*Aneta Zduniak1, Sylwia Olszewska2, Agnieszka Mielczarek1
Metalloproteinases and their role in the degradation of bonding systems. Part 2
Metaloproteinazy i ich udział w degradacji systemów wiążących. Część 2
1Department of Conservative Dentistry, Medical University of Warsaw
Head of Department: Agnieszka Mielczarek, MD, PhD
2Private practice: Klinika Radość, Warsaw
Head of Practice: Barbara Sobczak, MD, PhD
Stabilność warstwy hybrydowej jest kluczowa dla zapewnienia trwałości wypełnień z materiałów złożonych. Czynniki osłabiające siłę wiązania związane są m.in. z obecnością bakterii i ich enzymów w strukturze biofilmu bakteryjnego. Chroniczne uszkadzanie warstwy hybrydowej zachodzi także w wyniku hydrolizy i wypłukiwania monomerów adhezyjnych, które infiltrowały zdemineralizowaną matrycę zębiny. Do czynników sprzyjających degradacji zalicza się również nanoprzeciek. Bardzo wiele badań analizuje wpływ endogennych proteaz na degradację warstwy hybrydowej. Endogenne enzymy kolagenolityczne: metaloproteinazy (MMPs) i katepsyny cysteinowe, są odpowiedzialne za degradację matrycy kolagenowej w warstwie hybrydowej. Inhibicja endogennych proteaz jest zatem konieczna dla spowolnienia degradacji wypełnień. Aktywność enzymów w zębinie i warstwie hybrydowej może być regulowana przez endo- i egzogenne inhibitory.
Praca stanowi przegląd dostępnego piśmiennictwa opublikowanego w bazie medycznej PubMed i w polskich czasopismach stomatologicznych w latach 2002-2017. Jej celem jest ocena roli metaloproteinaz i katepsyn cysteinowych w degradacji warstwy hybrydowej i przegląd związków o działaniu inhibicyjnym w stosunku do tych grup enzymów.
The stability of the hybrid layer is crucial for ensuring the durability of fillings made of composite materials. Factors which weaken the bond strength are related to, among others, the presence of bacteria and their enzymes in the structure of the bacterial biofilm. Chronic damage the hybrid layer is also a result of hydrolysis and leaching of adhesive monomers which infiltrated the demineralised dentin matrix. Nanoleakage is also among the factors contributing to degradation. Many studies examine the effect of endogenous proteases on the degradation of the hybrid layer. Endogenous collagenolytic enzymes: metalloproteinases (MMPs) and cysteine cathepsins, are responsible for the degradation of the collagen matrix in the hybrid layer. Inhibition of endogenous proteases is therefore necessary to slow the degradation of fillings. The enzyme activity in dentine and in the hybrid layer can be regulated by endo- and exogenous inhibitors.
The paper is a review of the available literature published in the PubMed medical database, as well as in Polish dental journals in the years 2002-2017. Its aim is to assess the role of metalloproteinases and cysteine cathepsins in the degradation of the hybrid layer and to review the compounds with inhibitory properties in relation to these enzyme groups.
Performing the reconstruction of tooth hard tissues with a long period of clinical use is the measure of success in restorative dentistry. Currently, particular attention is given to the surface of adhesion between the tooth tissue and the filling. This is due to the fact that a gradual degradation of this zone is observed in the course of the functioning of a reconstruction. The exposure of collagen due to dentine etching or the application of self-etching primers removes or modifies the mineral phase of dentine. The exposed matrix is then impregnated with adhesive monomers, leading to the creation of the hybrid layer. The stability of resin polymers and the exposed collagen is crucial to the durability of the connection between dentine and the bonding material. The degradation of both these elements impairs adhesion and leads to the formation of a micro-gap between the tooth and the filling material, which can be penetrated by the bacterial flora (1).
Factors impairing the strength of the bond are connected with, among others, the presence of bacteria and their enzymes in the structure of the bacterial biofilm. It has been demonstrated that S. mutans has the capacity to release specific enzymes, esterases, which contribute to the degradation of resins in composite materials and bonding systems (2).
Chronic damage the hybrid layer is also a result of hydrolysis and leaching of adhesive monomers which infiltrated the demineralised dentin matrix. Leaching is facilitated by water sorption and its penetration through the zone of loose collagen fibres or the hydrophilic domains of bonding systems. Mechanical wear of the filling can further accelerate the degradation of this bond by abrading its surface and enlarging the enzyme and water penetration area. Hydrolytic degradation is considered to be the main cause of damage to the hybrid layer, leading to a reduction in bonding strength over time (3).
Nanoleakage is regarded as another factor contributing to the degradation of the hybrid layer, which is the penetration of small ions and molecules into the hybrid layer with no visible damage zones. Nanoleakage is formed as a result of a disturbed balance between the rate of dentine demineralisation and the level of its infiltration with bonding systems. This phenomenon is observed both in the case of systems in which tissues are etched in the course of a separate procedure and in the case of self-etching ones. Neither of the options provide sufficient collagen network saturation, giving rise to a hybrid layer of heterogeneous, diverse thickness (4).
