Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Niharika Swain
  • Jigna Pathak
  • Shilpa Patel
  • Rashmi Maruti Hosalkar
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_102000


Historical Background

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases which are capable of degrading all extracellular matrix (ECM) components as well as process a variety of non-ECM substrates. They are responsible for physiological and pathological tissue remodeling. They are expressed in neutrophils, endothelial cells, eosinophils, macrophages, and T lymphocytes (Fanjul-Fernández et al. 2010; Iyer et al. 2012).

In 1962, Woessner demonstrated a protein enzyme in mammalian uterus that could degrade collagen. Later on Jerome Gross and Charles Lapiere identified a matrix metalloproteinase using a biochemical approach in which they showed collagenolytic activity in the skin, gut, and gills of the tadpole during metamorphosis. Later the International Union of Biochemistry and Molecular Biology designated the family with a unique name MMP of which MMP-1 was first identified in 1966. In 1974, MMP-9 was first isolated in neutrophils and also coined as “neutrophil gelatinase” (Iyer et al. 2012; Klein and Bischoff 2011). Till date, 24 human MMPs have been identified out of 25 different vertebrate MMPs, including two recently duplicated genes encoding MMP-23 (Fanjul-Fernández et al. 2010).

Gene Transcription and Regulation of Expression

MMP-9 gene is mapped on chromosome 20q11.2-q13.1 and has 13 exons. Regulation of MMP-9 is a coordinated attempt of gene transcription, proenzyme activation, and endogenous inhibitors. Regulation of the gene expression is mainly at transcriptional level besides epigenetic and posttranscriptional regulation (Fig. 1). Classical activation includes disruption of the interaction between the zinc molecule in the catalytic domain and the cysteine switch in the pro-domain of MMP9. This leads to cleavage of the pro-domain and production of active enzyme. However, pro-MMPs can be activated by two mechanisms – proteolytic cleavage and allosteric activation. Furthermore, tissue inhibitor metalloproteinases (TIMP), endogenous inhibitors also regulate MMP expression, in specific TIMP-1 inhibits mainly MMP-9 but can inhibit all MMPs except MMP-14 (Fanjul-Fernández et al. 2010; Iyer et al. 2012; Hadler-Olsen et al. 2011).
MMP-9, Fig. 1

Schematic representation of different levels of regulation of expression of MMP-9 with various binding sites on its promoter

Protein Structure and Distribution

MMP-9 belongs to the gelatinase subgroup of MMPs due to its ability to degrade the specific substrate called gelatin. Though, the constitutive physiological MMP expression is normally low, transient higher expression could be expected during homeostasis linked matrix remodeling or specific developmental events. MMP-9 is secreted by a wide number of cell types, including neutrophils, macrophages, and fibroblasts. MMP-9 is also expressed by osteoblsts as its expression thought to be expressed by RUNX-2, it also supports its expression in osteoblasts (Löffek et al. 2011). The main structural components of human MMP-9 are an NH2-terminal pro-domain, a catalytic domain, a linker domain, and a COOH-terminal hemopexin-like domain. The catalytic domain of MMP-9 contains two zinc ions, five calcium ions, and three repeats homologous to the type II module of fibronectin. The zinc ions of the catalytic domain along with cysteine rich motif of the pro-domain of MMP-9 are structurally coordinated to keep the molecule inactive. The fibronectin-like domain is heavily O-glycosylated and also responsible for binding to denatured collagen or gelatin. Hemopexin-like domain, which shares a sequence similarity to plasma hemopexin, forms a tight complex with TIMP-1 and TIMP-3 though their COOH-terminal domains in pro-MMP-9. This complex formation occurs in Golgi apparatus before its secretion which leaves amino terminus capable of inhibiting other MMPs (Yabluchanskiy et al. 2013) (Fig. 2).
MMP-9, Fig. 2

Detailed structure of MMP-9 with the functional domains

MMP-9 in Physiology

MMPs have a well established role in degradation of extracellular matrix (ECM), so they are thought to be involved in ECM remodeling specially in tissue growth and morphogenesis. MMP-9 activity is required during embryological development and maintenance of physiology through (1) degradation of ECM molecules and allow cell migration; (2) modulation of the activity of biologically active molecules by direct cleavage, release from bound stores, or the modulating of the activity of their inhibitors.

Cell Migration

ECM behaves as a barrier for cell migration during early phase of embryogenesis. The in vitro studies using assays of cell migration observed the secretion of MMP-9 by trophoblast during implantation suggesting its potential to mediate physiological migration of cell by acting on specific substrate. In addition, during development of nervous system, MMP-9 also plays a crucial role in neurite growth, a phenomenon through which neurons extend their processes over long distances to form connections. In long bone development, migration of preosteoclastic cells is largely mediated by their increased MMP-9 expression so that they can invade the cartilage to initiate the process of endochondral ossification (Bruni-Cardoso et al. 2010).

