Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical Oral Investigations
Published in: Clinical Oral Investigations 7/2019

01-07-2019 | Review

Matrix metalloproteinases and inhibitors in dentistry

Authors: Gerd-Jan Boelen, Lucas Boute, Joëy d’Hoop, Mostafa EzEldeen, Ivo Lambrichts, Ghislain Opdenakker

Published in: Clinical Oral Investigations | Issue 7/2019

Login to get access

Abstract

Objectives

Matrix metalloproteinase (MMP) expression has been associated with tissue development, invasive cancer cell behavior, and inflammation. The associations of increased expression of MMPs with diseases have led to intensive research activities to develop MMP inhibitors. Here, the questions are addressed which associations between increased levels of any MMP with dental diseases may be cause or consequence, whether MMP levels may be of diagnostic value and whether and which MMP inhibitors need further investigations for use in dental diseases.

Methods

To study the role of MMPs and to discriminate between cause or consequence, the literature about measurements of MMPs and about the use of inhibitory drugs and genetic knockout animal models in dentistry was compared.

Results

The only FDA-approved treatment with MMP inhibitors is tetracyclines for periodontitis, whereas a diagnostic test for activated MMP-8 in oral fluids is valued in practical periodontology. The MMP literature in dentistry is artificially skewed to the gelatinases MMP-2 and MMP-9 and to enamelysin, alias MMP-20. The basis for this observation is, respectively, the widely used and sensitive technique of gelatin zymography and enamel proteins as substrates of MMP-20. Studies on additional MMPs are gaining interest in dentistry and MMP inhibitors may provide new applications. In addition, drugs with proven effects for the treatment of dental diseases may be found to act through MMP inhibition.

