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  • Sorsa, Timo; Alassiri, Saeed; Grigoriadis, Andreas; Räisänen, Ismo T.; Pärnänen, Pirjo; Nwhator, Solomon O.; Gieselmann, Dirk-Rolf; Sakellari, Dimitra (2020)
    The aim of this study was to investigate the utility of incorporating active matrix metalloproteinase-8 (aMMP-8) as a biomarker into the new periodontitis classification system (stage/grade) presented in 2018. This study included 150 Greek adults aged 25-78, of whom 74 were men and 76 women. Participants were tested with an aMMP-8 point-of-care mouthrinse test, after which a full-mouth clinical examination was performed to assess their periodontal and oral health. The aMMP-8 levels in mouthrinse were significantly lower among healthy patients compared with patients in more severe periodontitis stages and grades (Kruskal-Wallis test and Dunn-Bonferroni test for pairwise post-hoc comparisons; p <0.01 and p <0.05, respectively). Furthermore, aMMP-8 levels were less correlated with plaque levels than bleeding on probing (BOP) (Spearman's rho = 0.269, p <0.001; Spearman's rho = 0.586, p <0.001); respectively). Thus, aMMP-8 was more robust to the confounding effects of oral hygiene than traditional periodontal parameter bleeding on probing. The aMMP-8 point-of-care mouthrinse test can be utilized as an adjunctive and preventive diagnostic tool to identify periodontal disease, classified by stage and grade, and ongoing periodontal breakdown chairside in clinical practice in only 5 min. Overall, integrating aMMP-8 into the new periodontitis classification system seems beneficial.
  • Hernández, Marcela; Baeza, Mauricio; Räisänen, Ismo T.; Contreras, Johanna; Tervahartiala, Taina; Chaparro, Alejandra; Sorsa, Timo; Hernández-Ríos, Patricia (2021)
    Periodontitis is a host-mediated bacterial disease that affects the tooth attachment apparatus. Metalloproteinase-8 (MMP-8), a validated biomarker, could aid in clinical diagnosis. This study aimed to evaluate the diagnostic performance of active (a) MMP-8 immunotest versus total (t) MMP-8 ELISA for quantitative real-time diagnosis and assessment of periodontitis severity at the site level. Gingival crevicular fluid (GCF) was sampled from 30 healthy, 42 mild, and 59 severe periodontitis sites from thirty-one volunteers. MMP-8 concentrations were determined by time-resolved immunofluorometric assay (IFMA) and enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using the STATA package. Both active and total MMP-8-based methods discriminated among sites according to periodontal diagnosis and severity, with a positive correlation between the two tests (p < 0.001). (a) MMP-8 models showed the best performance in receiver operating characteristic (ROC) curves to discriminate between healthy and periodontitis sites (area under the curve [AUC] = 0.89), while (t) MMP-8 demonstrated a high diagnostic precision in the detection of mild from severe periodontitis sites (AUC ≥ 0.80). The use of (a) MMP-8 and (t) MMP-8 could represent a useful adjunctive tool for periodontitis diagnosis and severity. These results support the applicability of new point-of-care methods in the monitoring of high-risk periodontal patients.
  • Lähteenmäki, Hanna; Umeizudike, Kehinde A.; Heikkinen, Anna Maria; Räisänen, Ismo T.; Rathnayake, Nilminie; Johannsen, Gunnar; Tervahartiala, Taina; Nwhator, Solomon O.; Sorsa, Timo (2020)
    This communication article addresses currently available rapid non-invasive methods to screen and detect periodontitis and dental peri-implantitis. In this regard, oral fluid biomarkers have been researched extensively but self-reported oral health (SROH)-questionnaires have also been developed. Both alternatives may offer a quick and easy way to screen and detect diseased patients. Active matrix metalloproteinase (aMMP-8) is one of the most validated biomarkers for screening and detecting periodontal breakdown related to periodontitis and peri-implantitis and monitoring their treatment effects revealing successful, less- and non-successful treatment results. Currently available aMMP-8 lateral-flow technologies allow this kind of analysis, as demonstrated here, to be conducted quantitatively online and real-time as point-of-care/chairside testing in dental and even medical care settings. In this study, an aMMP-8 peri-implant sulcular fluid point-of-care-test diagnosed peri-implantitis and healthy implants far more accurately than bleeding-on-probing or the other biomarkers, such as polymorphonuclear (PMN)/neutrophil elastase, myeloperoxidase and MMP-9. Although, SROH-questionnaires allow screening in similar settings but they lack the information about the current disease activity of periodontitis and peri-implantitis, which is of essential value in periodontal diagnostics and treatment monitoring. Thus, both methods can be considered as adjunct methods for periodontitis and peri-implant diagnostics, but the value of oral fluid biomarkers analysis does not seem to be substitutable.
