Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of global morbidity and mortality. COPD usually arises from an interaction between both host and environmental risk factors. Cigarette smoking is the major known environmental risk factor for the development of COPD, however, only a minority of smokers (approximately 15 to 20%) develop symptoms.
COPD is known to cluster in families, which suggests that there is a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often unclear. Here we review evidence that genetic polymorphisms in matrix metalloproteinase genes MMP1, MMP9 and MMP12 may be important in the development of COPD. In a Caucasian population, polymorphisms in the MMP1 and MMP12 genes, but not MMP9, have been suggested to be either causative factors in smoking-related lung injury or are in linkage disequilibrium with other causative polymorphisms. Another study found an association between an MMP9 polymorphism and the development of smoking-induced pulmonary emphysema in Japanese smokers.
Understanding the role of genetic polymorphisms in MMP1, MMP9 and MMP12 may help in the discovery of new and more effective therapies.
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References
Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163: 1256–76
World Health Organization. World health report [online]. Geneva: WHO, 2000. Available from URL: http://www.who.int/whr/2000/en/statistics.htm [Accessed 2002 Feb 3]
Canadian Lung Association [online]. Available from URL: http://www.lung.ca [Accessed 2001 Nov 20]
Peto R, Chen ZM, Boreham J. Tobacco: the growing epidemic. Nat Med 1999; 5: 15–7
Beck GJ, Doyle CA, Schachter EN. Smoking and lung function. Am Rev Respir Dis 1981; 123: 149–55
Givelber RJ, Couropmitree NN, Gottlieb DJ, et al. Segregation analysis of pulmonary function among families in the Framingham Study. Am J Respir Crit Care Med 1998; 157: 1445–51
Redline S, Tishler PV, Lewitter FI, et al. Assessment of genetic and nongenetic influences on pulmonary function: a twin study. Am Rev Respir Dis 1987; 135: 217–22
Nakamura Y, Leppert M, O’Connell P, et al. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 1987; 235: 1616–22
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822): 860–921
Halushka MK, Fan JB, Bentley K, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239–47
Eriksson S. Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl 1965; 432: 1–85
Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand 1978; 204: 345–51
Piitulainen E, Eriksson S. Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ). Eur Respir J 1999; 13: 247–51
Silverman EK, Province MA, Campbell EJ, et al. Biochemical intermediates in alpha1-antitrypsin deficiency: residual family resemblance for total alpha1-antitrypsin, oxidised alpha1-antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus. Genet Epidemiol 1989; 7: 137–49
Sandford AJ, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med 2000; 21: 633–43
Silverman EK, Chapman H, Drazen JM, et al. Severe, early-onset COPD: linkage analysis of chromosomes 5q and 12q [abstract]. Am J Respir Crit Care Med 1999; 159: A802
Gross P, Pfitzer E, Tolker E, et al. Experimental emphysema: its production with papain in normal and silicotic rats. Arch Environ Health 1965; 11: 50–8
Laurell CB, Eriksson S. The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: 132–40
Barrett AJ. Classification of peptidases. Methods Enzymol 1994; 244: 1–15
Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6: 121–5
Birkedal-Hansen H, Moore WG, Bodden MK, et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993; 4: 197–250
Woessner Jr JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991; 5: 2145–54
Opdenakker G, Van den Steen PE, Dubois B, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001; 69: 851–9
Murphy G, Willenbrock F, Crabbe T, et al. Regulation of matrix metalloproteinase activity. Ann N Y Acad Sci 1994; 732: 31–41
Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997; 378: 151–60
Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997; 74:111–22
Woessner Jr JF. Matrix metalloproteinase inhibition: from the Jurassic to the third millennium. Ann N Y Acad Sci 1999; 878: 388–403
Mignatti P, Robbins E, Rifkin DB. Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 1986; 47: 487–98
Khokha R, Waterhouse P, Yagel S, et al. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 1989; 243: 947–50
McCachren SS. Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. Arthritis Rheum 1991; 34: 1085–93
Dean DD, Martel-Pelletier J, Pelletier JP, et al. Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989; 84: 678–85
Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A 1991; 88: 8154–8
Brophy CM, Reilly JM, Smith GJ, et al. The role of inflammation in nonspecific abdominal aortic aneurysm disease. Ann Vasc Surg 1991; 5: 229–33
Pozzi A, LeVine WF, Gardner HA. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene 2002 Jan 10; 21: 272–81
Zhu Y, Spitz MR, Lei L, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. Cancer Res 2001 Nov 1; 61: 7825–9
Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res 1998; 58: 5321–5
Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res 1999; 59: 4225–7
Nishioka Y, Kobayashi K, Sagae S, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter in endometrial carcinomas. Jpn J Cancer Res 2000 Jun; 91: 612–5
