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COMMENTARY
Year : 2014  |  Volume : 140  |  Issue : 5  |  Page : 585-587

Role of matrix metalloproteinases in physiological processes & disease


1 Asian Healthcare Foundation , Hyderabad 500 082, Telangana, India
2 Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, Telangana, India

Date of Web Publication9-Jan-2015

Correspondence Address:
D Nageshwar Reddy
Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, Telangana
India
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Source of Support: None, Conflict of Interest: None


PMID: 25579138

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How to cite this article:
Ravi Kanth V V, Reddy D N. Role of matrix metalloproteinases in physiological processes & disease. Indian J Med Res 2014;140:585-7

How to cite this URL:
Ravi Kanth V V, Reddy D N. Role of matrix metalloproteinases in physiological processes & disease. Indian J Med Res [serial online] 2014 [cited 2020 Sep 21];140:585-7. Available from: http://www.ijmr.org.in/text.asp?2014/140/5/585/148920

Proteases are enzymes that catalyze proteins by hydrolyzing peptide bonds that link the amino acids. Metzincins are a universally expressed family of multidomain zinc (II)-dependent endopeptidases [1],[2] , which includes metalloproteases such as matrix metalloproteinases (MMPs) [3] . A highly conserved motif containing 3 histidines that bind to zinc at the catalytic site and a conserved methionine that sits beneath the active site distinguishes the metzincin super family from others [4] . Metzincins, apart from participating in the digestion of proteins, tissue development, maintenance and remodelling, are also involved in highly specific cleavage events to activate or inactivate themselves or other proenzymes or active enzymes and bioactive peptides [5] . The MMPs dependence on metal ions as cofactors, their ability to degrade extracellular matrix and their specific evolutionary DNA sequence distinguish them from other endopeptidases [6] .

High levels of MMPs are usually observed in disease state and pathological processes involved in connective tissue degradation such as inflammation [7] . Timely degradation of extracellular matrix (ECM) is an important feature of tissue repair and modelling and is precisely regulated under normal physiological conditions, but when dysregulated, it is the cause of many diseases such as cancer, fibrosis in pancreatitis, etc[8] . Various types of proteinases are known to be implicated in ECM degradation, however, the major enzymes are MMPs also known as matrixins [9] .

Genes responsible for MMPs transcription are inducible and can also be activated by various chemicals such as phorbol esters. Transforming growth factor - beta (TGF-β), glucocorticoids and retinoic acid are some of the factors known to suppress the expression of matrix-metalloproteinase (MMP) genes. Activator proteins (AP) -1 and -2 sites, the polyomavirus enhancer-A binding protein-3 (PEA3) site, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) site, and the signal transducer and activator of transcription (STAT) site are some of the known key transcription binding sites involved in the regulation of MMP genes. MMP genes may also be induced through various signaling pathways (inflammatory cytokines like tumour necrosis factor and interleukin-1 indirectly influence the expression of MMP genes and trigger the ceramide signaling pathway). Finally and importantly, natural sequence variations in the promoter regions of the MMP genes may also modify the expression of the genes [7] .


   Plasma MMP levels, promoter polymorphisms and risk of pancreatitis Top


Several studies [10],[11],[12] have identified that plasma MMP-1, MMP-2, MMP-7 and MMP-9 levels may be susceptibility factor for chronic pancreatitis with higher levels associated with the pancreatitis group. Functional polymorphism of MMP-3 (5A/6A) was not associated with chronic pancreatitis (CP), however, higher levels of the protein were seen in the diseased group [13] . Another study [14] revealed a significant association of the MMP-1 -1607 1G/2G (rs1799750) gene promoter polymorphism with Indian CP. Polymorphisms in the promoter regions of MMP-2 (-1306 C>T, -735C>T), MMP-7 (-181 A>G) and MMP-9 (-1562 C>T) have been reported to be functional polymorphisms [15] . Shek et al[16] examined MMP and tissue inhibitor of metalloproteinase (TIMP) synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-β and concluded that pancreatic stellate cells expressed both mediators of matrix remodelling and the regulatory cytokine TGF- β 1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.


   Future perspectives Top


The precise role of these proteins in various pathways and their role in carcinogenesis, other tumour related processes, fibrosis in pancreatitis etc., needs to be understood. t0 here is a great potential in developing drugs that inhibit MMPs and studying the effects elicited by such drugs on critical aspects of pancreatitis and other important diseases. An interesting approach apart from synthetic MMPs inhibitor is the use of gene therapy aimed at delivering TIMPs at the site of the disease [17],[18] . Moreover, there is a new field of non-catalytic targeting of MMPs via substrate-targeted inhibitors. There is also a possibility to regulate transcription, activation and inhibition of MMPs, which may help in designing newer strategies to block their unwanted activity in disease process.

The first generation of MMP inhibitor drugs was based on the structure of collagen molecule. The MMP inhibitors first tested in patients could not show good oral bioavailability [19] . Most MMP inhibitors are unable to target specific MMPs associated with specific pathological conditions, instead these inhibit multiple MMPs, some of which might have protective functions [20] . Therefore, the primary goal of MMP inhibitor design is selectivity. The targeting of specific MMPs is expected to improve efficacy and prevent side effects. Three dimensional (3D) structure analyses of MMPs could provide a source of insight of the structural relationships for selectivity.

