Relationship between Serum Matrix Metalloproteinase-8 and Periodontitis: A PRISMA-Compliant Systematic Review and Meta-Analysis

Relationship between Serum Matrix Metalloproteinase-8 and Periodontitis: A PRISMA-Compliant Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Relationship between Serum Matrix Metalloproteinase-8 and Periodontitis: A PRISMA-Compliant Systematic Review and Meta-Analysis Yihong Deng, Hongxia You, Yuyan Zheng, Yiqun Jia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5461775/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives : To determine whether the serum matrix metalloproteinase-8 (MMP-8) level is elevated in periodontitis patients compared with that in periodontally healthy individuals, we conducted a meta-analysis to assess its diagnostic value. This study aims to provide insight into the increased prevalence and severity of systemic diseases in periodontitis patients, as well as the potential of serum MMP-8 in the rapid diagnosis of periodontitis. Methods : A comprehensive search following the PECO criteria of PubMed, Embase and the Cochrane Library from their inception to October 8, 2024, was conducted to retrieve comprehensive relevant articles. The complete selection procedure was meticulously documented with transparency and was registered in PROSPERO CRD42024608648. The methodological qualities of the included articles were evaluated following the Newcastle‒Ottawa Scale (NOS) grading system. The level of serum MMP-8 was converted to a standard (mean ± standard deviation (SD)), and meta-analysis was conducted with Review Manager 5.4 software. Sensitivity analyses were performed with Stata 17.0 software. Results : A total of 12 studies, including 10 case‒control studies and 2 cohort studies, were ultimately included, with a total of 871 participants. The results of the meta-analysis revealed higher serum MMP-8 levels in periodontitis patients than in healthy controls (SMD 0.64, 95% CI 0.27 to 1.01; 12 studies, 871 participants). High heterogeneity (I 2 = 86%) indicated variability in outcomes, possibly influenced by regional factors. Duval and Tweedie’s trim and fill procedure was conducted, and no evidence of a small study effect was found. Sensitivity analyses revealed great stability of the data included. Conclusions : Our meta-analysis revealed that the serum MMP-8 level in periodontitis patients was likely greater than that in healthy subjects, but further studies on regional factors are needed to clarify this conclusion considering the degree of heterogeneity. Periodontitis matrix metalloproteinase-8 meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Periodontitis is a chronic multifactorial inflammatory disease characterized by the progressive destruction of periodontal tissue, the common features of which include clinical attachment loss, the formation of periodontal pockets and gingival bleeding, and if left untreated, it may eventually lead to tooth loss [ 1 ]. At present, periodontitis is estimated to be the most common chronic inflammatory noncontagious disease, with a prevalence rate of 11% [ 2 – 3 ]. Moreover, the Global Burden of Disease (GBD) database revealed that the number of severe periodontitis cases worldwide reached 1.1 billion in 2019 [ 4 ]. Owing to its high incidence rate, periodontitis poses significant public health problems, such as impaired masticatory function, damaged aesthetics and edentulism. They subsequently lower quality of life, developing into the origin of social inequality. Pontitis not only harms in situ periodontal tissue but also promotes the development of multiple systematic diseases, such as coronary heart disease, rheumatoid arthritis and dementia [ 5 – 9 ]. These effects further damage the overall physiological and psychological health status of patients. Current mechanistic models of periodontitis suggest that local inflammation of the periodontium, resulting from a proinflammatory host immune response to bacteria, plays a vital role in its progression and recurrence [ 10 – 12 ]. Several studies have shown increased local levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and matrix metalloproteinase-8 (MMP-8), in patients with periodontitis [ 13 – 16 ]. According to previous studies, IL-6 is able to induce osteoclast differentiation and bone resorption, inhibit bone formation [ 10 ], and is correlated with the release and activation of MMP-8, which may then cause ECM breakdown [ 17 ]. In addition, periodontitis has been reported to increase systematic proinflammatory cytokines [ 11 , 18 – 21 ], which may be cofactors that accelerate the occurrence of inflammation in other distant parts of the body. [ 10 ] Therefore, hypotheses have been proposed that cytokines released by diseased periodontal tissue may enter the circulation, stimulate other parts of the body and eventually have an impact on systematic health [ 21 ], but further experiments are needed. Matrix metalloproteinases (MMPs) are members of a proteolytic enzyme family that are responsible for the remodeling and degradation of the extracellular matrix (ECM) [ 22 ]. Collagen I constitutes the main component of the periodontal extracellular matrix; therefore, collagenase has received special attention [ 23 ]. Among all collagenase proteins, MMP-8 is the most frequently mentioned member because it contributes to approximately 80% of all the collagenase identified in gingival crevicular fluid (GCF) [ 24 ]. Additionally, saliva MMP-8 is widely regarded as a potential biomarker for the diagnosis of periodontitis. MMP-8 can either be derived from bacteria in dental plaque or from cellular sources, and from both sources, it is capable of degrading almost all types of collagenous and noncollagenous proteins in the ECM [ 23 ], which may then lead to tissue destruction. In addition to periodontitis, excessive MMP-8 is involved in the pathogenesis of many other inflammatory diseases, such as pancreatitis and sepsis, and systematic diseases, such as rheumatoid arthritis [ 8 , 25 ]. Many MMP-8-related studies have been conducted in saliva, but only a small portion of these studies have focused on serum MMP-8 concentrations. However, increasing evidence has shown that circulating MMP levels are associated with several systemic diseases, such as hypertension, coronary artery disease, diabetes and rheumatoid arthritis [ 5 – 8 , 10 , 26 ]. Therefore, it is speculated that the increased concentrations of saliva MMP-8, which subsequently enter the circulation, may then result in elevated levels of serum MMP-8 and thus become a causal factor linking periodontitis with increased susceptibility to several systematic diseases. Therefore, it is essential to pay attention to the impact of periodontitis on the serum MMP-8 level. To the best of the author’s knowledge, no comprehensive systematic meta-analysis has been conducted to evaluate whether serum MMP-8 levels are significantly different between healthy individuals and periodontitis patients. To fill this gap, the present study aimed to confirm whether the level of MMP-8 in the serum of patients with periodontitis is greater than that in healthy individuals on the basis of a comprehensive review of all the existing studies. Methods Focused question Our research focused on the following question: “Is periodontitis status correlated with elevated levels of serum MMP-8 compared with those in periodontally healthy subjects?” If the answer is “yes”, then this research may provide some insight for solving the problem of increased prevalence and severity of systemic diseases in periodontitis patients. The focused question was formulated following the PECO criteria [ 27 ], which can be specifically interpreted as follows: P (Population): Adults E (Exposure): Periodontitis subjects C (Comparison): Periodontally healthy subjects O (Outcome): Serum MMP-8 concentration Search strategy We conducted a comprehensive search of PubMed, Embase and the Cochrane Library from their inception to October 8, 2024. To retrieve more comprehensive relevant articles, our search strategy was as follows: “(periodontitis OR periodontal disease) AND (serum OR plasma OR blood) AND (MMP-8 OR matrix metalloproteinase OR matrix metalloproteinase-8 OR biomarker OR cytokine)”. No restrictions on other conditions were applied. The detailed search strategy is shown in Table S1 . Additionally, we manually searched influential journals for relevant articles, such as the Journal of Clinical Periodontology (JCP), the Journal of Periodontology (JOP), Periodontology 2000, the Journal of Periodontal Research, the International Journal of Oral Science and Clinical Advances in Periodontics. Inclusion and exclusion criteria Articles that met the following criteria were included in our research. 