  • Mokkala, Kati; Juhila, Juuso; Houttu, Noora; Sorsa, Timo; Laitinen, Kirsi (2020)
    Lower level of insulin-like growth factor-binding protein (IGFBP-1) has been observed in insulin resistance, while higher level of matrix metalloproteinase-8 (MMP-8) has been linked to obesity. The aim here was to study in overweight and obese women, typically manifesting with insulin resistance, whether IGFBP-1 and MMP-8 are related to and reflect systemic low-grade inflammation, metabolism and diet. Fasting serum from overweight and obese pregnant women (n = 100) in early pregnancy were analysed for IGFBP-1, phosphorylated IGFBP-1 (phIGFBP-1) and MMP-8. High-sensitivity CRP and GlycA were used as markers for low grade inflammation. GlycA and lipids were quantified using NMR. IGFBP-1 associated negatively with GlycA, evidenced by higher concentrations in the lowest quartile (median 1.53 (IQR 1.45-1.72)) compared to the highest (1.46 (1.39-1.55)) (P = 0.03). Several lipid metabolites, particularly HDL-cholesterol, correlated inversely with phIGFBP-1 (FDR
  • Peltonen, Johanna; Tuomainen, Katja; Sallinen, Tobias; Faress, Islam; Suleymanova, Ilida; Al-Samadi, Ahmed; Salo, Tuula; Åström, Pirjo (2020)
    Background: Tongue cancer is more common in men than in women. Yet the effects of sex steroid hormones on the behaviour of oral tongue squamous cell carcinoma (OTSCC) are not well known. Matrix metalloproteinase 8 (MMP8) is expressed in OTSCC and can degrade estrogen receptors (ERs). Materials and Methods: Western blot was used to examine the levels of ER beta in OTSCC cell lines (HSC-3 and SCC-25). We evaluated the effects of estradiol and dihydrotestosterone (DHT) on HSC-3 and SCC-25 cell migration, invasion and viability. The effect of estradiol on the invasion of MMP8-overexpressing (MMP8(+)) and empty vector HSC-3 cells was examined using 3D spheroid invasion assay. Results: Both HSC-3 and SCC-25 cells expressed ER beta. In scratch assay, estradiol, but not DHT, reduced the migration and invasion of HSC-3 and SCC-25 cells. MMP8(+) HSC-3 cells showed weaker invasion than empty vector cells, in line with previous reports. However, MMP8 overexpression did not alter the effect of estradiol on HSC-3 cell invasion in spheroid assay. Conclusion: Estradiol inhibited the migration and invasion of OTSCC cells, whereas DHT had no effect. Our data suggest that MMP8 does not modulate the effect of estradiol in OTSCC cells. However, the sex difference in OTSCC incidence might partly be due to protective actions of estradiol in epithelial cell carcinogenesis.
  • Carpen, Timo; Sorsa, Timo; Jouhi, Lauri; Tervahartiala, Taina; Haglund, Caj; Syrjänen, Stina; Tarkkanen, Jussi; Mohamed, Hesham; Mäkitie, Antti; Hagström, Jaana; Mattila, Petri S. (2019)
    Background An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. Materials and methods A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). Results High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. Conclusion Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.
