Metalloproteinases and their role in the degradation of bonding systems. Part 1
Metaloproteinazy i ich udział w degradacji systemów wiążących. Część 1
The differences in the structure and level of mineralization of the teeth determine the speed and characteristics of caries process in the enamel and dentin. The primary aetiological factor of caries are organic acids produced by cariogenic bacteria. They initiate caries demineralization by decreasing the pH of the oral cavity and dissolve the dentin, exposing the extracellular matrix (ECM). The matrix is built of collagen proteins and glycoproteins. It acts as a scaffold for the dentin tissue structure. Type 1 collagen is the largest component of the extracellular matrix (90%) and determines the elasticity, durability and biomechanical properties of the dentin. Collagen fibres and non-collagenous proteins are synthesized and secreted by odontoblasts (1-4).
Uncontrolled progression of the caries process leads to the formation of a cavity. The treatment of cavities requires the reconstruction of the missing dental tissues. To this end, contemporary restorative dentistry promotes aesthetic composite materials. Their use involves certain procedures, including the use of adhesive systems. The application of acidic conditioners leads to superficial demineralization of the dentin. In order to create an optimal bonding zone – the so-called hybrid layer, built of type 1 collagen fibres and proteoglycans surrounded by polymer chains, dentin matrix etched with orthophosphoric acid needs to be thoroughly impregnated with resin (5-7). The hybrid layer, composed of collagen, resin, hydroxyapatite and water residues is also called the zone of mutual diffusion. Resin monomers penetrate water-filled spaces between neighbouring dentin fibres and create a retention element for the restorative material (8). The impregnation of collagen fibres with resin within the hybrid layer is incomplete and some fibres remain exposed. They can be degraded by metalloproteinases (MMPs), which reduces the strength of the bonding system and dentin. The shrinkage of the restorative material associated with its polymerization can cause bacterial leakage, dentin hypersensitivity and discolouration of the filling margins. With time, the degradation of the bonding resin is observed as loss of retention or the reduction of adhesion strength. A clinical review of various bonding systems used in Black class V cavities demonstrated the highest rate of retention loss in the examined teeth within five years of the use of self-etching systems; better results were achieved after the use of a two- or three-step adhesive system with etching. Glass-ionomer fillings demonstrated the highest clinical efficacy. Due to the problems discussed above fillings often need to be replaced (9).
The connection of bonding systems to the dentin matrix is an important topic since research shows that it deteriorates over time. This is due to the effect of multiple physical and chemical factors on the zone of adhesion. These include chewing forces and repeated expansion, stress and shrinkage caused by temperature changes in the oral cavity (10-17). These phenomena lead to the degradation of exposed collagen fibres, elution of resin monomers and breakdown of resin components (18, 19). Regardless of the bonding system used, there are unprotected and vulnerable collagen fibres left in the lower part of the hybrid layer. These fibres can be hydrolyzed by endogenous enzymes called metalloproteinases (MMPs) (20-22).
MMPs are enclosed inside mineralized dentin during the development of the tooth. They can hydrolyze the components of the extracellular matrix (23-25). They play an important role in physiological processes such as the development and restructuring of the dentin – dentinogenesis (26, 27). They have also been observed to be involved in different pathological processes. A number of metalloproteinases, particularly gelatinases and MMP-1 have been linked to angiogenesis (28). An increased activity of MMPs is observed in diseases of the oral cavity such as gingivitis, periodontitis, caries, periapical tissue lesions, lichen planus or squamous cell carcinoma (29, 30).
Metalloproteinases belong to the group of proteolytic enzymes which play an important role in the metabolism of the extracellular matrix. They are responsible for the progression of the caries process and damage to dentin which has not been completely penetrated by the bonding resin (20, 22). Collagen is broken down by collagenases, which degrade peptides between 1/4 and 3/4 of the protein chain length and subsequently by gelatinases, which decompose shorter peptides (28). Metalloproteinases are calcium and zinc ion-dependent. They can be activated in a neutral or slightly basic environment. In the human body 23 metalloproteinases have been identified, which have been divided into 6 groups. Table 1 presents a summary of metalloproteinases found in the human body.