1) Types of studies: observational studies, case‒control studies, cross-sectional studies, cohort studies and clinical trials in humans. 2) Participants: periodontitis subjects versus periodontally healthy subjects. 3) The evaluation index includes the serum MMP-8 level. 4) Articles published in English until Oct 8, 2024. 5) Extractable the numerical data. We excluded articles in our research following the criteria below. 1) Duplicate records. 2) Irrelevant topics. 3) Animal models. 4) Types of studies: reviews, case reports, abstracts, editorials, conference abstracts, and corresponding letters. 5) Study design not perspective. 6) Non-English records. Quality assessment To evaluate the methodological qualities of the included articles, two independent reviewers separately assessed each article following the Newcastle‒Ottawa Scale (NOS) grading system. The NOS grading system assigns a maximum of 9 points to three items: selection, comparability and ascertainment of exposure and outcomes for case‒control and cohort studies, respectively. Articles with a score of 7 or above were considered high-quality, those with a score of 4–6 were considered moderate-quality, and those with a score below 4 were considered low-quality. Literature screening and data extraction All the articles retrieved from the databases were first deduplicated, and then two independent reviewers screened the titles and abstracts of the articles to identify those that potentially met the inclusion criteria. The full texts of these articles were then screened to identify eligible articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The complete selection procedure was meticulously documented with transparency and was registered in PROSPERO CRD42024608648. All the procedures were executed in accordance with the registered protocol. When disagreements exsited during research, a third reviewer was consulted to make the final decision. Data, including study characteristics, patient and control demographics, MMP-8 levels, detection methods, sample size, sex allocation and other potentially important information, were extracted by two reviewers separately. The MMP-8 level is expressed as the mean and standard deviation (SD)[ 28 – 29 ]. The means and SDs cannot be estimated by medians and quartiles if the raw data are not normally distributed; therefore, data not following a normal distribution were not included. Data synthesis and statistical analysis All the data were first converted to standard form (mean ± standard deviation (SD)) and summarized in an Excel spreadsheet. We subsequently performed the meta-analysis with Review Manager 5.4 software and adopted a random effects model to analyze the standardized mean difference (SMD) and 95% CI of each study. The heterogeneity between studies was analyzed via Cochran’s Q test and quantified in the form of I 2 , values below 25% were classified as low heterogeneity, values between 25% and 75% were classified as medium heterogeneity, and values above 75% were classified as high heterogeneity. If the heterogeneity was high, then to further search for sources of heterogeneity, subgroup analyses and sensitivity analyses were performed. A funnel plot and Egger’s test were drawn to analyze the publication bias, and Duval and Tweedie’s trim-and-fill method was then conducted via RStudio software for further analysis if publication bias was statistically significant. Furthermore, sensitivity analyses were conducted via Stata 17.0 software. Results Study selection Under the search strategy, a total of 655 articles were retrieved from PubMed, Embase and the Cochrane Library. After the removal of duplications, the titles and abstracts of the remaining 415 articles were screened. Among them, 284 articles were excluded: 206 for irrelevant topics and 78 for studies conducted on animals. The remaining 131 articles were then selected for full-text assessment, and only 12 articles met the inclusion criteria. Characteristics of the included studies Among all the included studies (Table 1 ), 10 were case‒control studies, and 2 were cohort studies. The publication years of the studies ranged from 2011–2024, and four of them were conducted in Turkey, four in India, one each in Germany, Ukraine, America and Finland. The ages of the included patients with periodontitis ranged from 31–72 years, whereas those of the control group ranged from 23–74 years. The present meta-analysis included a total sample of 871 participants, including 502 periodontitis subjects and 369 periodontally healthy subjects. The study with the largest sample size was Finland, with a sample size of 141, whereas the Turkish study had the smallest sample size of only 36. With respect to the assays, five studies employed an immunofluorometric assay (IFMA), five studies used an enzyme-linked immunosorbent assay (ELISA), one study used polymerase chain reaction (PCR), and one study conducted both IFMA and ELISA. Table 1 Characteristics of the included studies. Author year Target Country/Region Ethnicity Sample type Sample size Gender M/F Detection method Outcome estimation Standard design NOS score Nizar Ahmed 2023[ 30 ] tMMP-8 India Asian Serum 40 NA PCR Reported P 7 H. Yemenoglu 2023[ 31 ] tMMP-8 Turkey Caucasian Serum 60 31/29 ELISA Reported P 6 I-Ching Wang 2021[ 32 ] tMMP-8 USA Caucasian Serum 117 NA ELISA Reported P 4 Zeynep Pinar Keles Yucel 2020[ 33 ] aMMP-8 Turkey Caucasian Serum 63 32/31 IFMA Reported P 9 Olena O. Fastovets 2020[ 34 ] tMMP-8 Ukraine Caucasian Serum 60 30/30 ELISA Reported P 6 G. Schmalz 2017[ 35 ] tMMP-8 Germany Caucasian Serum 56 29/27 ELISA Reported P 6 B. Noack 2016[ 36 ] aMMP-8 Germany Caucasian Serum 40 15/25 IFMA Estimated P 7 Nejat Nizam 2014[ 37 ] tMMP-8 Turkey Caucasian Serum 36 22/15 IFMA Estimated P 8 Oya Türkoğlu 2013[ 38 ] tMMP-8 Turkey Caucasian Serum 63 30/33 ELISA/IFMA Reported P 8 Hatem Alfakry 2011[ 39 ] tMMP-8 Finland Caucasian Serum 141 85/56 IFMA Estimated P 8 O Özçaka 2011[ 40 ] tMMP-8 Turkey Caucasian Serum 78 43/35 IFMA Reported P 8 Balwant Rai 2010[ 41 ] tMMP-8 India Asian Serum 87 45/42 ELISA Reported P 7 Quality assessment Quality assessments were conducted by two independent reviewers following the Newcastle‒Ottawa Scale (Table 2 ), and 9 of the included studies were considered good quality, with scores ranging from 7 to 9, whereas the others were rated between 4 and 6 and regarded as moderate quality. The high-quality studies all provided explicit definitions of cases and controls and received full marks in the ascertainment of exposure and outcomes. Table 2 Quality assessment of the included studies. Study Selection Comparability Exposure Score Quality Nizar Ahmed[ 30 ] ☆☆ ☆☆ ☆☆☆ 7 Good H. Yemenoglu[ 31 ] ☆☆ ☆ ☆☆☆ 6 Good I-Ching Wang[ 32 ] ☆ ☆☆ ☆ 4 Moderate Zeynep Pinar Keles Yucel[ 33 ] ☆☆☆☆ ☆☆ ☆☆☆ 9 Good Olena O. Fastovets[ 34 ] ☆☆ ☆ ☆☆☆ 6 Moderate G. Schmalz[ 35 ] ☆☆ ☆ ☆☆☆ 6 Moderate B. Noack[ 36 ] ☆☆☆☆ ☆☆☆ 7 Good Nejat Nizam[ 37 ] ☆☆☆☆ ☆ ☆☆☆ 8 Good Oya Türkoğlu[ 38 ] ☆☆☆ ☆☆ ☆☆☆ 8 Good Hatem Alfakry [ 39 ] ☆☆☆ ☆☆ ☆☆☆ 8 Good O Özçaka [ 40 ] ☆☆☆☆ ☆ ☆☆☆ 8 Good Balwant Rai [ 41 ] ☆☆ ☆☆ ☆☆☆ 7 Good Synthesis of results The forest plot (Fig. 2 ) shows the results of the meta-analysis comparing the level of MMP-8 in periodontitis patients with that in healthy controls. Since two detection methods were applied in one study for the same group of subjects (Oya Türkoğlu), two different data groups from the same research were marked by “E” for ELISA and “I” for IFMA in the forest plot. The overall standardized mean difference (SMD) in the serum MMP-8 level between periodontitis patients and healthy controls was significant ( P < 0.01). The range of MMP-8 levels varied significantly from 0.89 ± 0.61 ng/mL to 138.39 ± 82.59 ng/mL in periodontitis subjects and from 0.63 ± 0.21 ng/mL to 91.37 ± 67.49 ng/mL in periodontally healthy subjects. Furthermore, the heterogeneity among the studies was also significant (I 2 = 86%); thus, a random effects model was applied. To explore sources of heterogeneity, several subgroup analyses were performed, including analyses on the basis of molecule activation, detection methods, regions, article quality and ethnicity. First, we conducted subgroup analysis on the