Lack of saturation of the collagen network with the bonding system contributes to the phenomenon of collagen fibres degradation. Fibres which have not been infiltrated, are destroyed as a result of the removal of resin from the space between them and their disorganisation. The degree of degradation may differ depending on the bonding system (3).
More and more research examines the effect of endogenous proteases on the degradation of the hybrid layer. These reports have important clinical implications. Endogenous metalloproteinases, among others, MMP-9, are involved in the process of degradation. The presence of water is necessary to obtain the hydrolytic activity of MMPs. In humid conditions, MMPs hydrolyse peptide bonds, causing the degradation of the bond between dentine and resin (5-8).
Pashley et al. (9) studied the activity of proteolytic enzymes on demineralised dentine stored in water, artificial saliva and oil, and evaluated the role of proteolytic enzyme inhibitors in the protection of the demineralised collagen matrix. The results obtained suggest that the hydrolytic degradation of collagen occurs in the absence of bacteria. According to the authors, the metalloproteinases from the demineralised matrix may be activated during dentine etching or treatment and are probably responsible for the degradation of the hybrid layer in the aquatic environment.
Having confirmed the presence and action of endogenous metalloproteinases in dentine, the activity of these enzymes in the hybrid layer was assessed (10). It was demonstrated that active proteolytic enzymes are present inside the hybrid layer. Their activity was observed in the bottom zone of the hybrid layer, which correlates with the presence of areas of demineralised collagen, not saturated with the bonding system. Interestingly, exposed areas of collagen were found in the distribution area of nano pores in the hybrid layer, giving rise to progressing damage of the layer.
It has been proven that in dentine treated with an isolated etchant, as well as in one treated with self-etching systems, MMP-2 and MMP-9 enzymes are secreted. The effect of the metalloproteinases can be intensified as a result of the loss of the inhibitory properties of TIMP, the main natural MMPs inhibitors present in the tissues of the tooth. By combining with metalloproteinase molecules, these endogenous compounds inhibit their activity. Therefore, the balance between them and MMPs is crucial to ensuring the stability of healthy tooth tissues (10, 11). TIMPs control matrix metalloproteinases in two ways: by inhibiting the phase of proenzyme transformation into an enzyme, as well as by inhibiting the activity of MMPs.
So far, 4 types of TIMPs have been known (TIMP-1 to TIMP-4), which have the ability to create enzyme-inhibitor complexes. TIMPs are composed of two sub-units: the N-terminal and the C-terminal one. All TIMP inhibitors inhibit metalloproteinases. Under physiological conditions, at low concentrations of MMPs – usually inactive – the MMP-TIMP system works reliably and is involved in tissue modelling. In pathological conditions, however, the tissue inhibitors are unable to inhibit the activity of the increased titre of active MMPs (6, 12, 13).
In the process of bonding systems degradation, cathepsins also play a significant role. Lowered pH of the oral cavity environment, induced by the application of the procedures aimed at generating adhesion, creates conditions for the activation of these enzymes. Studies have shown the potential correlation between the activity of metalloproteinases and cathepsins, both in healthy and demineralised tissue (3, 14, 15). The application of acidic monomers activates both metalloproteinases and cathepsins. Cysteine cathepsins are an important group of proteolytic enzymes present in dentine. Their diversity is comparable with the number of existing metalloproteinases. Cathepsins demonstrate the ability to degrade dentine matrix in a physiological and pathological way. They also play a role in the course of tooth decay and gum and periodontium diseases, being responsible for the occurrence of a gradual loss of tightness of adhesive reconstructions. It has been observed that cathepsins have different degradation potential depending on the area of infected dentine, the location of a carious lesion and its activity. The levels of these enzymes increases significantly in very deep cavities located near the pulp, which indicates that cathepsins of dentine or pulp origin play a key role in the progress of active lesions and the hybrid layer degradation. They are self-activated at lowered pH. Under neutral conditions they remain inactive – in contrast to MMPs, which are the most active at neutral pH (3, 14-17).
In the light of the foregoing, it would seem to be the key to ensure the integrity of the collagen matrix by inhibiting endogenous proteases. This may increase the durability of the bond between dentine and the bonding system and ensure long-term sustenance of fillings from composite materials, thus inhibiting the development of secondary caries. The suspicion of secondary caries is the most common cause of tooth filling replacement. Therefore, in scientific considerations, much attention is given to the prevention of secondary caries formation and the possibility of carious dentine remineralisation. Modern strategies for carious lesions treatment are continuously sought, which would involve the strengthening of dentine structure and promote the use of metalloproteinase inhibitors. The activity of MMPs in dentine and the hybrid layer can be adjusted by endogenous and exogenous inhibitors. Endogenous compounds are obtained from human cells derived from other organs, while the exogenous ones are synthesised artificially (1).
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