Matrix metalloproteinases: the most important pathway involved with periodontal destruction


  • A.P De Souza Piracicaba Dental School/University of Campinas
  • R.A Da Silva Piracicaba Dental School/University of Campinas
  • M.A.D Da Silva Piracicaba Dental School/University of Campinas
  • Sérgio Augusto Catanzaro Guimarães PRPPG/University of Sagrado Coração
  • Sergio Roberto Peres Line Piracicaba Dental School/University of Campinas



MMP. Cytokine. Periodontitis. Genes polymorphisms


Periodontitis is an infectious disease estimated to occur in approximately a third of adults over the age of 35, being the major cause of adult tooth loss. The tissue destruction seems to be regulated by four major pathways. Plasminogen-dependent, phagocytic, osteoclastic and matrix metalloproteinase pathway. The matrix metalloproteinases (MMPs) pathway seems to be the most relevant in periodontal disease. The purpose of the current study was to review the roles of MMPs on periodontal disease, with emphasis on periodontal ligament and alveolar bone destruction. Particular attention is given on the mechanisms that control MMPs genes transcription, the regulation of protein activity, and the influence of MMP genes polymorphisms in inflammatory diseases.


Download data is not yet available.


Metrics Loading ...

Author Biographies

Sérgio Augusto Catanzaro Guimarães, PRPPG/University of Sagrado Coração

Possui graduação em Odontologia pela Faculdade de Odontologia de Araraquara(1961), especialização em Patologia Bucal e Geral pela Sociedade Brasileira de Patologia(1975), doutorado em Patologia pela Universidade de São Paulo(1967) e pós-doutorado pela Temple University School Of Medicine Usa(1972).

Sergio Roberto Peres Line, Piracicaba Dental School/University of Campinas

has graduation at Odontologia by Universidade Estadual de Campinas (1985) , Ph.D. at Patologia Experimental e Comparada by Universidade de São Paulo (1989) and Postdoctorate by National Institute Of Health (1991) . Currently is Servidor público ou celetista of Universidade Estadual de Campinas, Membro de corpo editorial of Journal of Applied Oral Science (Impresso), Membro de corpo editorial of Brazilian Journal of Oral Sciences (Impresso) e of Faculdade de Odontologia de Piracicaba-UNICAMP. Has experience in the area of Odontology. Focused, mainly, in the subjects: Laminina, Matriz extracelular, Menbrana Basal, Metaloproteases. 


Birkedal-Hansen H. Role of matrix metalloproteinase in human periodontal diseases. J Periodontol. 1993; 64(5 Suppl): 474-84.

Woessner Jr JF. The matrix metalloproteinase family. In: Parks WC, Mecham RP, editors. Matrix metalloproteinases. New York: Academic Press; 1998. p.1-14 3. Murphy G, Knäuper V. Relating matrix metalloproteinases structure to function: Why the “hemopexin”domain? Matrix Biol. 1997; 15: 511-8.

Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Ann Rev Cell Dev Biol. 2001; 17: 463-516.

Lohi J, Wilson CL, Roby JD, Parks WC. Epilysin: a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem. 2001; 276: 10134-44.

Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem. 1999; 274: 21491-4.

Reynolds JJ, Meikle MC. Mechanisms of connective tissue matrix destruction in periodontitis. Periodontol 2000. 1997; 14: 144-57.

Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004; 4: 617-29.

Johnson LL, Dyer R, Hupe DJ. Matrix metalloproteinases. Curr Opin Chem Biol. 1998; 2: 466-71.

Kerkvliet EH, Docherty AJP, Beertsen W, Everts V. Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase. Matrix Biol. 1999; 18: 373-80.

Damiens C, Fortun Y, Charrier C, Heymann D, Padrines M. Modulation by soluble factors of gelatinase activities released by osteoblastic cells. Cytokine. 2000; 12: 1727-31.

Page RC. The role of inflammatory mediators in the pathogenesis of periodontal disease. J Periodontal Res. 1991; 26: 230-42.

Page RC. Host response tests for diagnosing periodontal diseases. J Periodontol. 1992; 63: 356-66.

Genco RJ. Host responses in periodontal diseases: current concepts. J Periodontol. 1992; 63: 338-55.

Makela M, Salo T, Uitto VJ, Larjava H. Matrix metalloproteinases (MMP-2 and MMP-9) of the oral cavity: cellular origin and relationship to periodontal status. J Dent Res. 1994; 73: 1397-1406.

Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 2000. 1997; 14: 216-48.

Séguier S, Gogly B, Bodineau A, Godeau G, Brousse N. Is collagen breakdown during periodontitis linked to inflammatory cells and expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gingival tissue. J Periodontol. 2001; 72: 1398-1406.

Ejeil AL, Igondjo-Tchen S, Ghomrasseni S, Pellat B, Godeau G, Gogly B. Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy and disease human gingiva. J Periodontol. 2003; 74: 188-95.