basis of molecular activation (Fig. 3 ). The total MMP-8 (tMMP-8) subgroup consists of 11 data groups with a total sample size of 775. The pooled SMD of this subgroup was 0.65 [0.23, 1.08] ( P < 0.05), indicating that the difference between the experimental and control groups within this subgroup was statistically significant. The activated MMP-8 (aMMP-8) subgroup consisted of two studies with a total sample size of 96. The pooled SMD of this subgroup was 0.58 [0.17, 1.00] ( P < 0.05), indicating that a significant difference exists in this subgroup. In addition, there was no statistically significant difference between the two subgroups ( P = 0.81). After categorization into two subgroups, the heterogeneity presented different results, with I 2 values of 99% and 71%, respectively. Next, we performed subgroup analysis according to the detection methods (Fig. 4 ). All the studies were divided into 3 subgroups: IFMA, ELISA and PCR. The results revealed that in the subgroups subjected to ELISA and PCR, there were significant differences between the experimental and control groups; however, the IFMA subgroup presented different results, indicating that no significant difference existed. Notably, the P value for the test for subgroup differences was 0.16. Furthermore, we conducted subgroup analysis by region (Fig. 5 ) and divided the studies into 6 subgroups. All the subgroups, except for the Turkey, USA and Finland subgroups, were significantly different ( P < 0.05). Additionally, there was a significant difference between the subgroups ( P < 0.05). Similarly, subgroup analyses based on article quality and ethnicity (Fig. 6 & Fig. 7 ) were also conducted. The results of all the subgroups were similar, showing a significant difference between the experimental and control groups. Notably, the heterogeneity in the Asian subgroup and in the high-quality subgroup was relatively low, with I 2 values of 13% and 69%, respectively. According to the funnel plot (Fig. 8 ), the spots representing the included studies were slightly asymmetric, and Egger’s test indicated the presence of publication bias in the 12 studies ( P = 0.004). However, we then applied Duval and Tweedie’s trim-and-fill method to identify possible publication bias, and the results revealed that the “estimated number of missing studies on the left side was 0”, which means that studies not included did not have a significant impact on the overall effect. We also conducted sensitivity analyses (Fig. 9 ), and the results revealed that all the points fell within the 95% confidence interval. Discussion The present meta-analysis aimed to evaluate the serum MMP-8 level in periodontitis patients compared with that in periodontally healthy subjects. The results of these systematic reviews indicate that the serum MMP-8 level in periodontitis patients is relatively higher than that in healthy subjects. Moreover, the mean MMP-8 level among different studies has notable discrepancies. The overall heterogeneity was also notable since the I 2 value reached 86%; as a result, a random effects model was applied. The significant heterogeneity and highly variable SMDs and SDs might be explained by their different detection methods, regions, and other underlying diseases combined. Additionally, the diagnostic criteria for periodontitis and the inclusion criteria for the healthy controls in the included studies were not exactly the same, which may also have contributed to the heterogeneity. The next step of our study was to perform several subgroup analyses to explain the heterogeneity. The subgroup analyses were conducted on the basis of molecule activation, detection methods, regions, article quality and ethnicity. Although there was no solid explanation for why the heterogeneity was high, we still found some practical information. For subgroup analysis of molecule activation, the P value for heterogeneity within the tMMP-8 subgroup was less than 0.01, with an I 2 of 88%, which means that there was significant heterogeneity among the studies and that the differences between studies’ results cannot be simply attributed to random error; however, there might be some underlying factors or methodological differences that lead to significant differences between studies. In contrast, the P value for heterogeneity in the aMMP-8 subgroup was 0.91, far greater than 0.05, and the I 2 was 0%, which means that there was no significant heterogeneity between the two studies and that the intrasubgroup error can be attributed to random error. Although the heterogeneity between these two studies is low, it needs to be considered with caution because of the small sample size in the subgroup. Another point that cannot be ignored is that there was no significant difference between the tMMP-8 subgroup and the aMMP-8 subgroup (I 2 = 0%, P = 0.81), which indicates that whether MMP-8 is an activated molecule does not lead to significant heterogeneity between studies; therefore, combining studies detecting tMMP-8 or aMMP-8 for meta-analysis is reasonable. The SMD and 95% CI of the IFMA subgroup were 0.31 [-0.07,0.69], and its P value was 0.11, indicating that there was no significant difference between the experimental group and the control group in these studies. However, this result may not be accurate because the sample size of this subgroup was 421, with 226 in the experimental group and 195 in the control group, which was relatively small. To obtain more convincing results, studies with larger sample sizes might be necessary. Notably, the P value of the subgroup differences was 0.16, and the I 2 was 51.1%. This finding indicates that the subgroup difference was not statistically significant, but there was still moderate heterogeneity, which may suggest that there are indeed different trends in the results of some subgroups or that there are some unexplained factors that lead to differences. Therefore, further studies or explanations of the sources of these differences may be necessary. Articles with NOS scores greater than or equal to 7 are generally considered high quality. Within the high-quality article subgroup, I 2 decreased from 86–69% after the subgroup analysis, indicating that heterogeneity was reduced through subgroup analysis. The decrease in I 2 indicates that studies within this subgroup are more similar, and some heterogeneity may be related to subgroup differences. However, the P value of the subgroup difference was 0.16, which was still not sufficient to support this conclusion from a statistical perspective, so further research is needed. The results of the ethnicity-based subgroup analysis revealed that the results between the two subgroups were very similar, and the P value of subgroup differences was 0.92, with an I 2 of 0%. These findings indicate that the ethnic differences between Caucasians and Asians have little impact on the heterogeneity of the results. According to the funnel plot (Fig. 8 ), the spots were slightly asymmetric, but the results of Duval and Tweedie’s trim-and-fill method indicated that the model did not find evidence of significant publication bias. This may indicate that the slight asymmetry of the funnel plot is due to random error rather than publication bias. The sensitivity analyses (Fig. 9 ) revealed results similar to those of the primary analysis, indicating that the results were relatively stable. Saliva MMP-8 has already been recommended as a biomarker for rapid diagnosis of chronic periodontitis[ 42 ]; however, without the instructions of dental professionals, quickly and accurately sampling gingival crevicular fluid without further damage to patients’ periodontal tissue remains a problem. If serum MMP-8 could be more strongly proven to be higher in periodontitis patients, then it could be expected to suggest the possibility of chronic periodontitis. Doctors in inpatient wards might be more proficient in sampling blood, and they can perform it simultaneously with other serological tests without the need for secondary operations on patients, which is convenient for both patients and doctors. However, we also know that the serum MMP-8 level can be influenced by many other systemic diseases,[ 5 – 8 ] so this method can be used only as a preliminary detection method. In addition to serum MMP-8 levels, patients’ complaints and oral conditions should also be taken into consideration so that patients can be guided to the stomatology department for further diagnosis and treatment. Furthermore, elevated serum