Matrix metalloproteinases: role in the development of apical periodontitis and modulation after endodontic treatment

Francisco Wanderley Garcia de Paula e Silva, Maya Fernanda Manfrin Arnez, Luciano Aparecido de Almeida-Júnior, Marcio Santos de Carvalho, Renato Petille, Alexandra Mussolino de Queiroz, Léa Assed Bezerra da Silva


Introduction: Apical periodontitis represents a local immune response directed against the progression of microorganisms from the dental pulp to the apical foramen and periapical tissues, which results in bone and dental resorption. The aim of this review is to describe the expression of this group of proteases in apical periodontitis and its modulation during the periapical healing phase following root canal treatment. Literature review: The pathogenesis of apical periodontitis involves degradation of several extracellular matrix components. Matrix metalloproteinases (MMPs) are expressed in response to specific stimuli by resident cells of connective tissue during tissue remodeling and by inflammatory cells that arrive into the surrounding tissues during inflammatory events. MMPs have been reported in apical periodontitis, either experimentally induced or obtained from humans and there is evidence that these enzymes show diff erent expression patterns in granulomas and periapical cysts. Root canal therapy is important for the reduction of periapical inflammation as well as the synthesis of MMPs, especially when using a calcium hydroxide-based dressing. Conclusion: Apical periodontitis show high expression of matrix metalloproteinases and root canal treatment results in less expression of MMPs when compared to untreated apical periodontitis.


Endodontics; Peptide hydrolases; Extracellular matrix; Periapical periodontitis; Radicular cyst; Periapical granuloma


Graves DT, Oates T, Garlet GP. Review of osteoimmunology and the host response in endodontic and periodontal lesions. J Oral Microbiol. 2011;3:5304.

Paula-Silva FWG, Ribeiro-Santos FR, Petean IBF, Arnez MFM, Almeida-Junior LA, Carvalho FK, et al. Root canal contamination or exposure to lipopolysaccharide differentially modulate prostaglandin E 2 and leukotriene B 4 signaling in apical periodontitis. J Appl Oral Sci. 2020;28:e20190699.

Kakehashi S, Stanley HR, Fitzgerald RJ. The effects of surgical exposures of dental pulps in germ-free and conventional laboratory rats. Oral Surg Oral Med Oral Pathol. 1965;20(3):340-9.

Rocha CT, Rossi MA, Leonardo MR, Rocha LB, Nelson-Filho P, Silva LA. Biofilm on the apical region of roots in primary teeth with vital and necrotic pulps with or without radiographically evident apical pathosis. Int Endod J. 2008;41(8):664-9.

Neville BW. Doença pulpar e periapical. In: Neville BW, Damm DD, Allen CM, Chi AC, editores. Patologia oral e maxilofacial. Rio de Janeiro: Elsevier; 2016. p. 252-3.

Leonardo MR, Almeida WA, Ito IY, Silva LAB. Radiographic and microbiologic evaluation of posttreatment apical and periapical repair of root canals of dogs' teeth with experimentally induced chronic lesion. Oral Surg Oral Med Oral Pathol. 1994;78(2):232-8.

Paula-Silva FW, da Silva LA, Kapila YL. Matrix metalloproteinase expression in teeth with apical periodontitis is differentially modulated by the modality of root canal treatment. J Endod. 2010;36(2):231-7.

Corotti MV, Zambuzzi WF, Paiva KB, Menezes R, Pinto LC, Lara VS, et al. Immunolocalization of matrix metalloproteinases-2 and -9 during apical periodontitis development. Arch Oral Biol. 2009;54(8):764-71.

Araújo RVS, Silva FO, Melo-Júnior MR, Porto ALF. Metaloproteinases: aspectos fisiopatológicos sistêmicos e sua importância na cicatrização. R Ci md biol. 2011;10(1):82-8.

Romualdo PC, Lucisano MP, Paula-Silva FWG, Leoni GB, Sousa-Neto MD, Silva RAB, et al. Ovariectomy exacerbates apical periodontitis in rats with an increase in expression of proinflammatory cytokines and matrix metalloproteinases. J Endod. 2018;44(5):780-5.

Rossa C Jr, Liu M, Patil C, Kirkwood KL. MKK3/6-p38 MAPK negatively regulates murine MMP-13 gene expression induced by IL-1beta and TNF-alpha in immortalized periodontal ligament fibroblasts. Matrix Biol. 2005;24(7):478-88.

Araújo AA, Morais HB, Medeiros CACX, Brito GAC, Guedes PMM, Hiyari S, et al. Gliclazide reduced oxidative stress, inflammation, and bone loss in an experimental periodontal disease model. J Appl Oral Sci. 2019;27: e20180211.

Paula-Silva FW, D'Silva NJ, da Silva LA, Kapila YL. High matrix metalloproteinase activity is a hallmark of periapical granulomas. J Endod. 2009;35(9):1234-42.

D'addazio G, Artese L, Piccirilli M, Perfetti G. Role of matrix metalloproteinases in radicular cysts and periapical granulomas. Minerva Stomatol. 2014 Nov-Dec;63(11-12):411-20.

Pereira Faustino IS, Azevedo RS, Takahama A Jr. Metalloproteinases 2 and 9 immunoexpression in periapical lesions from primary endodontic infection: possible relationship with the histopathological diagnosis and the presence of pain. J Endod. 2016 Apr;42(4):547-51.

Torres AFC, Antunes LS, Oliveira NF, Küchler EC, Gomes CC, Antunes LAA. Genetic polymorphism and expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in periapical lesions: systematic review. J Endod. 2020 Jan;46(1):3-11.e1.