Eeckhout Y, Delaisse JM. The role of collagenase in bone resorption: an overview. Pathol Biol. 1988; 36: 1139-46.

Holliday LS, Welgus HG, Fliszar CJ, Veith GM, Jeffrey JJ, Gluck SL. Initiation of osteoclast bone resorption by intersttial collagenase. J Biol Chem. 1997; 272: 22053-8.

Uchida M, Shima M, Shimoaka T, Fujieda A, Obara K, Suzuki H, et al. Regulation of matrix metalloproteinases (MMPS) and tissue inhibitors of metalloproteinases (TIMPs) by bone resorptive factors in osteoblastic cells. J Cell Physiol. 2000; 185: 207-14.

Freije JM, Diez-Itza I, Balbin M, Sanchez LM, Blasco R, Tolivia J. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994; 269: 16766–73.

Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, et al. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest. 1996; 97: 761–8.

Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J. The new collagenase, collagenase-3, is ex pressed and synthesized by human chondrocytes but not by synoviocytes: A role in osteoarthritis. J Clin Invest. 1996; 97: 2011–9.

Wernicke D, Seyfert C, Hinzmann B, Gromnica-Ihle E. Cloning of collagenase-3 from the synovial membrane and its expression in rheumatoid arthritis and osteoarthritis. J Rheumatol. 1996; 23: 590–5.

Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G. Biochemical characterization of human collagenase-3. J Biol Chem. 1996; 271: 1544–50.

Johansson N, Saarialho-Kere U, Airola K, Herva R, Nissinen L, Westermarck J, et al. Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development. Dev Dyn. 1997; 208: 387-97.

Stahle-Backdahl M, Sandstedt B, Bruce K, Lindahl A, Jimenez MG, Vega JA, et al. Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis. Lab Invest. 1997; 76: 717-28.

Okada Y, Naka K, Kawamura K, Matsumoto T, Nakanishi I, Fujimoto N, et al. Localization of matrix metalloproteinase, 9 (92-kilodalton gelatinase/ type IV collagenase = gelatinase B) in osteoclasts: implications for bone resorption. Lab Invest. 1995; 72: 311-22.

Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, et al. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology. 1998; 139: 1338-45.

Inui T, Ishibashi O, Origane Y, Fujimori K, Kokubo T, Nakajima M. Matrix metalloproteinases and lysosomal cysteine proteases in osteoclasts contribute to bone resorption through distinct modes of action. Biochem Biophys Res Commun. 1999; 29: 173-8.

Uchida M, Shima M, Chikazu D, Fujieda A, Obara K, Suzuki H. Transcriptional induction of matrix metalloproteinase-13 (collagenase-3) by 1alpha,25-dihydroxyvitamin D3 in mouse osteoblastic MC3T3-E1 cells. J Bone Miner Res. 2001; 16: 221-30.

Ramamurthy NS, Rifkin BR, Greenwald RA, Xu JW, Liu Y, Turner G, et al. Inhibition of matrix metalloproteinase mediated periodontal bone loss in rats: A comparison of 6 chemically modified tetracyclines. J Periodontol. 2002; 73: 726-34.

Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 1990; 6: 121-5.

Fini ME, Cook JR, Mohan R, Brinckerhoff CE. Regulation of matrix metalloproteinases gene expression. In: Parks WC, Mecham RP, editors. Matrix Metalloproteinases. New York: Academic Press; 1998. p.299-356.

Ye S. Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol. 2000; 19: 623-9.

Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995; 270: 5331-8.

Overral CM, Wrana JL, Sodek J. Transcriptional and posttranscriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-b1 in human fibroblasts Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem. 1991; 266: 14064-71.

Kheradmand F, Werner E, Tremble P, Symons M, Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science. 1998; 280: 898-902.

Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997; 1: 13-23.

Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1997; 1: 25-34.

Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463-516.

Uria JA, Jimenez MG, Balbin M, Freije JM, Lopez-Otin C. Differential effects of transforming growth factor-beta on the expression of collagenase-1 and collagenase-3 in human fibroblasts. J Biol Chem. 1998; 273: 9769-77.

Julovi SM, Yasuda T, Shimizu M, Hiramitsu T, Nakamura T. Inhibition of interleukin-1beta-stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage. Arthritis Rheum. 2004; 50: 516-25.

Liacini A, Sylvester J, Li WQ, Huang W, Dehnade F, Ahmad M et al. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Expe Cell Res. 2003; 288: 208-17.

Opdenakker G, den Steen PEV, Dubois B, Nelissen I, Coillie EV, Masure S, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol. 2001; 69: 851-9.

Overral CM. Molecular determinantes of metalloproteinase substrate specificity. Matrix metalloproteinase substrate binding domains, modules and exosites. Mol Biotechnol. 2002; 22: 51-86.

Stern DL.. Perspective: Evolutionary developmental biology and the problem of variation. Evolution. 2000; 54: 1079-91.

Arnone MI, Davidson EH. The hardwiring of development: organization and function of genomic regulatory systems. Development. 1997;124: 1851-64.