|Group of metalloproteinases||MMP||Popular name||Substrate|
|collagenases||MMP-1||collagenase||type I, II, III, V, VII, VIII, X collagen|
|MMP-8||collagenase 2||type I, II, III, IV collagen|
|MMP-13||collagenase 3||type I, II, III, IV, V, IX, X, XI collagen, gelatine, laminan|
|MMP-18||collagenase 4, Xenopus||type I collagen, gelatine|
|stromelysins||MMP-3||stromelysin 1, proteoglycanase||elastin, proglycans, aggrecans, gelatine, proMMP-1, -8, -9|
|MMP-10||stromelysin 2||type I, II, III, V collagen|
|MMP-11||stromelysin 3||laminan, proteinase inhibitor 1, antitrypsin|
|gelatinases||MMP-2||gelatinase||type I, IV, V, VII, X collagen, gelatine, elastin|
|MMP-9||gelatinase B||type IV collagen, gelatine, laminan|
|matrilysins||MMP-7||matrilysin, metaloendopeptidase||type IV collagen, glycoproteins, gelatine|
|MMP-26||matrilysin, endometase||type IV collagen, gelatine, fibrinogen, fibronectin, vitronectin, casein, pro-MMP-9|
|membrane MMPs||MMP-14||MT1-MMP||type I, II, III collagen, gelatine, laminan, aggrecans, proMMP-2, -13|
|MMP-15||MT2-MMP||type I, II, III collagen, gelatine, proMMP-13|
|MMP-16||MT3-MMP||type I, II collagen, laminan, proMMP-2, -13|
|MMP-17||MT4-MMP||fibronectin, fibrin, gelatine|
MMPs not classified under any other group
|MMP-19||RASI 1||type I, IV collagen, gelatine, fibronectin, laminin, aggrecan, entactin, tenascin|
Metalloproteinases are produced by structural tissue cells: odontoblasts, fibroblasts, osteoblasts as well as by inflammatory reaction cells: macrophages, T-cells, monocytes and neutrophils. MMPs are built of a catalytic domain, prodomain, haemopexin domain and a flexible linker. MMPs have a signal peptide and a prodomain at the N-terminus. The catalytic domain is responsible for the proteolytic effect of the enzyme. It is composed of one zinc ion and usually three calcium ions. The prodomain includes a propeptide responsible for keeping the enzyme in an inactive state. The haemopexin domain is important for the correct detection of the substrate. In the case of collagenases it allows for the digestion of the collagen superhelix to be initiated (31-33).
1. Chaussain C, Boukpessi T, Khaddam M et al.: Dentin matrix degradation by host-matrix metalloproteinases: inhibition and clinical perspectives toward regeneration. Front Physiol 2013; 4(308): 1-7.
2. Konopka Ł, Brzezińska-Błaszczyk E: Rola metaloproteinaz w chorobach jamy ustnej – nowe możliwości terapii. Dent Med Probl 2008; 45(3): 229-235.
3. Goldberg M, Takagi M: Dentine proteoglycans: composition, ultrastructure and functions. Histochem J 1993; 25(11): 781-806.
4. Linde A, Goldberg M: Dentinogenesis. Crit Rev Oral Biol Med 1993; 4(5): 679-728.
5. Breschi L, Perdigâo J, Gobbi P et al.: Immunocytochemical identification of type I collagen in acid-etched dentin. J Biomed Mater Res 2003; 4(66A): 764-769.
6. Breschi L, Prati C, Gobbi P et al.: Immunohistochemical analysis of collagen fibrils within the hybrid layer: a FEISEM study. Oper Dent 2004; 29(5): 538-546.
7. Marshall GW Jr, Marshall SJ, Kinneyt JH, Balooch M: The dentin substrate: structure and properties related to bonding. J Dent 1997; 25(6): 441-458.
8. Nakabayashi N, Kojima K, Masuhara E: The promotion of adhesion by the infiltration of monomers into tooth substrates. J Biomed Mater Res 1982; 16(3): 265-273.
9. Peumans M, Kanumilli P, De Munck J et al.: Clinical effectiveness of contemporary adhesives: A systematic review of current clinical trials. Dent Mater 2005; 21(9): 864-881.
10. De Munck J, Van Landuyt K, Peumans M et al.: A critical review of the durability of adhesion to tooth tissue: methods and results. J Dent Res 2005; 84(2): 118-132.
11. Sano H, Yoshikawa T, Pereira PNR et al.: Long-term durability of dentin bonds made with a self-etching primer, in vivo. J Dent Res 1999; 78(4): 906-911.
12. Hashimoto M, Ohno H, Kaga M et al.: In vivo degradation of resin-dentin bonds in humans over 1 to 3 years. J Dent Res 2000; 79(6): 1385-1391.
13. Hashimoto M, Ohno H, Sano H et al.: Micromorphological changes in resin-dentin bonds after 1 year of water storage. J Biomed Mater Res 2002; 63(3): 306-311.
14. Takahashi A, Inoue S, Kawamoto C et al.: In vivo long-term durability of the bond using two adhesive systems. J Adhes Dent 2002; 4(2): 151-159.
15. Hashimoto M, Ohno H, Sano H, Kaga M et al.: In vitro degradation of resin-dentin bonds analyzed by microtensile bond test, scanning and transmission electron microscopy. Biomaterials 2003; 24(21): 3795-3803.