MMP-8 levels in periodontitis patients may also lead to the occurrence and development of other systemic diseases, as previous studies have reported that elevated serum MMP-8 levels are associated with many systematic diseases. Therefore, in the process of diagnosing and treating periodontitis patients, dentists should not only focus on local periodontal symptoms but also combine patients’ complaints and overall conditions to detect other possible diseases in a timely manner, make accurate judgments, and guide them to relevant departments to avoid delaying the best treatment timing. Moreover, these findings may provide inspiration: for patients who suffer from periodontitis and systemic diseases concurrently, lowering their serum MMP-8 level with medication may improve both diseases simultaneously. Our research has several limitations that need improvement. First, due to high heterogeneity, the results of this study should be interpreted with caution. In addition, several factors contribute to these limitations, such as small sample sizes, inconsistent detection methods, unstrict study designs and different study populations (age, sex). Moreover, we included only articles published in English, which may have resulted in incomplete data. Therefore, studies with larger sample sizes, unified detection methods, improved study designs, and similar study populations are recommended to be conducted to further increase the credibility of our conclusions. Conclusions The evidence from twelve studies indicates that periodontitis is associated with elevated serum MMP-8 levels. In the future, studies with larger sample sizes are still needed to further support this conclusion. Further studies are needed to clarify the molecular mechanisms through which periodontitis elevates serum MMP-8 levels, which will help to uncover new mechanisms by which chronic periodontitis promotes systemic diseases. Declarations Supplementary Information The online version contains supplementary material available at Additional files 1-3. Acknowledgements Not applicable. Author Contributions Y.D. and Y.J. conceived and designed the research, analyzed the data and wrote the paper. H.Y. and Y.Z. evaluated the quality of the literature and prepared the figures and tables. All the authors read and approved the final manuscript. Funding: This research was funded by the Sanming Project of Medicine in Shenzhen (Grant number: SZSM202311009), the Shenzhen Medical Research Fund (Grant number: A2303027) and the Shenzhen Science and Technology Program (Grant number: JCYJ20220530152204011). Data availability All data generated or analysed during this study are included in this published article and its supplementary files. Human ethics and consent to participate Not applicable. Consent to participate Not applicable. Competing interests The authors declare no competing interests. Clinical trial number Not applicable. Author details 1 Guanghua School of Stomatology, Sun Yat-sen University, No.74, Zhongshan Second Road, Guangzhou 510055, Guangdong Province, China. 2 Stomatology Center, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, No.1017, Dongmen North Road, Shenzhen 518020, Guangdong Province, China. 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Batool A, Vaithilingam RD, Mohamad Hassan NH, Safii SH, Saub R. Evaluating the potential of matrix metalloproteinase as a diagnostic biomarker in rheumatoid arthritis and periodontitis: A systematic review and meta-analysis. Med (Baltim). 2023;102(41):e35340. Turunen A, Kuuliala K, Kuuliala A, Tervahartiala T, Mustonen H, Puolakkainen P, Kylanpaa L, Sorsa T. Activated matrix metalloproteinase 8 in serum predicts severity of acute pancreatitis. Pancreatology. 2021;21(5):862–9. Turkoglu O, Baris N, Tervahartiala T, Senarslan O, Sorsa T, Atilla G. Evaluation of systemic levels of neutrophilic enzymes in patients with hypertension and chronic periodontitis. J Periodontol. 2014;85(7):908–16. Maia LC, Antonio AG. Systematic reviews in dental research. A guideline. J Clin Pediatr Dent. 2012;37(2):117–24. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–805. Ahmed N, Arul D. Matrix Metalloproteinase Activity in Gingival Crevicular Fluid and Periodontal Health Status in Down Syndrome Patients: A Comparative Study. Cureus. 2023:40280. Yemenoglu H, Senkal R, Kose O, Yılmaz A, Mataracı Karakaş S, Akyıldız K. The effect of interleukin-20 on periodontal tissue destruction in individuals with periodontitis. J Periodontal Res. 2024;59(3):480–90. Wang IC, Sugai JV, Majzoub J, Johnston J, Giannobile WV, Wang HL. Pro-inflammatory profiles in cardiovascular disease patients with peri‐implantitis. J Periodontol. 2022;93(6):824–36. Keles Yucel ZP, Afacan B, Emingil G, Tervahartiala T, Kose T, Sorsa T. Local and systemic levels of aMMP-8 in gingivitis and stage 3 grade C periodontitis. J Periodontal Res. 2020;55(6):887–94. Olena OF, Ivan VM, Anna YL, EVALUATION OF BONE RESORPTIVE POTENTIAL IN THE TREATMENT OF GENERALIZED PERIODONTITIS. Wiad Lek. 2021;73(11):2396–402. Schmalz G, Davarpanah I, Jäger J, Mausberg RF, Krohn-Grimberghe B, Schmidt J, Haak R, Sack U, Ziebolz D. MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression – First results of a cross-sectional study. J Microbiol Immunol Infect. 2019;52(3):386–94. Noack B, Kipping T, Tervahartiala T, Sorsa T, Hoffmann T, Lorenz K. Association between serum and oral matrix metalloproteinase-8 levels and periodontal health status. J Periodontal Res. 2017;52(5):824–31. Nizam N, Gümüş P, Pitkänen J, Tervahartiala T, Sorsa T, Buduneli N. Serum and Salivary Matrix Metalloproteinases, Neutrophil Elastase, Myeloperoxidase in Patients with Chronic or Aggressive Periodontitis. Inflammation. 2014;37(5):1771–8. Türkoğlu O, Barış N, Tervahartiala T, Şenarslan Ö, Sorsa T, Atilla G. Evaluation of Systemic Levels of Neutrophilic Enzymes in Patients With Hypertension and Chronic Periodontitis. J Periodontol. 2014;85(7):908–16. Alfakry H, Sinisalo J, Paju S, Nieminen MS, Valtonen V, Tervahartiala T, Pussinen PJ, Sorsa T. The Association of Serum Neutrophil Markers and Acute Coronary Syndrome. Scand J Immunol. 2012;76(2):181–7. Özçaka Ö, Bıçakcı N, Pussinen P, Sorsa T, Köse T, Buduneli N. Smoking and matrix metalloproteinases, neutrophil elastase and myeloperoxidase in chronic periodontitis. Oral Dis. 2010;17(1):68–76. Rai B, Kaur J, Anand SC. Possible relationship between periodontitis and dementia in a North Indian old age population: a pilot study. Gerodontology. 2010;29(2):1741–2358. Zalewska EA, Ławicka R, Grygorczuk P, Nowosielska M, Kicman A, Ławicki S. Importance of Metalloproteinase 8 (MMP-8) in the Diagnosis of Periodontitis. Int J Mol Sci. 2024;25(5):25052721. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1TableS1.docx Additionalfile2PRISMA2020checklist.docx Additionalfile3Minimaldataset.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5461775","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":382792266,"identity":"c87e2e9e-c65f-4ee5-9144-4e3bbe04888a","order_by":0,"name":"Yihong Deng","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yihong","middleName":"","lastName":"Deng","suffix":""},{"id":382792267,"identity":"c3f6cc11-9ccb-4c24-aecb-4660a37f4ce4","order_by":1,"name":"Hongxia You","email":"","orcid":"","institution":"ShenZhen People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongxia","middleName":"","lastName":"You","suffix":""},{"id":382792268,"identity":"e90e9a43-97e0-4f2f-8ce6-fb0783cc02e7","order_by":2,"name":"Yuyan Zheng","email":"","orcid":"","institution":"ShenZhen People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuyan","middleName":"","lastName":"Zheng","suffix":""},{"id":382792269,"identity":"242b03a7-06ee-49ee-b69c-91617f0288e0","order_by":3,"name":"Yiqun 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presenting the standardized mean difference (SMD) in serum MMP-8 levels between periodontitis patients and healthy controls.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/d8a4083fdcb5c39718a34c8e.png"},{"id":71881024,"identity":"4056f7e0-3372-4c57-9f91-afc6427d2a2e","added_by":"auto","created_at":"2024-12-19 11:36:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":808240,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of serum MMP-8 levels according to molecule activation.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/374bc4d9a11788dda62f07be.png"},{"id":71880278,"identity":"f2a00ffc-4ea6-4e73-874c-5afe4ceccfcd","added_by":"auto","created_at":"2024-12-19 11:28:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":870173,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of serum MMP-8 levels according to detection methods.