Delzangles B, Boy-Lefevre ML, Forest N. Glycoproteins expression in apical pathologic tissues: clinical incidences. J Endod. 1997;23(9):565-8.

Takahama A Jr, Rôças IN, Faustino ISP, Alves FRF, Azevedo RS, Gomes CC, et al. Association between bacteria occurring in the apical canal system and expression of bone-resorbing mediators and matrix metalloproteinases in apical periodontitis. Int Endod J. 2018;51(7):738-46.

Tsai CH, Chen YJ, Huang FM, Su YF, Chang YC. The upregulation of matrix metalloproteinase-9 in inflamed human dental pulps. J Endod. 2005;31(12):860-2.

Álvares PR, Arruda JAA, Silva LPD, Nascimento GJFD, Silveira MFD, Sobral APV. Immunohistochemical expression of TGF-β1 and MMP-9 in periapical lesions. Braz Oral Res. 2017 Jul 3;31:e51.

Carneiro E, Menezes R, Garlet GP, Garlet GP, Garcia RB, Bramante CM, et al. Expression analysis of matrix metalloproteinase-9 in epithelialized and nonepithelialized apical periodontitis lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(1):127-32.

Morimoto T, Yamasaki M, Nakata K, Tsuji M, Nakamura H. The expression of macrophage and neutrophil elastases in rat periradicular lesions. J Endod. 2008;34(9):1072-6.

Hong CY, Lin SK, Kok SH, Cheng SJ, Lee MS, Wang TM, et al. The role of lipopolysaccharide in infectious bone resorption of periapical lesion. J Oral Pathol Med. 2004;33(3):162-9.

Lin SK, Chiang CP, Hong CY, Lin CP, Lan WH, Hsieh CC, et al. Immunolocalization of interstitial collagenase (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in radicular cysts. J Oral Pathol Med. 1997;26(10):458-63.

Andrade AL, Santos EM, Carmo AF, Freitas RA, Galvão HC. Analysis of tryptase-positive mast cells and immunoexpression of MMP-9 and MMP-13 in periapical lesions. Int Endod J. 2017 May;50(5):446-54.

Metzger Z, Belkin D, Kariv N, Dotan M, Kfir A. Low-dose doxycycline inhibits bone resorption associated with apical periodontitis. IntEndod J. 2008;41(4):303-9.

Tjäderhane L, Hotakainen T, Kinnunen S, Ahonen M, Salo T. The effect of chemical inhibition of matrix metalloproteinases on the size of experimentally induced apical periodontitis. IntEndod J. 2007;40(6):282-9.

Wan C, Yuan G, Yang J, Sun Q, Zhang L, Zhang J, et al. MMP9 deficiency increased the size of experimentally induced apical periodontitis. J Endod. 2014;40(5):658-64.

Barreiros D, Nelson P Filho, Paula-Silva FWG, Oliveira KMH, Lucisano MP, De Rossi A, et al. MMP2 and MMP9 are associated with apical periodontitis progression and might be modulated by TLR2 and MyD88. Braz Dent J. 2018;29(1):43-7.

Verma RP, Hansch C. Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem. 2007;15(6):2223-68.

Leonardo MR, Hernandez ME, Silva LA, Tanomaru-Filho M. Effect of a calcium hydroxide-based root canal dressing on periapical repair in dogs: a histological study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(5):680-5.

Fabricius L, Dahlén G, Sundqvist G, Happonen RP, Möller AJ. Influence of residual bacteria on periapical tissue healing after chemomechanical treatment and root filling of experimentally infected monkey teeth. Eur J Oral Sci. 2006;114(4):278-85.

Yang WK, Kim MR, Lee Y, Son HH, Lee W. Effect of calcium hydroxide-treated prevotellanigrescens on the gene expression of matrix metalloproteinase and its inhibitor in MG63 cells. J Endod. 2006;32(12):1142-5.

Safavi KE, Nichols FC. Effect of calcium hydroxide on bacterial lipopolysaccharide. J Endod. 1993;19(2):76-8.

Silva LAB, da Silva RA, Branco LG, Navarro VP, Nelson-Filho P. Quantitative radiographic evaluation of periapical bone resorption in dog's teeth contaminated with bacterial endotoxin (LPS) associated or not with calcium hydroxide. Braz Dent J. 2008;19(4):296-300.

Özdemir MB, Karataş E, Albayrak M, Bayır Y. Effect of intracanal medicaments on matrix metalloproteinase-9 and vasoactive intestinal peptide secretion in periapical lesions of re-treated canals: a randomized controlled clinical study. Clin Oral Investig. 2019 Feb;23(2):921-8.

García CC, Sempere FV, Diago MP, Bowen EM. The post-endodontic periapical lesion: histologic and etiopathogenic aspects. Med Oral Patol Oral Cir Bucal. 2007;12(8):e585-90.

Fu X, Kassim SY, Parks WC, Heinecke JW. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J BiolChem. 2001;276(44):41279-87.

Leeman MF, Curran S, Murray GI. The structure, regulation, and function of human matrix metalloproteinase-13. Crit Rev Biochem Mol Biol. 2002;37(3):149-66.

Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 2003;253(1-2):269-85.

Martinho FC, Teixeira FF, Cardoso FG, Ferreira NS, Nascimento GG, Carvalho CA, et al. Clinical investigation of matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase complexes and their networks in apical periodontitis. J Endod. 2016;42(7):1082-8.

Belmar MJ, Pabst C, Martínez B, Hernández M. Gelatinolytic activity in gingival crevicular fluid from teeth with periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(6):801-6.


e-ISSN 2177-0018 / ISSN 0566-1854. Indexers: descrição da foto descrição da foto descrição da foto