Variability of Gingival Crevicular Fluid Matrix Metalloproteinase -8 Levels in Respect to Point-of-Care Diagnostics in Periodontal Diseases

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http://urn.fi/URN:ISBN:978-951-51-1997-1
Title: Variability of Gingival Crevicular Fluid Matrix Metalloproteinase -8 Levels in Respect to Point-of-Care Diagnostics in Periodontal Diseases
Author: Leppilahti, Jussi
Contributor: University of Helsinki, Faculty of Medicine, Institute of Dentistry, Department of Oral and Maxillofacial Diseases
Publisher: Helsingin yliopisto
Date: 2016-06-03
Belongs to series: URN:ISSN:2342-317X
URI: http://urn.fi/URN:ISBN:978-951-51-1997-1
http://hdl.handle.net/10138/161021
Thesis level: Doctoral dissertation (article-based)
Abstract: Matrix metalloproteinases (MMP) and especially MMP-8 is one of the most widely reported oral fluid biomarkers and a promising target candidate for periodontal point-of-care (POC) diagnostics. Periodontitis is associated with increased oral fluid MMP-8 levels, which typically decrease after conventional periodontal treatments. Employing the measurement of oral fluid MMP-8 levels diagnostically, however, is complicated due to high variability. Chronic periodontal inflammation can induce MMP-8 expression in a wide array of cell types, although a great extent of the MMP-8 detected from the gingival crevicular fluid (GCF) originates from polynuclear neutrophil granulocytes (neutrophils). MMP-8 mediates periodontal tissue breakdown by processing extracellular matrix (ECM) proteins with a wide substrate specificity. There is also increasing evidence that MMP-8 contributes to inflammatory signaling cascades and has a protective role in periodontitis and cancer. Thus, it is important to define and differentiate a (statistical) range of physiological fluctuations in the oral fluid MMP-8 POC diagnostics, from the pathologically high MMP-8 levels. The aim of this study was to study methodological and biological reasons for the large variability of GCF MMP-8 and further to evaluate the utility of GCF MMP-8 for POC diagnostics and its ability to predict the treatment outcome after the conventional scaling and root plaining (SRP) treatment and during the supportive maintenance period. Different laboratory and POC MMP-8 detecting methods were compared to study methodological reasons of variability in the GCF MMP-8 levels. In addition, correlations between different inflammatory GCF biomarkers and MMP-8 were compared. The MMP-8 levels measured with laboratory methods or POC tests/devices based on the same monoclonal antibody were clearly in agreement and correlated significantly. There was surprisingly large variability in MMP-8 levels, however, when measured with different assays based on different antibodies. The comparison of different GCF biomarkers revealed highly discriminating properties, especially for myeloperoxidase (MPO) and MMP-8, to differentiate both healthy and gingivitis sites from moderate to advanced chronic periodontitis sites. The longitudinal variability in GCF MMP-8 response patterns was explored and the prognostic utility of GCF MMP-8 was studied. Distinct response patterns during the maintenance period could be found via cluster analysis, especially among smoking patients. High MMP-8 levels at baseline and especially the high-responding pattern among smokers during the maintenance period predicted the compromised treatment outcome. The utility of the GCF MMP-8 levels in the prognostic POC diagnostics was further studied within a heterogenic population by combining different independent datasets. Continuously high MMP-8 levels, at baseline and during the maintenance period, predicted an increased risk for compromised treatment outcome for both non- smoking and smoking patients. Low MMP-8 levels decreased the risk respectively. Overall, the different MMP-8 antibodies can have a quite large difference in affinities to different MMP-8 isoforms, causing variability to the measured levels. If researchers fail to use the same detection methods in different studies, result comparisons may be complicated. GCF MMP-8, however, is a promising candidate as a prognostic biomarker to identify sites with an increased risk for compromised treatment outcome. This study also strongly supports the evidence that MMP-8 can diagnostically differentiate between periodontitis and healthy or gingivitis sites and can also be used for the quantitative, therapeutic monitoring of treatment outcome. Different GCF MMP-8 cutoff levels should be applied for smokers and non-smokers in the MMP-8 based POC diagnostics, however.Hampaan kiinnityskudosten tulehdus eli parodontiitti on aikuisväestössä yleinen sairaus, joka pitkälle edenneenä voi johtaa lopulta hampaiden menettämiseen. Parodontiitin varhainen diagnoosi on sairauden pitkäaikaisennusteen kannalta erittäin tärkeää. Matriksin metalloproteinaasi (MMP)- 8 on osoittautunut aikaisemmissa tutkimuksissa lupaavaksi merkkiaineeksi käytettäväksi parodontiitin diagnostiikassa. Aktiivinen MMP-8 - entsyymi pilkkoo kollageeneja ja muita sidekudoksen proteiineja. MMP-8:a vapautuu erityisesti neutrofiilisistä granulosyyteistä, mutta krooninen tulehdus lisää myös monissa muissa solutyypeissä MMP-8 geenin ilmentymistä. Kohonnut MMP-8 pitoisuus suunesteissä, mm. ientaskunesteessä tai syljessä, on yhdistetty parodontiittiin useissa tutkimuksissa ja pitoisuuksien on osoitettu laskevan onnistuneen hoidon jälkeen. Toisaalta, suunesteiden MMP-8 pitoisuuksissa on havaittavissa suurta vaihtelua potilaiden välillä, mikä vaikeuttaa sen soveltamista parodontiitin diagnostiikassa. Tämän väitöskirjatutkimuksen tarkoitus on vertailla ns. tuolinvierustestejä ja laboratoriossa käytettäviä immunologisia MMP-8:n mittausmenetelmiä sekä tutkia tupakoinnin vaikutusta ientaskunesteen MMP-8 pitoisuuden vaihteluun, ja edelleen MMP-8 käytettävyyttä parodontiitin diagnostiikassa. Tutkimuksessa vertailtiin MMP-8:n ja muiden ientaskunesteen tulehdusmerkkiaineiden kykyä erottaa parodontiitti terveestä, mutta myös pinnallisesta ientulehduksesta eli gingiviitistä. Lisäksi selvitettiin voiko ientaskunesteen MMP-8 ennustaa parodontiitin kliinistä hoitovastetta. Tutkimustulosten yhteenvetona voidaan todeta, että immunologisissa mittausmenetelmissä käytettävien eri vasta-aineiden kyky sitoutua MMP-8:n erilaisiin muotoihin vaihtelee aiheuttaen hajontaa mittaustuloksissa. Näin ollen tutkimusten välinen vertaileminen voi olla vaikeaa, jos MMP-8:n mittausmenetelmät eivät ole yhteneviä. Ientaskunesteen MMP-8 on lupaava merkkiaine käytettäväksi parodontiitin hoitovasteen ennustamiseen. Tämä tutkimus myös tukee aikaisempia tuloksia, joiden mukaan ientaskunesteen MMP-8 pitoisuuden avulla voidaan erottaa terve hampaan kiinnityskudos pinnallisesta ientulehduksesta ja keskivaikeasta tai pitkälle edenneestä parodontiittista. Tupakointi tulee kuitenkin ottaa huomioon ientaskunesteen MMP-8 pitoisuuksien diagnostisessa tulkinnassa.
Subject: hammaslääketiede
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