Thrombospondins, intervertebral disc proteins, regulate interaction with matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling.[10]
MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines.[12] In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in sepsis.[13]
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.[14] 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.[15] Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis [16]
Wound repair
MMP9 is greatly upregulated during human respiratory epithelial healing.[17] 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.[18] When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.[19]
Structure
ProMMP9 (pro-peptide (red), catalytic domain (green) with fibronectin domains (cyan), with detail of the "cysteine switch" (from PDB entry 1L6J)
MMP9 is synthesized as preproenzyme of 707 amino-acid residues, including a 19 amino acidsignal 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 catalyticzinc to maintain the enzyme in an inactive state.[6]
MMP-9 catalytic domain in complex with a fluorogenic synthetic peptidic substrate. From PDB entry 4JIJ.[20]
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.[21] In the active enzyme a substrate, or a fluorogenic activity probe.,[20] 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.[22] 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.[23] 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.
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.[26] Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis.[27] 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 [28]
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.[29]
MMP9 has been found to be associated with the development of aortic aneurysms,[31] and its disruption prevents the development of aortic aneurysms.[32]Doxycycline suppresses the growth of aortic aneurysms in animal models through its inhibition of MMP9 reduces aortic inflammation in humans.[33]
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.[34]
^Vandooren J, Van den Steen PE, Opdenakker G (2013). "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. doi:10.3109/10409238.2013.770819. PMID23547785. S2CID33781725.
^Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (December 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. PMID12540195. S2CID35833950.
^Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A (March 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. PMID8845180.
^Bode W, Gomis-Rüth FX, Stöckler W (September 1993). "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. doi:10.1016/0014-5793(93)80312-I. PMID8405391. S2CID27244239.
^Gomis-Rüth FX, Gohlke U, Betz M, Knäuper V, Murphy G, López-Otín C, Bode W (December 1996). "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. doi:10.1006/jmbi.1996.0661. PMID8969305.
^Gruber BL, Sorbi D, French DL, Marchese MJ, Nuovo GJ, Kew RR, Arbeit LA (February 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. PMID8625558.
^Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR (November 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. PMID9464653. S2CID916260.
Starckx S, Van den Steen PE, Wuyts A, Van Damme J, Opdenakker G (February 2002). "Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization". Leukemia & Lymphoma. 43 (2): 233–41. doi:10.1080/10428190290005982. PMID11999552. S2CID940921.
Bischof P, Meisser A, Campana A (2002). "Control of MMP-9 expression at the maternal-fetal interface". Journal of Reproductive Immunology. 55 (1–2): 3–10. doi:10.1016/S0165-0378(01)00142-5. PMID12062817.
St-Pierre Y, Van Themsche C, Estève PO (September 2003). "Emerging features in the regulation of MMP-9 gene expression for the development of novel molecular targets and therapeutic strategies". Current Drug Targets. Inflammation and Allergy. 2 (3): 206–15. doi:10.2174/1568010033484133. PMID14561155. S2CID453825.