  • Mauramo, Matti; Mauramo, Elina; Sorsa, Timo; Tervahartiala, Taina; Räisänen, Ismo T.; Waltimo, Tuomas (2021)
    Objectives: This case control study examined the associations of HLA antigens and periodontitis with the salivary level of active MMP-8 (aMMP-8). Materials and Methods: A total of 202 subjects, registered as Swiss bone marrow donors, participated in the study. HLA-A, -B, and -C types were determined by serology or PCR. Saliva samples were collected from subjects, followed by a periodontal examination. The salivary level of aMMP-8 was determined with immunofluorometric assay. Results: The mean salivary level of aMMP-8 was directly comparable to the grade of periodontitis and increased from healthy to mild/moderate to severe (125.0 +/- 132.1, 200.6 +/- 170.2, 290.1 +/- 202.3 ng/ml; p < 0.001 between each group, respectively). The only association between the HLA types and the salivary level of aMMP-8 was observed in subjects with HLA-A11. Subjects with healthy periodontium and HLA-A11 had a lower level of aMMP-8 (49.2 +/- 32.5 ng/ml) compared with subjects without HLA-A11 (123.6 +/- 119.2; p = 0.048). Among subjects with periodontitis, a higher level of aMMP-8 (394.2 +/- 255.6 ng/ml) was observed in subjects with HLA-A11 compared with subjects without HLA-A11 (201.1 +/- 146.1 ng/ml; p < 0.002). This finding was statistically significant also after adjusting for sex, age, smoking, tooth brushing and the number of medications (p < 0.05). Conclusions: HLA-A11 is associated with the salivary level of aMMP-8 which contributes to the subject's immune and inflammatory response in periodontium.
  • Äyräväinen, Leena; Heikkinen, Anna Maria; Kuuliala, Antti; Ahola, Kirsi; Koivuniemi, Riitta; Laasonen, Leena; Moilanen, Eeva; Hämäläinen, Mari; Tervahartiala, Taina; Meurman, Jukka H.; Leirisalo-Repo, Marjatta; Sorsa, Timo (2018)
    Objective: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. Methods: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. Results: Serum MMP-8 (p <.001; p <.001) and IL-6 (p <.001; p =.002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p =.010) and IL-6 (p =.010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. Conclusion: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation.
  • Juurikka, K.; Dufour, A.; Pehkonen, K.; Mainoli, B.; Campioni Rodrigues, P.; Solis, N.; Klein, T.; Nyberg, P.; Overall, C. M.; Salo, T.; Åström, P. (2021)
    Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.
  • Räisänen, Ismo T.; Heikkinen, Anna Maria; Nwhator, Solomon O.; Umeizudike, Kehinde A.; Tervahartiala, Taina; Sorsa, Timo (2019)
    This study investigated the diagnostic utility of mouthrinse and saliva in aMMP-8 measurements to analyze patients' risk for active periodontal tissue destruction and progression of periodontal disease among 47 adolescents. Results show that measurements from mouthrinse produce better discrimination and should be used instead of saliva measurements. (C) 2019 Elsevier Inc. All rights reserved.
  • Räisänen, Ismo T.; Umeizudike, Kehinde A.; Pärnänen, Pirjo; Heikkilä, Pia; Tervahartiala, Taina; Nwhator, Solomon O.; Grigoriadis, Andreas; Sakellari, Dimitra; Sorsa, Timo (2020)
    Periodontal disease is a chronic multifactorial infectious and inflammatory disease associated with several chronic systemic diseases, such as diabetes, cardiovascular diseases (CVD), chronic obstructive pulmonary disease, hypertension, Alzheimer's disease and so on. These same systemic diseases have been associated with severe COVID-19 infections. Several recent studies have suggested hypotheses for the potential association between periodontal disease and severe COVID-19. Periodontal disease is also one of the most prevalent diseases globally. All this supports the importance of good oral health, also in the COVID-19 era. Thus, new strategies and approaches to identify patients at risk of periodontal disease could be beneficial to enhance secondary prevention, especially if targeted to COVID-19 risk groups. Diagnostic biomarkers for periodontal disease have been researched extensively. Potential biomarkers in oral fluid with currently available rapid non-invasive point-of-care technology, such as aMMP-8, could help to extend screening and identification of patients at risk for periodontal disease also to situations and places where professional dental expertise and equipment are limited or unavailable. i.e., nursing and care homes, and rural and distant places. The oral fluid point-of-care technologies could also be useful in the hands of medical professionals (diabetes, CVD, etc.) to identify patients at risk for undiagnosed periodontal disease and to refer them to a dentist for examination and evaluation. Finally, if there is a causality between periodontal disease and severe COVID-19 infections, these point-of-care oral fluid biomarker technologies could possibly also help in the assessment of the risk of deterioration and complications.