Conclusion and relevance

In conclusion, research on MMPs and inhibitors may provide practical applications beyond diagnosis and treatment of periodontitis and will be, directly or indirectly, beneficial for patients with dental or periodontal diseases.
Literature
1.
Nagase H, Barrett AJ, Woessner JF Jr (1992) Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl 1:421–424PubMed
2.
Gross J, Lapière CM (1962) Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci U S A 48:1014–1022PubMedPubMedCentral
3.
Harris ED Jr (1972) A collagenolytic system produced by primary cultures of rheumatoid nodule tissue. J Clin Invest 51(11):2973–2976PubMedPubMedCentral
4.
Sapolsky AI, Howell DS, Woessner JF Jr (1974) Neutral proteases and cathepsin D in human articular cartilage. J Clin Invest 53(4):1044–1053PubMedPubMedCentral
5.
Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6:480–498PubMed
6.
Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (2002) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 37(6):375–536PubMed
7.
Cauwe B, Van den Steen PE, Opdenakker G (2007) The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 42(3):113–185PubMed
8.
Cauwe B, Opdenakker G (2010) Intracellular substrate cleavage: a novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases. Crit Rev Biochem Mol Biol 45:351–423PubMed
9.
Vandooren J, Van den Steen PE, Opdenakker G (2013) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol 48:222–272PubMed
10.
de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G (2016) The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 51(5):295–358PubMed
11.
Iwata T, Yamakoshi Y, Hu JC, Ishikawa I, Bartlett JD, Krebsbach PH, Simmer JP (2007) Processing of ameloblastin by MMP-20. J Dent Res 86:153–157PubMed
12.
Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G (2000) Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96:2673–2681PubMed
13.
Cauwe B, Martens E, Proost P, Opdenakker G (2009) Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates. Integr Biol. (Camb.) 1:404–426
14.
15.
Ortega N, Behonick D, Stickens D, Werb Z (2003) How proteases regulate bone morphogenesis. Ann N Y Acad Sci 995:109–116PubMed
16.
Van Wart HE, Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 87:5578–5582PubMedPubMedCentral
17.
Khokha R, Murthy A, Weiss A (2013) Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13:649–665PubMed
18.
Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93:411–422PubMedPubMedCentral
19.
Fanchon S, Bourd K, Septier D, Everts V, Beertsen W, Menashi S, Goldberg M (2004) Involvement of matrix metalloproteinases in the onset of dentin mineralization. Eur J Oral Sci 112:171–176PubMed
20.
Bourd-Boittin K, Fridman R, Fanchon S, Septier D, Goldberg M, Menashi S (2005) Matrix metalloproteinase inhibition impairs the processing, formation and mineralization of dental tissues during mouse molar development. Exp Cell Res 304:493–505PubMed
21.
Nagano T, Kakegawa A, Yamakoshi Y, Tsuchiya S, Hu JC, Gomi K, Arai T, Bartlett JD, Simmer JP (2009) Mmp-20 and Klk4 cleavage site preferences for amelogenin sequences. J Dent Res 88:823–828PubMedPubMedCentral
22.
Bartlett JD, Simmer JP (1999) Proteinases in developing dental enamel. Crit Rev Oral Biol Med 10:425–441PubMed
23.
Bourd-Boittin K, Septier D, Hall R, Goldberg M, Menashi S (2004) Immunolocalization of enamelysin (matrix metalloproteinase-20) in the forming rat incisor. J Histochem Cytochem 52:437–445PubMed
24.
25.
Sulkala M, Larmas M, Sorsa T, Salo T, Tjäderhane L (2002) The localization of matrix metalloproteinase-20 (MMP-20, enamelysin) in mature human teeth. J Dent Res 81:603–607PubMed
26.
Jain A, Bahuguna R (2015) Role of matrix metalloproteinases in dental caries, pulp and periapical inflammation: an overview. J Oral Biol Craniofac Res 5:212–218PubMedPubMedCentral
27.
Kim S, Trowbridge H, Suda H (2002) In: Cohen S, Burns RC (eds) Pathways of the pulp. Mosby, St. Louis, p 573
28.
Maciejczyk M, Pietrzykowska A, Zalewska A, Knaś M, Daniszewska I (2016) The significance of matrix metalloproteinases in oral diseases. Adv Clin Exp Med 25:383–390PubMed
29.
Sorsa T, Tjäderhane L, Salo T (2004) Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis 10:311–318PubMed
30.
Smith AJ (2002) Pulpal responses to caries and dental repair. Caries Res 36:223–232PubMed
31.
Zheng L, Amano K, Iohara K (2009) Matrix metalloproteinase-3 accelerates wound healing following dental pulp injury. Am J Pathol 175:1905–1914PubMedPubMedCentral
32.