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/8475a25eb41f3bc395267fe3.png"},{"id":71880276,"identity":"943594c0-c4ce-4d62-9294-f508ad0d61e5","added_by":"auto","created_at":"2024-12-19 11:28:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1061101,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of serum MMP-8 levels according to region.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/ff99be7d48924e3ed573658f.png"},{"id":71882396,"identity":"e884203f-592d-4920-82ff-bd91456a234c","added_by":"auto","created_at":"2024-12-19 11:44:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":811402,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of serum MMP-8 levels according to article quality.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/a65dfa2c4632847a9507463c.png"},{"id":71880280,"identity":"042f0214-010a-4c15-acc2-cffc48812b9c","added_by":"auto","created_at":"2024-12-19 11:28:31","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":813310,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of serum MMP-8 levels according to ethnicity.\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/75f1b1f5982efae29351a9f3.png"},{"id":71880282,"identity":"39742423-5803-43ec-b418-03daf241a170","added_by":"auto","created_at":"2024-12-19 11:28:31","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":148629,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for serum MMP-8 levels among different studies.\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/ec8422038ebbe79f529e0a67.png"},{"id":71880288,"identity":"01cdd409-d348-4e9a-88de-eada83aff09a","added_by":"auto","created_at":"2024-12-19 11:28:31","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":321967,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis for the included studies.\u003c/p\u003e","description":"","filename":"Figure9.png","url":"https://assets-eu.researchsquare.com/files/rs-5461775/v1/39377313483c9ff062990984.png"},{"id":86347001,"identity":"57b09f1f-6bad-4570-bcab-625a5a19f9d5","added_by":"auto","created_at":"2025-07-09 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Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePeriodontitis is a chronic multifactorial inflammatory disease characterized by the progressive destruction of periodontal tissue, the common features of which include clinical attachment loss, the formation of periodontal pockets and gingival bleeding, and if left untreated, it may eventually lead to tooth loss [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. At present, periodontitis is estimated to be the most common chronic inflammatory noncontagious disease, with a prevalence rate of 11% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moreover, the Global Burden of Disease (GBD) database revealed that the number of severe periodontitis cases worldwide reached 1.1\u0026nbsp;billion in 2019 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Owing to its high incidence rate, periodontitis poses significant public health problems, such as impaired masticatory function, damaged aesthetics and edentulism. They subsequently lower quality of life, developing into the origin of social inequality. Pontitis not only harms in situ periodontal tissue but also promotes the development of multiple systematic diseases, such as coronary heart disease, rheumatoid arthritis and dementia [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These effects further damage the overall physiological and psychological health status of patients.\u003c/p\u003e \u003cp\u003eCurrent mechanistic models of periodontitis suggest that local inflammation of the periodontium, resulting from a proinflammatory host immune response to bacteria, plays a vital role in its progression and recurrence [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Several studies have shown increased local levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and matrix metalloproteinase-8 (MMP-8), in patients with periodontitis [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. According to previous studies, IL-6 is able to induce osteoclast differentiation and bone resorption, inhibit bone formation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and is correlated with the release and activation of MMP-8, which may then cause ECM breakdown [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, periodontitis has been reported to increase systematic proinflammatory cytokines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], which may be cofactors that accelerate the occurrence of inflammation in other distant parts of the body. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Therefore, hypotheses have been proposed that cytokines released by diseased periodontal tissue may enter the circulation, stimulate other parts of the body and eventually have an impact on systematic health [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], but further experiments are needed.\u003c/p\u003e \u003cp\u003eMatrix metalloproteinases (MMPs) are members of a proteolytic enzyme family that are responsible for the remodeling and degradation of the extracellular matrix (ECM) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Collagen I constitutes the main component of the periodontal extracellular matrix; therefore, collagenase has received special attention [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Among all collagenase proteins, MMP-8 is the most frequently mentioned member because it contributes to approximately 80% of all the collagenase identified in gingival crevicular fluid (GCF) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Additionally, saliva MMP-8 is widely regarded as a potential biomarker for the diagnosis of periodontitis. MMP-8 can either be derived from bacteria in dental plaque or from cellular sources, and from both sources, it is capable of degrading almost all types of collagenous and noncollagenous proteins in the ECM [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], which may then lead to tissue destruction. In addition to periodontitis, excessive MMP-8 is involved in the pathogenesis of many other inflammatory diseases, such as pancreatitis and sepsis, and systematic diseases, such as rheumatoid arthritis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMany MMP-8-related studies have been conducted in saliva, but only a small portion of these studies have focused on serum MMP-8 concentrations. However, increasing evidence has shown that circulating MMP levels are associated with several systemic diseases, such as hypertension, coronary artery disease, diabetes and rheumatoid arthritis [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Therefore, it is speculated that the increased concentrations of saliva MMP-8, which subsequently enter the circulation, may then result in elevated levels of serum MMP-8 and thus become a causal factor linking periodontitis with increased susceptibility to several systematic diseases. Therefore, it is essential to pay attention to the impact of periodontitis on the serum MMP-8 level. To the best of the author\u0026rsquo;s knowledge, no comprehensive systematic meta-analysis has been conducted to evaluate whether serum MMP-8 levels are significantly different between healthy individuals and periodontitis patients. To fill this gap, the present study aimed to confirm whether the level of MMP-8 in the serum of patients with periodontitis is greater than that in healthy individuals on the basis of a comprehensive review of all the existing studies.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eFocused question\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eOur research focused on the following question: \u0026ldquo;Is periodontitis status correlated with elevated levels of serum MMP-8 compared with those in periodontally healthy subjects?\u0026rdquo; If the answer is \u0026ldquo;yes\u0026rdquo;, then this research may provide some insight for solving the problem of increased prevalence and severity of systemic diseases in periodontitis patients.