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
Protein Structure and Distribution
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.
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.
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.
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
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.