Goda S, Kato Y, Domae E, Hayashi H, Tan-Ishii N, Iida J, Ikeo T (2015) Effects of JNK1/2 on the inflammation cytokine TNF-α-enhanced production of MMP-3 in human dental pulp fibroblast-like cells. Int Endod J 48:1122–1128PubMed
33.
Tester AM, Cox JH, Connor AR, Starr AE, Dean RA, Puente XS, López-Otín C, Overall CM (2007) LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PLoS One 2(3):e312PubMedPubMedCentral
34.
D’Haese A, Wuyts A, Dillen C, Dubois B, Billiau A, Heremans H, Van Damme J, Arnold B, Opdenakker G (2000) In vivo neutrophil recruitment by granulocyte chemotactic protein-2 is assisted by gelatinase B/MMP-9 in the mouse. J Interf Cytokine Res 20(7):667–674
35.
Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJL, Marcenes W (2014) Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res 93:1045–1053PubMedPubMedCentral
36.
37.
Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, Golub LM, Brown DL, Mäntylä P (2006) Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann Med 38:306–321PubMed
38.
Hernández M, Gamonal J, Tervahartiala T, Mäntylä P, Rivera O, Dezerega A, Dutzan N, Sorsa T (2010) Associations between matrix metalloproteinase-8 and -14 and myeloperoxidase in gingival crevicular fluid from subjects with progressive chronic periodontitis: a longitudinal study. J Periodontol 81:1644–1652PubMed
39.
Emingil G, Kuula H, Sorsa T, Atilla G (2006) Gingival crevicular fluid matrix metalloproteinase-25 and -26 levels in periodontal disease. J Periodontol 77(4):664–671PubMed
40.
Kuula H, Salo T, Pirilä E, Hagström J, Luomanen M, Gutierrez-Fernandez A, Romanos GE, Sorsa T (2008) Human beta-defensin-1 and -2 and matrix metalloproteinase-25 and -26 expression in chronic and aggressive periodontitis and in peri-implantitis. Arch Oral Biol 53(2):175–186PubMed
41.
42.
43.
44.
Pirilä E, Korpi JT, Korkiamäki T, Jahkola T, Gutierrez-Fernandez A, Lopez-Otin C, Saarialho-Kere U, Salo T, Sorsa T (2007) Collagenase-2 (MMP-8) and matrilysin-2 (MMP-26) expression in human wounds of different etiologies. Wound Repair Regen 15(1):47–57PubMed
45.
Leppilahti JM, Harjunmaa U, Järnstedt J, Mangani C, Hernández M, Tervahartiala T, Lopez R, Ashorn U, Ashorn P, Gieselmann DR, Sorsa T (2018) Diagnosis of newly delivered mothers for periodontitis with a novel oral-rinse aMMP-8 point-of-care test in a rural Malawian population. Diagnostics (Basel) 8(3). https://​doi.​org/​10.​3390/​diagnostics80300​67
46.
Alassiri S, Parnanen P, Rathnayake N, Johannsen G, Heikkinen AM, Lazzara R, van der Schoor P, van der Schoor JG, Tervahartiala T, Gieselmann D, Sorsa T (2018) The ability of quantitative, specific, and sensitive point-of-care/chair-side oral fluid immunotests for aMMP-8 to detect periodontal and peri-implant diseases. Dis Markers 2018:1306396. https://​doi.​org/​10.​1155/​2018/​1306396 eCollection 2018CrossRefPubMedPubMedCentral
47.
48.
Räisänen IT, Heikkinen AM, Siren E, Tervahartiala T, Gieselmann DR, van der Schoor GJ, van der Schoor P, Sorsa T (2018) Point-of-care/chairside aMMP-8 analytics of periodontal Diseases’ activity and episodic progression. Diagnostics (Basel). 8(4). https://​doi.​org/​10.​3390/​diagnostics80400​74
49.
Mäntylä P, Stenman M, Kinane DF, Tikanoja S, Luoto H, Salo T, Sorsa T (2003) Gingival crevicular fluid collagenase-2 (MMP-8) test stick for chair-side monitoring of periodontitis. J Periodontal Res 38:436–439PubMed
50.
Korpi JT, Aström P, Lehtonen M, Tjäderhane L, Kallio-Pukkinen S, Siponen M, Sorsa T, Pirilä E, Salo T (2009) Healing of extraction sockets in collagenase-2 (matrix metalloproteinase-8)-deficient mice. Eur J Oral Sci 117:248–254PubMed
51.
Opdenakker G, Van Damme J, Vranckx J (2018) Immunomodulation as rescue for chronic atonic skin wounds. Trends Immunol 39(4):341–354PubMed
52.
Jones CG (1997) Chlorhexidine: is it still the gold standard? Periodontol 2000 15:55–62PubMed
53.
Epasinghe DJ, Yiu CK, Burrow MF, Hiraishi N, Tay FR (2013) The inhibitory effect of proanthocyanidin on soluble and collagen-bound proteases. J Dent 41:832–839PubMed
54.
Newman MG, Kornman KS, Doherty FM (1994) A 6-month multi-center evaluation of adjunctive tetracycline fiber therapy used in conjunction with scaling and root planing in maintenance patients: clinical results. J Periodontol 65:685–691PubMed
55.
Lee HM, Ciancio SG, Tüter G, Ryan ME, Komaroff E, Golub LM (2004) Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. J Periodontol 75:453–463PubMed
56.
