Alternative titles; symbols
HGNC Approved Gene Symbol: MMP8
SNOMEDCT: 312974005;
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,711,796-102,724,954 (from NCBI)
Neutrophil collagenase, a member of the family of matrix metalloproteinases, is distinct from the collagenase of skin fibroblasts and synovial cells in substrate specificity and immunologic crossreactivity. Hasty et al. (1990) cloned and sequenced a cDNA encoding human neutrophil collagenase using a lambda-gt11 cDNA library constructed from mRNA extracted from the peripheral leukocytes of a patient with chronic granulocytic leukemia. The coding sequence predicts a 467-amino acid protein. It hybridized to a 3.3-kb mRNA from human bone marrow. Other features of the primary structure confirmed that neutrophil collagenase is a member of the family of matrix metalloproteinases (e.g., MMP1; 120353) but distinct from other members of the family. Neutrophil collagenase shows a preference for type I collagen in contrast with the greater susceptibility of type III collagen to digestion by fibroblast collagenase. Devarajan et al. (1991) isolated a 2.4-kb cDNA clone encoding human neutrophil collagenase. From its sequence, it was shown to encode a 467-residue protein which exhibited 58% homology to human fibroblast collagenase and had the same domain structure.
Yang-Feng et al. (1991) mapped the CLG1 gene to 11q21-q22 by in situ hybridization. The expression of neutrophil collagenase is closely linked to that of transcobalamin I in the secondary 'specific' granules of the granulocyte. Interestingly, the genes for both are located on the long arm of chromosome 11. 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--MMP3 (185250)--MMP12 (601046)--MMP7 (178990)--MMP13 (600108)--tel.
In a case-control study of African American neonates and 3 SNPs in the MMP8 gene (120355.0001), Wang et al. (2004) found a statistically significant association between the 3-minor-allele haplotype, which displayed the highest MMP8 promoter activity in trophoblast cells, and preterm premature rupture of membranes (PPROM; 610504), with an odds ratio (OR) of 4.63 (p less than 0.0001). Homozygosity for the major allele promoter haplotype appeared to be protective (OR = 0.52, p less than 0.0002).
Wang et al. (2006) found no evidence for linkage disequilibrium between a SERPINH1 -656C-T SNP (600943.0001), located approximately 27 Mb from MMP8 on chromosome 11q22.2 and also associated with PPROM in African American neonates, and the previously studied MMP8 alleles. The authors further noted that the previously described linkage disequilibrium within the MMP8 haplotype (17C-G and -799C-T) was confirmed in this study population.
Palavalli et al. (2009) performed mutation analysis of the MMP gene family in human melanoma and identified somatic mutations in 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8, reduced MMP enzyme activity. Expression of wildtype but not mutant MMP8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wildtype MMP8 has the ability to inhibit melanoma progression.
Nagase et al. (1992) provided a nomenclature and glossary of the matrix metalloproteinases, indicating neutrophil collagenase as matrix metalloproteinase-8.
Balbin et al. (2003) referred to matrix metalloproteinase-8 as collagenase-2. It is produced mainly by neutrophils in inflammatory reactions and detected in some malignant tumors. They found that loss of Mmp8 did not cause abnormalities during mouse embryonic development or in adult mice. Contrary to previous studies with Mmp-deficient mice, however, the absence of Mmp8 strongly increased the incidence of skin tumors in male Mmp8 -/- mice. Female Mmp8 -/- mice whose ovaries were removed or were treated with tamoxifen were also more susceptible to tumors compared with wildtype mice. Bone marrow transplantation experiments confirmed that Mmp8 supplied by neutrophils was sufficient to restore the natural protection against tumor development mediated by this protease in male mice. Histopathologic analysis showed that mutant mice had abnormalities in the inflammatory response induced by carcinogens. The study identified a paradoxical protective role for Mmp8 in cancer and provided a genetic model to evaluate the molecular basis of gender differences in cancer susceptibility.
Wang et al. (2004) identified 3 SNPs in the MMP8 gene, -799C-T, -381A-G, and 17C-G, the positions of which were numbered relative to the major transcription start site. A promoter fragment containing the 3 minor alleles (TGG) had 3-fold greater activity in chorion-like trophoblast cells compared with the major allele promoter construct. Differences in nuclear protein binding to oligonucleotides representing the -381A-G and -799C-T SNPs suggested that the minor alleles may have reduced transcription factor binding. A case-control study of African American neonates revealed a statistically significant association between the 3-minor-allele haplotype, which displayed the highest MMP8 promoter activity in trophoblast cells, and preterm premature rupture of membranes (PPROM; 610504), with an odds ratio (OR) of 4.63 (p less than 0.0001). Homozygosity for the major allele promoter haplotype appeared to be protective (OR = 0.52, p less than 0.0002).
Balbin, M., Fueyo, A., Tester, A. M., Pendas, A. M., Pitiot, A. S., Astudillo, A., Overall, C. M., Shapiro, S. D., Lopez-Otin, C. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet. 35: 252-257, 2003. [PubMed: 14517555] [Full Text: https://doi.org/10.1038/ng1249]
Devarajan, P., Mookhtiar, K., Van Wart, H., Berliner, N. Structure and expression of the cDNA encoding human neutrophil collagenase. Blood 77: 2731-2738, 1991. [PubMed: 1646048]
Hasty, K. A., Pourmotabbed, T. F., Goldberg, G. I., Thompson, J. P., Spinella, D. G., Stevens, R. M., Mainardi, C. L. Human neutrophil collagenase: a distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem. 265: 11421-11424, 1990. [PubMed: 2164002]
Nagase, H., Barrett, A. J., Woessner, J. F., Jr. Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl. 1: 421-424, 1992. [PubMed: 1480083]
Palavalli, L. H., Prickett, T. D., Wunderlich, J. R., Wei, X., Burrell, A. S., Porter-Gill, P., Davis, S., Wang, C., Cronin, J. C., Agrawal, N. S., Lin, J. C., Westbroek, W., and 12 others. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nature Genet. 41: 518-520, 2009. [PubMed: 19330028] [Full Text: https://doi.org/10.1038/ng.340]
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]
Wang, H., Parry, S., Macones, G., Sammel, M. D., Ferrand, P. E., Kuivaniemi, H., Tromp, G., Halder, I., Shriver, M. D., Romero, R., Strauss, J. F., III. Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM). Hum. Molec. Genet. 13: 2659-2669, 2004. [PubMed: 15367487] [Full Text: https://doi.org/10.1093/hmg/ddh287]
Wang, H., Parry, S., Macones, G., Sammel, M. D., Kuivaniemi, H., Tromp, G., Argyropoulos, G., Halder, I., Shriver, M. D., Romero, R., Strauss, J. F., III. A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. Proc. Nat. Acad. Sci. 103: 13463-13467, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19212 only, 2006. [PubMed: 16938879] [Full Text: https://doi.org/10.1073/pnas.0603676103]
Yang-Feng, T. L., Berliner, N., Deverajan, P., Johnston, J. Assignment of two human neutrophil secondary granule protein genes, transcobalamin I and neutrophil collagenase to chromosome 11. (Abstract) Cytogenet. Cell Genet. 58: 1974 only, 1991.