\u003c/p\u003e \u003cp\u003eThe focused question was formulated following the PECO criteria [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], which can be specifically interpreted as follows:\u003c/p\u003e \u003cp\u003eP (Population): Adults\u003c/p\u003e \u003cp\u003eE (Exposure): Periodontitis subjects\u003c/p\u003e \u003cp\u003eC (Comparison): Periodontally healthy subjects\u003c/p\u003e \u003cp\u003eO (Outcome): Serum MMP-8 concentration\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eWe conducted a comprehensive search of PubMed, Embase and the Cochrane Library from their inception to October 8, 2024. To retrieve more comprehensive relevant articles, our search strategy was as follows: \u0026ldquo;(periodontitis OR periodontal disease) AND (serum OR plasma OR blood) AND (MMP-8 OR matrix metalloproteinase OR matrix metalloproteinase-8 OR biomarker OR cytokine)\u0026rdquo;. No restrictions on other conditions were applied. The detailed search strategy is shown in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Additionally, we manually searched influential journals for relevant articles, such as the Journal of Clinical Periodontology (JCP), the Journal of Periodontology (JOP), Periodontology 2000, the Journal of Periodontal Research, the International Journal of Oral Science and Clinical Advances in Periodontics.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eArticles that met the following criteria were included in our research.\u003c/p\u003e \u003cp\u003e1) Types of studies: observational studies, case‒control studies, cross-sectional studies, cohort studies and clinical trials in humans.\u003c/p\u003e \u003cp\u003e2) Participants: periodontitis subjects versus periodontally healthy subjects.\u003c/p\u003e \u003cp\u003e3) The evaluation index includes the serum MMP-8 level.\u003c/p\u003e \u003cp\u003e4) Articles published in English until Oct 8, 2024.\u003c/p\u003e \u003cp\u003e5) Extractable the numerical data.\u003c/p\u003e \u003cp\u003eWe excluded articles in our research following the criteria below.\u003c/p\u003e \u003cp\u003e1) Duplicate records.\u003c/p\u003e \u003cp\u003e2) Irrelevant topics.\u003c/p\u003e \u003cp\u003e3) Animal models.\u003c/p\u003e \u003cp\u003e4) Types of studies: reviews, case reports, abstracts, editorials, conference abstracts, and corresponding letters.\u003c/p\u003e \u003cp\u003e5) Study design not perspective.\u003c/p\u003e \u003cp\u003e6) Non-English records.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTo evaluate the methodological qualities of the included articles, two independent reviewers separately assessed each article following the Newcastle‒Ottawa Scale (NOS) grading system. The NOS grading system assigns a maximum of 9 points to three items: selection, comparability and ascertainment of exposure and outcomes for case‒control and cohort studies, respectively. Articles with a score of 7 or above were considered high-quality, those with a score of 4\u0026ndash;6 were considered moderate-quality, and those with a score below 4 were considered low-quality.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eLiterature screening and data extraction\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAll the articles retrieved from the databases were first deduplicated, and then two independent reviewers screened the titles and abstracts of the articles to identify those that potentially met the inclusion criteria. The full texts of these articles were then screened to identify eligible articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The complete selection procedure was meticulously documented with transparency and was registered in PROSPERO CRD42024608648. All the procedures were executed in accordance with the registered protocol. When disagreements exsited during research, a third reviewer was consulted to make the final decision.\u003c/p\u003e \u003cp\u003eData, including study characteristics, patient and control demographics, MMP-8 levels, detection methods, sample size, sex allocation and other potentially important information, were extracted by two reviewers separately. The MMP-8 level is expressed as the mean and standard deviation (SD)[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The means and SDs cannot be estimated by medians and quartiles if the raw data are not normally distributed; therefore, data not following a normal distribution were not included.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData synthesis and statistical analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAll the data were first converted to standard form (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD)) and summarized in an Excel spreadsheet. We subsequently performed the meta-analysis with Review Manager 5.4 software and adopted a random effects model to analyze the standardized mean difference (SMD) and 95% CI of each study. The heterogeneity between studies was analyzed via Cochran\u0026rsquo;s Q test and quantified in the form of I\u003csup\u003e2\u003c/sup\u003e, values below 25% were classified as low heterogeneity, values between 25% and 75% were classified as medium heterogeneity, and values above 75% were classified as high heterogeneity. If the heterogeneity was high, then to further search for sources of heterogeneity, subgroup analyses and sensitivity analyses were performed. A funnel plot and Egger\u0026rsquo;s test were drawn to analyze the publication bias, and Duval and Tweedie\u0026rsquo;s trim-and-fill method was then conducted via RStudio software for further analysis if publication bias was statistically significant. Furthermore, sensitivity analyses were conducted via Stata 17.0 software.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eUnder the search strategy, a total of 655 articles were retrieved from PubMed, Embase and the Cochrane Library. After the removal of duplications, the titles and abstracts of the remaining 415 articles were screened. Among them, 284 articles were excluded: 206 for irrelevant topics and 78 for studies conducted on animals. The remaining 131 articles were then selected for full-text assessment, and only 12 articles met the inclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the included studies\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAmong all the included studies (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), 10 were case‒control studies, and 2 were cohort studies. The publication years of the studies ranged from 2011\u0026ndash;2024, and four of them were conducted in Turkey, four in India, one each in Germany, Ukraine, America and Finland. The ages of the included patients with periodontitis ranged from 31\u0026ndash;72 years, whereas those of the control group ranged from 23\u0026ndash;74 years. The present meta-analysis included a total sample of 871 participants, including 502 periodontitis subjects and 369 periodontally healthy subjects. The study with the largest sample size was Finland, with a sample size of 141, whereas the Turkish study had the smallest sample size of only 36. With respect to the assays, five studies employed an immunofluorometric assay (IFMA), five studies used an enzyme-linked immunosorbent assay (ELISA), one study used polymerase chain reaction (PCR), and one study conducted both IFMA and ELISA.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTarget\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry/Region\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEthnicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSample type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGender M/F\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDetection method\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003cp\u003eestimation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eStandard design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNOS score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNizar Ahmed 2023[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH. Yemenoglu 2023[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31/29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI-Ching Wang 2021[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZeynep Pinar Keles Yucel 2020[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32/31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlena O. Fastovets 2020[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUkraine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30/30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG. Schmalz 2017[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29/27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB. Noack 