Murray GI, Duncan ME, O’Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med 1996; 2: 461–2
Murray GI, Duncan ME, O’Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol 1998; 185: 256–61
Hewitt RE, Leach IH, Powe DG, et al. Distribution of collagenase and tissue inhibitor of metalloproteinases (TIMP) in colorectal tumours. Int J Cancer 1991; 49: 666–72
Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997; 89: 1260–70
Joos L, He JQ, Shepherdson MB, et al. The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet 2002; 11:569–76
Zhang B, Henney A, Eriksson P, et al. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2–13.1. Hum Genet 1999; 105: 418–23
Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 1999; 99: 1788–94
Shimajiri S, Arima N, Tanimoto A, et al. Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 1999; 455: 70–4
Comings DE. Polygenic inheritance and micro/minisatellites. Mol Psychiatry 1998; 3: 21–31
Jormsjo S, Ye S, Moritz J, et al. Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ Res 2000 May 12; 86: 998–1003
D’Armiento J, Dalai SS, Okada Y, et al. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 1992; 71: 955–61
Hautamaki RD, Kobayashi DK, Senior RM, et al. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997; 277: 2002–4
Gerhard DS, Jones C, Bauer EA, et al. Human collagenase gene is located on 11q [abstract]. Cytogenet Cell Genet 1987; 46: 619
Buttice G, Duterque-Coquillaud M, Basuyaux JP, et al. Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene 1996; 13: 2297–306
Finlay GA, Russell KJ, McMahon KJ, et al. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997; 52: 502–6
Finlay GA, O’Driscoll LR, Russell KJ, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 1997; 156: 240–7
Segura-Valdez L, Pardo A, Gaxiola M, et al. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000 Mar; 117: 684–94
Imai K, Dalal SS, Chen ES, et al. Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am J Respir Crit Care Med 2001 Mar; 163: 786–91
Wilhelm SM, Collier IE, Manner BL, et al. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem 1989; 264: 17213–21
Huhtala P, Tuuttila A, Chow LT, et al. Complete structure of the human gene for 92-kDa type IV collagenase: divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J Biol Chem 1991; 266: 16485–90
Okada Y, Nagase H, Harris Jr ED. A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components: purification and characterization. J Biol Chem 1986; 261: 14245–55
Liotta LA, Tryggvason K, Garbisa S, et al. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980; 284: 67–8
Nordheim A, Rich A. The sequence (dC-dA)n X (dG-dT)n forms left-handed Z-DNA in negatively supercoiled plasmids. Proc Natl Acad Sci U S A 1983; 80: 1821–5
Haniford DB, Pulleyblank DE. Facile transition of poly[d(TG) x d(CA)] into a left-handed helix in physiological conditions. Nature 1983; 302: 632–4
Boone TC, Johnson MJ, De Clerck YA, et al. cDna cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proc Natl Acad Sci U S A 1990; 87: 2800–4
Carmichael DF, Sommer A, Thompson RC, et al. Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proc Natl Acad Sci U S A 1986; 83: 2407–11
Greene J, Wang M, Liu YE, et al. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 1996; 271: 30375–80
Leco KJ, Khokha R, Pavloff N, et al. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994; 269: 9352–60
Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phagocytes: potential roles in destructive lung disease. Am J Respir Crit Care Med 1994; 150: S160–4
Vignola AM, Riccobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med 1998; 158: 1945–50
Ohnishi K, Takagi M, Kurokawa Y, et al. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 1998; 78: 1077–87
Belaaouaj A, Shipley JM, Kobayashi DK, et al. Human macrophage metalloelastase: genomic organization, chromosomal location, gene linkage, and tissue-specific expression. J Biol Chem 1995; 270: 14568–75
Shapiro SD, Kobayashi DK, Ley TJ. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem 1993; 268: 23824–9
Werb Z, Gordon S. Elastase secretion by stimulated macrophages: characterization and regulation. J Exp Med 1975; 142: 361–77
Banda MJ, Werb Z. Mouse macrophage elastase: purification and characterization as a metalloproteinase. Biochem J 1981; 193: 589–605
Murphy G, Cockett MI, Ward RV, et al. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan: a quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J 1991; 277: 277–9
Senior RM, Griffin GL, Fliszar CJ, et al. Human 92- and 72-kilodalton type IV collagenases are elastases. J Biol Chem 1991; 266: 7870–5
Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1; the Lung Health Study. JAMA 1994; 272: 1497–505
Minematsu N, Nakamura H, Tateno H, et al. Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema. Biochem Biophys Res Commun 2001 Nov 23; 289: 116–9
Acknowledgements
Dr Wallace is supported by a Harry & Florence Dennison Fellowship in Medical Research. Dr Sandford was supported by a Parker B. Francis Fellowship and is a recipient of a Canada Research Chair in genetics.
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Wallace, A.M., Sandford, A.J. Genetic Polymorphisms of Matrix Metalloproteinases. Am J Pharmacogenomics 2, 167–175 (2002). https://doi.org/10.2165/00129785-200202030-00002
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DOI: https://doi.org/10.2165/00129785-200202030-00002