  • Räisänen, Ismo T.; Heikkinen, Anna Maria; Siren, Eva; Tervahartiala, Taina; Gieselmann, Dirk-Rolf; van der Schoor, Gerrit-Jan; van der Schoor, Peter; Sorsa, Timo (2018)
    Traditional periodontal disease diagnostics are based mainly on clinical examination and radiographs. They assess only past tissue destruction and provide no information on the current disease status or its future progression. The objective is to find out if an active matrix metalloproteinase-8 (aMMP-8) point-of-care (PoC) test could provide a cost-effective way to get around this limitation. This cross-sectional study used 47 adolescents and 70 adults, who were clinically examined and their aMMP-8 PoC tested. The aMMP-8 PoC test results and patients' treatment need, based on the community periodontal index of treatment needs (CPITN), were compared and analyzed using Fisher's exact test. In terms of CPITN, the aMMP-8 PoC test gave no false positives for both adolescents and adults. All healthy patients got a negative test result, while a positive test result indicated periodontal treatment need correctly. Finally, there was a significant association between a patient's aMMP-8 PoC test result and his/her treatment need (p = 0.001 for adolescents, p = 0.001 for adults). In conclusion, more accurate diagnostics of periodontal diseases' activity and progression using an aMMP-8 PoC test may help to reduce oral health care costs by reducing patient overtreatment, improving patient outcome, and reducing the need for complex periodontal therapy.
  • Nascimento, Gustavo G.; Baelum, Vibeke; Sorsa, Timo; Tervahartiala, Taina; Skottrup, Peter D.; Lopez, Rodrigo (2019)
    Aim: This study aimed to investigate the association between salivary levels of myeloperoxidase (MPO), neutrophil elastase (NE), soluble urokinase-type plasminogen activator receptor (suPAR), matrix metalloproteinase (MMP)-8 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and gingival inflammation development during an experimental gingivitis study. Methods: A three-week experimental gingivitis study was conducted. Clinical recordings of dental plaque biofilm (Modified Quigley Hein Plaque Index, TQHPI) and gingival inflammation (Modified Gingival Index, MGI) were made at specific time points for each of the 42 participants. Salivary levels of MPO, NE, suPAR, MMP-8 and TIMP-1 at the same time points were measured using distinct immunoassays. For data analysis growth curve modelling was employed to account for the time-varying outcome (MGI score) and the time-varying covariates (salivary marker levels, and TQHPI score). Analyses were stratified according to the MGI-score trajectory groups previously identified as 'fast', respectively 'slow' responders. Results: Overall, higher MGI scores were statistically significantly positively associated with higher levels of MPO, MMP-8 and TIMP-1. Stratified analysis according to inflammation development trajectory group revealed higher levels of salivary MPO, MMP-8 and MMP-8/TIMP-1 ratio among the 'fast' responders than among 'slow' responders. None of the investigated salivary protein markers was associated with a 'slow' inflammation development response. Conclusions: Salivary levels of MPO, MMP-8 and TIMP-1 were associated with the extent and severity of gingival inflammation. While the 'fast' gingival inflammation response was associated with increased levels of MPO, MMP-8 and MMP-8/TIMP-1 ratio, the 'slow' response was not associated with any of the salivary protein markers investigated in this study. Neutrophil activity seems to orchestrate a 'fast' gingival inflammatory response among participants previously primed to gingival inflammation.