2016[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15/25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEstimated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNejat Nizam 2014[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEstimated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOya T\u0026uuml;rkoğlu 2013[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30/33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA/IFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHatem Alfakry 2011[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFinland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e85/56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEstimated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO \u0026Ouml;z\u0026ccedil;aka 2011[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCaucasian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e43/35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBalwant Rai 2010[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etMMP-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45/42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eQuality assessments were conducted by two independent reviewers following the Newcastle‒Ottawa Scale (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and 9 of the included studies were considered good quality, with scores ranging from 7 to 9, whereas the others were rated between 4 and 6 and regarded as moderate quality. The high-quality studies all provided explicit definitions of cases and controls and received full marks in the ascertainment of exposure and outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuality assessment of the included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSelection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComparability\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eScore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQuality\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNizar Ahmed[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH. Yemenoglu[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI-Ching Wang[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZeynep Pinar Keles Yucel[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlena O. Fastovets[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG. Schmalz[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB. Noack[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNejat Nizam[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOya T\u0026uuml;rkoğlu[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHatem Alfakry [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO \u0026Ouml;z\u0026ccedil;aka [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBalwant Rai [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e☆☆☆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSynthesis of results\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe forest plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) shows the results of the meta-analysis comparing the level of MMP-8 in periodontitis patients with that in healthy controls. Since two detection methods were applied in one study for the same group of subjects (Oya T\u0026uuml;rkoğlu), two different data groups from the same research were marked by \u0026ldquo;E\u0026rdquo; for ELISA and \u0026ldquo;I\u0026rdquo; for IFMA in the forest plot. The overall standardized mean difference (SMD) in the serum MMP-8 level between periodontitis patients and healthy controls was significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The range of MMP-8 levels varied significantly from 0.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.61 ng/mL to 138.39\u0026thinsp;\u0026plusmn;\u0026thinsp;82.59 ng/mL in periodontitis subjects and from 0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21 ng/mL to 91.37\u0026thinsp;\u0026plusmn;\u0026thinsp;67.49 ng/mL in periodontally healthy subjects. Furthermore, the heterogeneity among the studies was also significant (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;86%); thus, a random effects model was applied.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTo explore sources of heterogeneity, several subgroup analyses were performed, including analyses on the basis of molecule activation, detection methods, regions, article quality and ethnicity. First, we conducted subgroup analysis on the basis of molecular activation (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The total MMP-8 (tMMP-8) subgroup consists of 11 data groups with a total sample size of 775. The pooled SMD of this subgroup was 0.65 [0.23, 1.08] (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that the difference between the experimental and control groups within this subgroup was statistically significant. The activated MMP-8 (aMMP-8) subgroup consisted of two studies with a total sample size of 96. The pooled SMD of this subgroup was 0.58 [0.17, 1.00] (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that a significant difference exists in this subgroup. In addition, there was no statistically significant difference between the two subgroups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.81). After categorization into two subgroups, the heterogeneity presented different results, with I\u003csup\u003e2\u003c/sup\u003e values of 99% and 71%, respectively.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eNext, we performed subgroup analysis according to the detection methods (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). All the studies were divided into 3 subgroups: IFMA, ELISA and PCR. The results revealed that in the subgroups subjected to ELISA and PCR, there were significant differences between the experimental and control groups; however, the IFMA subgroup presented different results, indicating that no significant difference existed. Notably, the P value for the test for subgroup differences was 0.16.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eFurthermore, we conducted subgroup analysis by region (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) and divided the studies into 6 subgroups. All the subgroups, except for the Turkey, USA and Finland subgroups, were significantly different (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, there was a significant difference between the subgroups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSimilarly, subgroup analyses based on article quality and ethnicity (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e \u0026amp; Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e) were also conducted. The results of all the subgroups were similar, showing a significant difference between the experimental and control groups. Notably, the heterogeneity in the Asian subgroup and in the high-quality subgroup was relatively low, with I\u003csup\u003e2\u003c/sup\u003e values of 13% and 69%, respectively.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAccording to the funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e), the spots representing the included studies were slightly asymmetric, and Egger\u0026rsquo;s test indicated the presence of publication bias in the 12 studies (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). However, we then applied Duval and Tweedie\u0026rsquo;s trim-and-fill method to identify possible publication bias, and the results revealed that the \u0026ldquo;estimated number of missing studies on the left side was 0\u0026rdquo;, which means that studies not included did not have a significant impact on the overall effect. We also conducted sensitivity analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e), and the results revealed that all the points fell within the 95% confidence interval.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe present meta-analysis aimed to evaluate the serum MMP-8 level in periodontitis patients compared with that in periodontally healthy subjects. The results of these systematic reviews indicate that the serum MMP-8 level in periodontitis patients is relatively higher than that in healthy subjects. Moreover, the mean MMP-8 level among different studies has notable discrepancies. The overall heterogeneity was also notable since the I\u003csup\u003e2\u003c/sup\u003e value reached 86%; as a result, a random effects model was applied. The significant heterogeneity and highly variable SMDs and SDs might be explained by their different detection methods, regions, and other underlying diseases combined. Additionally, the diagnostic criteria for periodontitis and the inclusion criteria for the healthy controls in the included studies were not exactly the same, which may also have contributed to the heterogeneity.