Modulation of Bioactive Molecules

Several biological active molecules get proteolytically cleaved by MMP-9 to acquire new activities. For example, Angiostatin is a fragment of plasminogen produced by cleavage mediated by MMP-9 to act as a potent angiogenesis inhibitor. Likewise, activation of IL-1β can be processed from its precursor by MMP-9. So prolonged incubation with MMPs results in IL-1β degradation and loss of its biological activity. MMPs may also cleave cell surface molecules, thereby modulating their activity. An example is alteration in signal tansducing property of gelactin-3. Cleavage of galectin-3 by MMP-9 alters the carbohydrate recognition domain of galectin-3 and reduces self-association of the galectin molecules. MMP-9 cleaves and activates many immune-related molecules such as interleukin-8 to its more potent truncated form and activates IL-1β and transforming growth factor β. Proteomics techniques revealed a role of active MMP-9 in shedding β2 integrin from macrophages. Besides these contributions, MMP-9 has been described to release the biologically active form of vascular endothelial growth factor (VEGF) which is complemented by the direct proteolytic degradation of vascular basement membrane proteins, indicating that MMP-9 may play a crucial role in the formation of new blood vessels (Vu and Werb 2000; Klein and Bischoff 2011).

MMP-9 in Diseases

Various experimental cell line and clinical studies have implicated role of MMP9 in many human diseases including respiratory diseases, cardiovascular disorders, neuropsychiatric disorder, autoimmune diseases, and cancer. Recently, MMP9 has been shown to be increasingly important in several aspects of central nervous system activity. Furthermore, a pathogenic role for this enzyme has been suggested in such neuropsychiatric disorders as schizophrenia, bipolar illness, and multiple sclerosis. Genetic aspect of etiopathogenic role of MMP-9 suggests the relation between T allele of the 1562 polymorphism of MMP9 gene to its increased transcriptional activity of the gene specially in aforementioned diseases and disorders.

Respiratory Diseases

The role of gelatinases in pathology has been studied extensively, especially in lung diseases like asthma and chronic obstructive pulmonary disease (COPD). If not in chronic asthma, increased MMP-9 and the MMP-9/TIMP-1 ratio are found to be useful indicator in exacerbations of acute asthma. This phenomenon may be explained by increase in MMP-9 concentration in infiltrating neutrophils that is released during the asthmatic attack. Degranulation of neutrophil granule leads to an increase in the local concentration of proteolytically active MMP-9, which contributes in the symptoms observed in acute asthma via various mechanisms like airway obstruction due to desquamation of epithelial cells and increased mucus production by goblet cells. Ability of MMP-9 to cause ECM destruction and degradation of α1-protease inhibitor is thought to be an important factor in COPD development and its progression. MMP-9 is further capable of chemotaxis of neutrophils (a major source of MMP-9) by production of the biologically more active truncated form of IL-8, causing a vicious circle of MMP-9 activity in the lung pathology.

Cardiovascular Diseases

In cardiovascular diseases like coronary artery diseases, hypertrophic cardiomyopathy, aortic aneurysm, and hypertensive diseases, serum MMP-9 has been considered to be a valuable prognostic indicator. In plaque formation, one of the important pathogenic roles of MMP-9 includes increased migration and proliferation of vascular smooth muscle cells through elastic lamina into the intimal space. Likewise, both human and animal studies have shown a relationship between elevated MMP-9 levels and abdominal aortic aneurysms. Altered level of MMP-9 and its genetic polymorphism were found to be related with poorer prognosis of coronary heart disease (Rybakowski 2009).

MMPs in Cancer

Since its first isolations, evidences supporting the close association of MMP-9 and various domains of carcinogenesis (cell proliferation, survival, association with inflammation, angiogenesis, cell migration, metastatic niche formation) are mounting up in various cancers like ovarian, gastric, oral, and breast cancer (Fig. 3). MMP-9 is a proteolytic enzyme that degrades basal membrane and the extracellular matrix which are prerequisite steps of carcinogenesis. Sequentially it has the ability to promote cancer progression by increasing cancer cell proliferation, migration, invasion, metastasis, and angiogenesis by exploiting its physiological role like cleaving a diverse group of substrates, including structural components of the extracellular matrix, growth factor-binding proteins, growth factor precursors, receptor tyrosine kinases, cell-adhesion molecules, and other proteinases. Expression of MMP-9 by both tumor and stromal cells make the scenario more complex as both bidirectional talk between these cells via MMP-9 influences the cancer biology to a large extent (Wu et al. 2014; Kessenbrock et al. 2010).
MMP-9, Fig. 3

Putative role of MMP-9 in tumorigenesis with controversial aspect of its effect on angiogenesis


Combining all the physiological and pathological regulatory effects of MMP-9, it can be appreciated that we are only at the tip of iceberg to understand its nonproteolytic functions, and hence further studies are required for in-depth analysis and evaluation of its pathophysiologic role in various human diseases. However, it is also tempting to explore the exact functions of MMP-9 beside proteolysis and utility of the all structural domain in the field of anticancer therapeutics.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Niharika Swain
    • 1
  • Jigna Pathak
    • 1
  • Shilpa Patel
    • 1
  • Rashmi Maruti Hosalkar
    • 2
    • 3
  1. 1.MGM Dental College and HospitalNavi MumbaiIndia
  2. 2.Indian Association of Oral and Maxillofacial PathologistsMumbaiIndia
  3. 3.Maharashtra State Dental CouncilMumbai, MaharashtraIndia