Buduneli E, Vardar-Sengül S, Buduneli N, Atilla G, Wahlgren J, Sorsa T (2007) Matrix metalloproteinases, tissue inhibitor of matrix metalloproteinase-1, and laminin-5 gamma2 chain immunolocalization in gingival tissue of endotoxin-induced periodontitis in rats: effects of low-dose doxycycline and alendronate. J Periodontol 78:127–134PubMed
57.
Gomes KDN, Alves APNN, Dutra PGP, Viana GSB (2017) Doxycycline induces bone repair and changes in Wnt signalling. Int J Oral Sci 9:158–166PubMedPubMedCentral
58.
Sorsa T, Tervahartiala T, Leppilahti J, Hernandez M, Gamonal J, Tuomainen AM, Lauhio A, Pussinen PJ, Mäntylä P (2011) Collagenase-2 (MMP-8) as a point-of-care biomarker in periodontitis and cardiovascular diseases. Therapeutic response to non-antimicrobial properties of tetracyclines. Pharmacol Res 63:108–113PubMed
59.
Choi DH, Moon IS, Choi BK, Paik JW, Kim YS, Choi SH, Kim CK (2004) Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis. J Periodontal Res 39:20–26PubMed
60.
Buduneli E, Mäntylä P, Emingil G, Tervahartiala T, Pussinen P, Barış N, Akıllı A, Atilla G, Sorsa T (2011) Acute myocardial infarction is reflected in salivary matrix metalloproteinase-8 activation level. J Periodontol 82:716–725PubMed
61.
Ipshita S, Kurian IG, Dileep P, Kumar S, Singh P, Pradeep AR (2018;in press) One percent alendronate and aloe vera gel local host modulating agents in chronic periodontitis patients with class II furcation defects: a randomized, controlled clinical trial. J Investig Clin Dent 9:e12334PubMed
62.
Almahdy A, Koller G, Sauro S, Bartsch JW, Sherriff M, Watson TF, Banerjee A (2012) Effects of MMP inhibitors incorporated within dental adhesives. J Dent Res 91:605–611PubMedPubMedCentral
63.
De Munck J, Van den Steen PE, Mine A, Van Landuyt KL, Poitevin A, Opdenakker G, Van Meerbeek B (2009) Inhibition of enzymatic degradation of adhesive-dentin interfaces. J Dent Res 88:1101–1106PubMed
64.
Hanabusa M, Mine A, Kuboki T, Momoi Y, Van Ende A, Van Meerbeek B, De Munck J (2012) Bonding effectiveness of a new ‘multi-mode’ adhesive to enamel and dentine. J Dent 40:475–484PubMed
65.
Castellan CS, Pereira PN, Grande RH, Bedran-Russo AK (2010) Mechanical characterization of proanthocyanidin-dentin matrix interaction. Dent Mater 26:968–973PubMedPubMedCentral
66.
Hechler B, Yao X, Wang Y (2012) Proanthocyanidins alter adhesive/dentin bonding strengths when included in a bonding system. Am J Dent 25:276–280PubMedPubMedCentral
67.
Liu RR, Fang M, Zhang L, Tang CF, Dou Q, Chen JH (2014) Anti-proteolytic capacity and bonding durability of proanthocyanidin-biomodified demineralized dentin matrix. Int J Oral Sci 6:168–174PubMedPubMedCentral
68.
Rohani MG, Parks WC (2015) Matrix remodeling by MMPs during wound repair. Matrix Biol 44-46:113–121PubMed
69.
Greenwald RA (2011) The road forward: the scientific basis for tetracycline treatment of arthritic disorders. Pharmacol Res 64:610–613PubMed
70.
Hannocks MJ, Zhang X, Gerwien H, Chashchina A, Burmeister M, Korpos E, Song J, Sorokin L (2018) The gelatinases, MMP-2 and MMP-9, as fine tuners of neuroinflammatory processes. Matrix Biol 75-76:102–113
Metadata
Title
Matrix metalloproteinases and inhibitors in dentistry
Authors
Gerd-Jan Boelen
Lucas Boute
Joëy d’Hoop
Mostafa EzEldeen
Ivo Lambrichts
Ghislain Opdenakker
Publication date
01-07-2019
Publisher
Springer Berlin Heidelberg
Published in
Clinical Oral Investigations / Issue 7/2019
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-019-02915-y

Other articles of this Issue 7/2019

Clinical Oral Investigations 7/2019 Go to the issue

Original Article

Development of a quantitative preclinical screening model for implant osseointegration in rat tail vertebra

Original Article

The influence of enamel sandblasting on the shear bond strength and fractography of the bracket-adhesive-enamel complex tested in vitro by the DIN 13990:2017-04 standard

Correction

Correction to: Induced surface proteins of Staphylococcus epidermidis adhering to titanium implant substrata

Original Article

Micro-CT comparison of XP-endo Finisher and passive ultrasonic irrigation as final irrigation protocols on the removal of accumulated hard-tissue debris from oval shaped-canals

Review

Antifungal activity and Shore A hardness of a tissue conditioner incorporated with terpinen-4-ol and cinnamaldehyde

Original Article

Comparison of the hospitalization period after microvascular reconstruction flap in trismus patients: free anterolateral thigh flap versus free forearm flap