Alternative titles; symbols
HGNC Approved Gene Symbol: MMP12
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,862,736-102,874,982 (from NCBI)
The matrix metalloproteases (MMPs) are a family of related matrix-degrading enzymes that are important in tissue remodeling and repair during development and inflammation. Abnormal expression is associated with various diseases such as tumor invasiveness, arthritis, and atherosclerosis. MMP activity may also be related to cigarette-induced pulmonary emphysema. Shapiro et al. (1993) cloned a cDNA for a metalloproteinase produced by human alveolar macrophages, which are known to have the capacity to degrade elastin (130160), by screening an alveolar macrophage cDNA library and a genomic library with the previously cloned mouse gene (Shapiro et al., 1992). The human gene, which they designated HME (human macrophage metalloelastase), produces a 1.8-kb transcript encoding a 470-amino acid protein that is 64% identical to the mouse protein. Both the mRNA and protein were detected in alveolar macrophages. As in the mouse, the predicted human 54-kD protein is processed by loss of both N- and C-terminal residues to a 22-kD mature form. The authors showed that recombinantly expressed HME was able to degrade insoluble elastin.
Belaaouaj et al. (1995) localized the MMP12 gene to chromosome 11q22.2-q22.3 by fluorescence in situ hybridization. Pendas et al. (1996) isolated a 1.5-Mb YAC clone mapping to 11q22.3. Detailed analysis of this nonchimeric YAC clone ordered 7 MMP genes as follows: cen--MMP8 (120355)--MMP10 (185260)--MMP1 (120353)--MMP3 (185250)--MMP12--MMP7 (178990)--MMP13 (600108)--tel.
Belaaouaj et al. (1995) described the genomic organization of the HME gene (also symbolized MMP12). The 13-kb gene is composed of 10 exons and shares the highly conserved intron-exon borders of other MMPs. The authors also demonstrated tissue-specific expression in macrophages and stromal cells.
Curci et al. (1998) reported that the total MMP12 recoverable from abdominal aortic aneurysm (AAA; 100070) tissue was 7-fold greater than that from normal aorta. They demonstrated its distinct localization to residual elastic fiber fragments, indicating that the enzyme participates in aortic elastin degradation. They suggested that MMP12 has a more central role in aneurysm disease than do other elastolytic MMPs.
Hunninghake et al. (2009) tested for an association between SNPs in MMP12 and a measure of lung function, prebronchodilator forced expiratory volume in 1 second (FEV1), in more than 8,300 subjects in 7 cohorts that included children and adults. They also examined the association between these SNPs and development of COPD in the adult cohorts. Hunninghake et al. (2009) found that the minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109, -82A-G) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P = 2 x 10(-6)). This allele was also associated with a reduced risk of onset of COPD (see 606963) in the Normative Aging Study cohort (hazard ratio, 0.65; 95% CI, 0.46-0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (OR = 0.63; 95% CI, 0.45-0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006). Hunninghake et al. (2009) concluded that the minor allele of rs2276109 is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers. Hunninghake et al. (2009) noted that this minor allele has been associated with decreased promoter activity through less efficient binding of AP1 (165160) in both murine and human monocytic cell lines (Jormsjo et al., 2000), and that deletion of the AP1 binding site abolishes both basal and stimulated expression of MMP12 (Wu et al., 2003).
Hautamaki et al. (1997) demonstrated that macrophage elastase must be present for chronic cigarette smoke exposure to induce emphysema in mice. Mice homozygous for a knockout of the macrophage elastase gene (Mme -/-) (Shipley et al., 1996), in contrast to wildtype mice, did not show increased numbers of macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed Mme -/- mice that received monthly intratracheal instillations of monocyte chemoattractant protein-1 (158105) showed accumulation of alveolar macrophages but did not develop air space enlargement. Thus, Hautamaki et al. (1997) concluded that macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
Through a global analysis of pulmonary gene expression in the lungs of mice lacking integrin beta-6 (147558), Kaminski et al. (2000) identified a marked induction of macrophage metalloelastase, a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Morris et al. (2003) demonstrated that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta-6 integrin subunit that support TGFB activation, or by the loss of MMP12. Furthermore, Morris et al. (2003) showed that the effects of ITGB6 deletion are overcome by simultaneous transgenic expression of active TGFB1. Morris et al. (2003) concluded that they had uncovered a pathway in which the loss of integrin-mediated activation of latent TGFB causes age-dependent pulmonary emphysema through alterations of macrophage MMP12 expression. Furthermore, they showed that a functional alteration in the TGFB activation pathway affects susceptibility to this disease.
By examining the effects of an Il13 (147683) transgene on wildtype mice and mice lacking Mmp9 (120361) or Mmp12, Lanone et al. (2002) determined that the IL13-mediated eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung that occurs in asthma (600807), COPD (606963), and interstitial lung disease is dependent on both MMP9 and MMP12 mechanisms. The results indicated that MMP9 inhibits neutrophil accumulation, but, unlike MMP12, has no effect on eosinophil, macrophage, or lymphocyte accumulation. Furthermore, IL13-induced production of MMP2 (120360), MMP9, MMP13, and MMP14 (600754) was found to be dependent on MMP12.
Houghton et al. (2009) showed that Mmp12-null mice exhibited impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxyl-terminal domain. This domain contains a unique 4-amino acid sequence on an exposed beta-loop of the protein that is required for the observed antimicrobial activity. Houghton et al. (2009) concluded that their study represented the first report of direct antimicrobial activity by a matrix metallopeptidase, and described a new antimicrobial peptide that is sequentially and structurally unique in nature.