Rutter JL, Mitchell TI, Butticè G, Meyer J, Gusella JF, Ozelius LJ, 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, Kobayashi K, Sagae S, Kt Terakawa N, et al. Correlation between expression of the matrix metalloproteinase gene in ovarian cancers and an insertion/deletion polymorphism its promoter region. Cancer Res. 1999; 59: 4225-7.

Noll WW, Belloni DR, Rutter JL, Storm CA, Schned AR, TitusErnstaff L, et al. Loss of heterozygosity on chromosome 11q22- 23 in melanoma is associated with retention of the insertionpolymorphism in the matrix metalloproteinase-1 promoter. Am J Pathol. 2001; 158: 691-7.

Souza AP, Trevilatto PC, Scarel-Caminaga RM, de Brito Jr RB, Line SRP. MMP-1 promoter polymorphism: association with chronic periodontitis severity in a Brazilian population. J Clin Periodontol. 2003; 30: 154-8.

Santos MCL, Campos MIG, de Souza AP, Trevilatto PC, Line SRP. Analysis of MMP-1 and MMP-9 promoter polymorphism in early osseointegrated implant failure. Int J Oral Maxillofac Implants. 2004; 19: 38-43.

Itagaki M, Kubota T, Tai H, Shimada Y, Morozumi T, Yamazaki K. Matrix metalloprotenase-1 and –3 gene promoter polymorphisms in Japanese patientis with periodontitis. J Clin Periodontol. 2004; 31: 764-9.

Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999; 99: 1788-94.

Wang J, Warzecha D, Wilcken D, Wang XL. Polymorphism in the gelatinase B gene and the severity of coronary arterial stenosis. Clin Sci. 2001; 101: 87-92.

Shimajiri S, Arima N, Tanimoto A, Murata Y, Hamada T, Wang KY, et al. Shortened microsatellite d(CA)21 sequence downregulates promoter activity of matrix metalloproteinase-9 gene. FEBS Lett. 1999; 455: 70-4.

Fiotti N, Zivadinov R, Altamura N, Nasuelli D, Bratina A, Tommasi MA, et al. MMP-9 microsatellite polymorphism and multiple sclerosis. J Neuroimmunol. 2004; 52: 147-53.

Wagner S, Kluge B, Koziol JA, Grau AJ, Grond-Ginsbach C. MMP-9 polymorphisms are not associated with spontaneous cervical artery dissection. Stroke. 2004; 35: 62-4.

Nelissen I, Vandenbroeck K, Fiten P, Hillert J, Olsson T, Marrosu MG, et al. Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis. J Neuroimmunol. 2000; 105: 58-63.

Peters DG, Kassam A, St Jean PL, Yonas H, Ferrell RE. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranialaneurysm. Stroke. 1999; 30: 2612-6.

Souza AP, Trevilatto PC, Scarel-Caminaga RM, de Brito Jr RB, Barros SP, Line SRP. Analysis of the MMP-9 (C-1562 T) and TIMP-2 (G-418C) gene promoter polymorphisms in patients with chronic periodontitis. J Clin Periodontol. 2005; 32: 207- 11 64. Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J. 1995; 73: 209-15.

Maat MP, Jukema JW, Ye S. Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis. Am J Cardiol. 1999; 83: 852-6.

Terashima M, Akita H, Kanazawa K. Stromelysin promoter 5A/ 6A polumorphism is associated with acute myocardial infarction. Circulation. 1999; 99: 2717-9.

Ryan MA, Ramamurthy NS, Golub LM. Matrix metalloproteinases and their inhibition in periodontal treatment. Curr Opin Periodontol. 1996; 3: 85-96.

Hammani K, Blakis A, Morsette D, Bowcock AM, Schmutte C, Henriet P. Structure and Characterization of the human tissue inhibitor of metalloproteinases-2 gene. J Biol Chem. 1996; 271: 25498-505.

Hodgson JA. Remodeling MMPIs. Biotechnol. 1995; 30: 554-7.

Peterson JT. Matrix metalloproteinases inhibitor development and the remodeling of drug discovery. Heart Fail Rev. 2004; 9: 63-79.

Mudgett JS, Hutchinson NI, Chartrain NA, Forsyth AJ, McDonnell J, Singer II, et al. Susceptibility of stromelysin 1- deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum. 1998; 41: 110-21.

Caton JG, Ciancio SG, Blieden TM, Bradsham M, Crout RJ, Hefti AF, et al. Subantimicrobial dose doxycycline as an adjunct to scaling and root planing: post-treatment effects. J Clin Periodontol. 2001; 28: 782-9.




How to Cite

De Souza A, Da Silva R, Da Silva M, Guimarães SAC, Line SRP. Matrix metalloproteinases: the most important pathway involved with periodontal destruction. Braz. J. Oral Sci. [Internet]. 2015 Nov. 19 [cited 2022 Nov. 28];4(15):884-90. Available from:



Literature Reviews

Most read articles by the same author(s)