In general, individual single nucleotide polymorphisms (SNPs) have limited value as predictors of complex multifactorial disease because of their modest effect on the phenotype. The ability to predict the susceptibility of a population to a disease increases tremendously with identification of newer susceptibility loci. SNPs in various genes have been identified for chronic pancreatitis namely SPINK1, chymotrypsin C (CTRC), calcium sensing receptor (CASR), trypsinogen gene (PRSS1, 2 and 3), cathepsin B (CTSB), serine protease inhibitor kazal type 1 (SPINK1/PST1), cystic fibrosis trans-membrane conductance regulator (CFTR) gene [21] . Most of these are in the pancreatic trypsin regulatory mechanism, however, many genetic factors outside this mechanism are being discovered for their role in pancreatitis namely claudin-2 (CLDN2), carboxypeptidase A1 (CPA1), etc. The study by Sri Manjari et al[22] in this issue looked at the association between a SNP in MMP-7 gene (-181 A/G, rs11568818), serum levels of the protein and chronic pancreatitis. They report a significant association of the GG genotype with the disease, however, there is no significant difference in the serum levels of MMP-7 between patients and controls. Further, they suggest that there is a high risk of pancreatitis in alcoholics and those with the GG genotype. Finally, the polymorphisms identified in MMP genes with functional significance could add to the already existing markers for pancreatitis and could be used in the diagnostic workup for patients with pancreatitis.

 
   References Top

1.
Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: Multidomain proteins with multiple functions. Genes Dev 2003; 17 : 7-30.  Back to cited text no. 1
    
2.
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3.
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4.
Oberholzer A, Bumann M, Hege T, Russo S, Baumann U. Metzincin's canonical methionine is responsible for the structural integrity of the zinc-binding site. Biol Chem 2009; 390 : 875-81.  Back to cited text no. 4
    
5.
Gomis-R. h FX. Catalytic domain architecture of metzincin metalloproteases. J Biol Chem 2009; 284 : 29077-86.  Back to cited text no. 5
    
6.
Combier JP, Vernie T, de Billy F, El Yahyaoui F, Mathis R, Gamas P. The MtMMPL1 early nodulin is a novel member of the matrix metalloendoproteinase family with a role in Medicago truncatula infection by Sinorhizobium meliloti. Plant Physiol 2007; 144 : 703-16.  Back to cited text no. 6
    
7.
Zitka O, Kukacka J, Krizkova S, Huska D, Adam V, Masarik M, et al. Matrix metalloproteinases. Curr Med Chem 2010; 17 : 3751-68.  Back to cited text no. 7
    
8.
Lu P, Takai K, Weaverr VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 2011; 3pii: a005058.  Back to cited text no. 8
    
9.
Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69 : 562-73.  Back to cited text no. 9
    
10.
Venkateshwari A, Sri Manjari K, Krishnaveni D, Nallari P, Vidyasagar A, Jyothy A. Role of Plasma MMP 9 levels in the pathogenesis of chronic pancreatitis. Indian J Clin Biochem 2011; 26 : 136-9.  Back to cited text no. 10
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11.
Sri Manjari K, Nallari P, Vidyasagar A, Jyothy A, Venkateshwari A. Plasma TGF-β1, MMP-1 and MMP-3 levels in chronic pancreatitis. Indian J Clin Biochem 2012; 27 : 152-6.  Back to cited text no. 11
    
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Muhs BE, Patel S, Yee H, Marcus S, Shamamian P. Increased matrix metalloproteinase expression and activation following experimental acute pancreatitis. J Surg Res 2001; 101 : 21-8.  Back to cited text no. 12
    
13.
Sri Manjari K, Krishnaveni D, Vidyasagar A, Prabhakar B, Jyothy A, Nallari P, et al. Role of matrix metalloproteinase 3 gene promoter polymorphism in chronic pancreatitis. Indian J Gastroenterol 2011; 30 : 217-20.  Back to cited text no. 13
    
14.
Sri Manjari K, Nallari P, Balakrishna N, Vidyasagar A, Prabhakar B, Jyothy A, et al. Influence of matrix metalloproteinase-1 gene -1607 (1G/2G) (rs1799750) promoter polymorphism on circulating levels of MMP-1 in chronic pancreatitis. Biochem Genet 2013; 51 : 644-54.  Back to cited text no. 14
    
15.
Peng B, Cao L, Ma X, Wang W, Wang D, Yu L. Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 2010; 25 : 371-9.  Back to cited text no. 15
    
16.
Shek FW, Benyon RC, Walker FM, McCrudden PR, Pender SL, Williams EJ, et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 2002; 160 : 1787-98.  Back to cited text no. 16
    
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Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002; 115 : 3719-27.  Back to cited text no. 17
    
18.
Zacchigna S, Zentilin L, Morini M, Dell'Eva R, Noonan DM, Albini A, et al. AAV-mediated gene transfer of tissue inhibitor of metalloproteinases-1 inhibits vascular tumor growth and angiogenesis in vivo. Cancer Gene Ther 2004; 11 : 73-80.  Back to cited text no. 18
    
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Brown PD. Matrix metalloproteinase inhibitors in the treatment of cancer. Med Oncol 1997; 14 : 1-10.  Back to cited text no. 19
    
20.
Durrant JD, de Oliveira CAF, McCammon JA. Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors. Chemical Biol Drug Design 2011; 78 : 191-8.  Back to cited text no. 20
    
21.
Ravi Kanth VV, Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: An update. World J Gastrointest Pathophysiol 2014; 5 : 427-37.  Back to cited text no. 21
    
22.
Sri Manjari K, Jyothy A, Shravan Kumar P, Prabhakar B, Nallari P, Venkateshwari A. Association of matrix metalloproteinase-7 (-181 A/G) promoter polymorphism in chronic pancreatitis. Indian J Med Res 2014; 140 : 609-14.  Back to cited text no. 22
    




 

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