Joos et al. (2002) investigated the role of MMP polymorphisms (including G-1607GG in MMP1 and asn357ser in MMP12) in the development of chronic obstructive lung disease. The authors determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart, Lung, and Blood Institute Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of 5 polymorphisms among 3 MMP loci, only G-1607GG was associated with a rate of decline in lung function. This allele was associated with a fast rate of decline (p = 0.02). However, haplotypes consisting of alleles from the G-1607GG and asn357ser polymorphisms were associated with rate of decline of lung function (p = 0.0007). The authors concluded that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.
The elastase secreted by leukocytes (ELA2; 130130) is a serine protease inhibitable by alpha-1-protease inhibitor (107400), whereas the elastase secreted by macrophages is a metalloprotease not inhibitable by alpha-1-protease inhibitor (Rosenbloom, 1984).
Belaaouaj, A., Shipley, J. M., Kobayashi, D. K., Zimonjic, D. B., Popescu, N., Silverman, G. A., Shapiro, S. D. Human macrophage metalloelastase: genomic organization, chromosomal location, gene linkage, and tissue-specific expression. J. Biol. Chem. 270: 14568-14575, 1995. [PubMed: 7782320] [Full Text: https://doi.org/10.1074/jbc.270.24.14568]
Curci, J. A., Liao, S., Huffman, M. D., Shapiro, S. D., Thompson, R. W. Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J. Clin. Invest. 102: 1900-1910, 1998. [PubMed: 9835614] [Full Text: https://doi.org/10.1172/JCI2182]
Hautamaki, R. D., Kobayashi, D. K., Senior, R. M., Shapiro, S. D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277: 2002-2004, 1997. [PubMed: 9302297] [Full Text: https://doi.org/10.1126/science.277.5334.2002]
Houghton, A. M., Hartzell, W. O., Robbins, C. S., Gomis-Ruth, F. X., Shapiro, S. D. Macrophage elastase kills bacteria within murine macrophages. Nature 460: 637-641, 2009. [PubMed: 19536155] [Full Text: https://doi.org/10.1038/nature08181]
Hunninghake, G. M., Cho, M. H., Tesfaigzi, Y., Soto-Quiros, M. E., Avila, L., Lasky-Su, J., Stidley, C., Melen, E., Soderhall, C., Hallberg, J., Kull, I., Kere, J., and 14 others. MMP12, lung function, and COPD in high-risk populations. New Eng. J. Med. 361: 2599-2608, 2009. [PubMed: 20018959] [Full Text: https://doi.org/10.1056/NEJMoa0904006]
Joos, L., He, J.-Q., Shepherdson, M. B., Connett, J. E., Anthonisen, N. R., Pare, P. D., Sandford, A. J. The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum. Molec. Genet. 11: 569-576, 2002. Note: Erratum: Hum. Molec. Genet. 12: 803-804, 2003. [PubMed: 11875051] [Full Text: https://doi.org/10.1093/hmg/11.5.569]
Jormsjo, S., Ye, S., Moritz, J., Walter, D. H., Dimmeler, S., Zeiher, A. M., Henney, A., Hamsten, A., Eriksson, P. 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. 86: 998-1003, 2000. [PubMed: 10807873] [Full Text: https://doi.org/10.1161/01.res.86.9.998]
Kaminski, N., Allard, J. D., Pittet, J. F., Zuo, F., Griffiths, M. J., Morris, D., Huang, X., Sheppard, D., Heller, R. A. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Nat. Acad. Sci. 97: 1778-1783, 2000. [PubMed: 10677534] [Full Text: https://doi.org/10.1073/pnas.97.4.1778]
Lanone, S., Zheng, T., Zhu, Z., Liu, W., Lee, C. G., Ma, B., Chen, Q., Homer, R. J., Wang, J., Rabach, L. A., Rabach, M. E., Shipley, J. M., Shapiro, S. D., Senior, R. M., Elias, J. A. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110: 463-474, 2002. [PubMed: 12189240] [Full Text: https://doi.org/10.1172/JCI14136]
Morris, D. G., Huang, X., Kaminski, N., Wang, Y., Shapiro, S. D., Dolganov, G., Glick, A., Sheppard, D. Loss of integrin alpha-v-beta-6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422: 169-173, 2003. [PubMed: 12634787] [Full Text: https://doi.org/10.1038/nature01413]
Pendas, A. M., Santamaria, I., Alvarez, M. V., Pritchard, M., Lopez-Otin, C. Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics 37: 266-269, 1996. [PubMed: 8921407] [Full Text: https://doi.org/10.1006/geno.1996.0557]
Rosenbloom, J. Elastin: relation of protein and gene structure to disease. Lab. Invest. 51: 605-623, 1984. [PubMed: 6150137]
Shapiro, S. D., Griffin, G. L., Gilbert, D. J., Jenkins, N. A., Copeland, N. G., Welgus, H. G., Senior, R. M., Ley, T. J. Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metalloelastase. J. Biol. Chem. 267: 4664-4671, 1992. [PubMed: 1537850]
Shapiro, S. D., Kobayashi, D. K., Ley, T. J. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 268: 23824-23829, 1993. [PubMed: 8226919]
Shipley, J. M., Wesselschmidt, R. L., Kobayashi, D. K., Ley, T. J., Shapiro, S. D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Nat. Acad. Sci. 93: 3942-3946, 1996. [PubMed: 8632994] [Full Text: https://doi.org/10.1073/pnas.93.9.3942]
Wu, L., Tanimoto, A., Murata, Y., Sasaguri, T., Fan, J., Sasaguri, Y., Watanabe, T. Matrix metalloproteinase-12 gene expression in human vascular smooth muscle cells. Genes Cells 8: 225-234, 2003. [PubMed: 12622720] [Full Text: https://doi.org/10.1046/j.1365-2443.2003.00628.x]