16. Hashimoto M, Sano H, Yoshida E et al.: Effects of multiple adhesive coatings on dentin bonding. Oper Dent 2004; 29: 416-423.
17. Yang B, Adelung R, Ludwig K et al.: Effect of structural change of collagen fibrils on the durability of dentin bonding. Biomaterials 2005; 26(24): 5021-5031.
18. Eick JD, Gwinnett AJ, Pashley DH, Robinson SJ: Current concepts on adhesion to dentin. Crit Rev Oral Biol Med 1997; 81(3): 306-335.
19. Finer Y, Santerre JP: Salivary esterase activity and its association with the biodegradation of dental composites. J Dent Res 2004; 83(1): 22-26.
20. Pashley DH, Tay FR, Yiu C et al.: Collagen degradation by host-derived enzymes during aging. J Dent Res 2004; 83(3): 216-221.
21. Carrilho MRO, Carvalho RM, Goes MF et al.: Chlorhexidine preserves dentin bond in vitro. J Dent Res 2007; 86(1): 90-94.
22. Tjaderhane L, Larjava H, Sorsa T et al.: The activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesions. J Dent Res 1998; 77(8): 1622-1629.
23. van Strijp AJ, Jansen DC, DeGroot J et al.: Host-derived proteinases and degradation of dentine collagen in situ. Caries Res 2003; 37: 58-65.
24. Brinckerhoff CE, Matrisian LM: Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002; 3(3): 207-214.
25. Martin-De Las Heras S, Valenzuela A, Overall CM: The matrix metalloproteinase gelatinase A in human dentine. Oral Biol 2000; 45(9): 757-765.
26. Sulkala M, Wahlgren J, Larmas M et al.: The effects of MMP inhibitors on human salivary MMP activity and caries progression in rats. J Dent Res 2001; 80(6): 1545-1549.
27. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92(8): 827-839.
28. Handsley MM, Edwards DR: Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 2005; 115(6): 849-860.
29. Zhou XJ, Sugerman PB, Savage NW, Walsh LJ: Matrix metalloproteinases and their inhibitors in oral lichen planus. J Cutan Pathol 2001; 28(2): 72-82.
30. Chaussain-Miller C, Fioretti F, Goldberg M, Menashi S: The role of matrix metalloproteinases (MMPs) in human caries. J Dent Res 2006; 85(1): 22-32.
31. Mazzoni A, Mannello F, Tay FR: Zymographic analysis and characterization of MMP-2 and -9 forms in human sound dentin. J Dent Res 2007; 86(5): 436-440.
32. Maskos K: Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie 2005; 87(3-4): 249-263.
33. Murphy G, Allan JA, Willenbrock F et al.: The role of the C-terminal domain in collagenase and stromelysin specificity. J Biol Chem 1992; 267(14): 9612-9618.
34. Nagase H: Activation mechanisms of matrix metalloproteinases. Biol Chem 1997; 378(3-4): 151-160.
35. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2(3): 161-174.
36. Hartung HP, Kieseier BC: The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system. J Neuroimmunol 2000; 107(2): 140-147.
37. Jańczuk Z, Kaczmarek U, Lipski M: Stomatologia zachowawcza z endodoncją. Zarys kliniczny. Wyd. 4. PZWL, Warszawa 2014: 67-69.
38. Lipka D, Boratyński J: Metaloproteinazy MMP. Struktura i funkcja. Post Hig Med Dosw 2008; 62: 328-336.
39. Jung P, Zimowska M: Metaloproteinazy macierzy zewnątrzkomórkowej w rozwoju, fizjologii i procesach degeneracyjnych mięśni szkieletowych. Postępy Biochemii 2016; 62(1): 25-35.
40. Lehmann N, Debret R, Romèas A et al.: Self-etching increases matrix metalloproteinase expression in the dentin-pulp complex. J Dent Res 2009; 88(1): 77-82.
41. Mazzoni A, Pashley DH, Nishitani Y et al.: Reactivation of inactivated endogenous proteolytic activities in phosphoric acid-etched dentine by etch-and-rinse adhesives. Biomaterials 2006; 27(25): 4470-4476.
42. Nishitani Y, Yoshiyama M, Wadgaonkar B et al.: Activation of gelatinolytic/collag enolytic activity in dentin by self-etching adhesives. Eur J Oral Sci 2006; 114(2): 160-166.
43. Breschi L, Mazzoni A, Ruggeri A et al.: Dental adhesion review: aging and stability of the bonded interface. Dent Mater 2008; 24(1): 90-101.
44. Perdigao J, Lambrechts P, Van Meerbeek B et al.: Morphological field emission-SEM study of the effect of six phosphoric acid etching agents on human dentin. Dent Mater 1996; 12(4): 262-271.