\u003c/p\u003e \u003cp\u003eThe next step of our study was to perform several subgroup analyses to explain the heterogeneity. The subgroup analyses were conducted on the basis of molecule activation, detection methods, regions, article quality and ethnicity. Although there was no solid explanation for why the heterogeneity was high, we still found some practical information.\u003c/p\u003e \u003cp\u003eFor subgroup analysis of molecule activation, the P value for heterogeneity within the tMMP-8 subgroup was less than 0.01, with an I\u003csup\u003e2\u003c/sup\u003e of 88%, which means that there was significant heterogeneity among the studies and that the differences between studies\u0026rsquo; results cannot be simply attributed to random error; however, there might be some underlying factors or methodological differences that lead to significant differences between studies. In contrast, the P value for heterogeneity in the aMMP-8 subgroup was 0.91, far greater than 0.05, and the I\u003csup\u003e2\u003c/sup\u003e was 0%, which means that there was no significant heterogeneity between the two studies and that the intrasubgroup error can be attributed to random error. Although the heterogeneity between these two studies is low, it needs to be considered with caution because of the small sample size in the subgroup. Another point that cannot be ignored is that there was no significant difference between the tMMP-8 subgroup and the aMMP-8 subgroup (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.81), which indicates that whether MMP-8 is an activated molecule does not lead to significant heterogeneity between studies; therefore, combining studies detecting tMMP-8 or aMMP-8 for meta-analysis is reasonable.\u003c/p\u003e \u003cp\u003eThe SMD and 95% CI of the IFMA subgroup were 0.31 [-0.07,0.69], and its P value was 0.11, indicating that there was no significant difference between the experimental group and the control group in these studies. However, this result may not be accurate because the sample size of this subgroup was 421, with 226 in the experimental group and 195 in the control group, which was relatively small. To obtain more convincing results, studies with larger sample sizes might be necessary. Notably, the P value of the subgroup differences was 0.16, and the I\u003csup\u003e2\u003c/sup\u003e was 51.1%. This finding indicates that the subgroup difference was not statistically significant, but there was still moderate heterogeneity, which may suggest that there are indeed different trends in the results of some subgroups or that there are some unexplained factors that lead to differences. Therefore, further studies or explanations of the sources of these differences may be necessary.\u003c/p\u003e \u003cp\u003eArticles with NOS scores greater than or equal to 7 are generally considered high quality. Within the high-quality article subgroup, I\u003csup\u003e2\u003c/sup\u003e decreased from 86\u0026ndash;69% after the subgroup analysis, indicating that heterogeneity was reduced through subgroup analysis. The decrease in I\u003csup\u003e2\u003c/sup\u003e indicates that studies within this subgroup are more similar, and some heterogeneity may be related to subgroup differences. However, the P value of the subgroup difference was 0.16, which was still not sufficient to support this conclusion from a statistical perspective, so further research is needed.\u003c/p\u003e \u003cp\u003eThe results of the ethnicity-based subgroup analysis revealed that the results between the two subgroups were very similar, and the P value of subgroup differences was 0.92, with an I\u003csup\u003e2\u003c/sup\u003e of 0%. These findings indicate that the ethnic differences between Caucasians and Asians have little impact on the heterogeneity of the results.\u003c/p\u003e \u003cp\u003eAccording to the funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e), the spots were slightly asymmetric, but the results of Duval and Tweedie\u0026rsquo;s trim-and-fill method indicated that the model did not find evidence of significant publication bias. This may indicate that the slight asymmetry of the funnel plot is due to random error rather than publication bias. The sensitivity analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e) revealed results similar to those of the primary analysis, indicating that the results were relatively stable.\u003c/p\u003e \u003cp\u003eSaliva MMP-8 has already been recommended as a biomarker for rapid diagnosis of chronic periodontitis[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]; however, without the instructions of dental professionals, quickly and accurately sampling gingival crevicular fluid without further damage to patients\u0026rsquo; periodontal tissue remains a problem. If serum MMP-8 could be more strongly proven to be higher in periodontitis patients, then it could be expected to suggest the possibility of chronic periodontitis. Doctors in inpatient wards might be more proficient in sampling blood, and they can perform it simultaneously with other serological tests without the need for secondary operations on patients, which is convenient for both patients and doctors. However, we also know that the serum MMP-8 level can be influenced by many other systemic diseases,[\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] so this method can be used only as a preliminary detection method. In addition to serum MMP-8 levels, patients\u0026rsquo; complaints and oral conditions should also be taken into consideration so that patients can be guided to the stomatology department for further diagnosis and treatment. Furthermore, elevated serum MMP-8 levels in periodontitis patients may also lead to the occurrence and development of other systemic diseases, as previous studies have reported that elevated serum MMP-8 levels are associated with many systematic diseases. Therefore, in the process of diagnosing and treating periodontitis patients, dentists should not only focus on local periodontal symptoms but also combine patients\u0026rsquo; complaints and overall conditions to detect other possible diseases in a timely manner, make accurate judgments, and guide them to relevant departments to avoid delaying the best treatment timing. Moreover, these findings may provide inspiration: for patients who suffer from periodontitis and systemic diseases concurrently, lowering their serum MMP-8 level with medication may improve both diseases simultaneously.\u003c/p\u003e \u003cp\u003eOur research has several limitations that need improvement. First, due to high heterogeneity, the results of this study should be interpreted with caution. In addition, several factors contribute to these limitations, such as small sample sizes, inconsistent detection methods, unstrict study designs and different study populations (age, sex). Moreover, we included only articles published in English, which may have resulted in incomplete data. Therefore, studies with larger sample sizes, unified detection methods, improved study designs, and similar study populations are recommended to be conducted to further increase the credibility of our conclusions.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe evidence from twelve studies indicates that periodontitis is associated with elevated serum MMP-8 levels. In the future, studies with larger sample sizes are still needed to further support this conclusion. Further studies are needed to clarify the molecular mechanisms through which periodontitis elevates serum MMP-8 levels, which will help to uncover new mechanisms by which chronic periodontitis promotes systemic diseases.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe online version contains supplementary material available at Additional files 1-3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.D. and Y.J. conceived and designed the research, analyzed the data and wrote the paper. H.Y. and Y.Z.\u0026nbsp;evaluated the quality of the literature and prepared the figures and tables. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Sanming Project of Medicine in Shenzhen\u0026nbsp;(Grant number: SZSM202311009), the Shenzhen Medical Research Fund (Grant number: A2303027)\u0026nbsp;and the Shenzhen Science and Technology Program (Grant number: JCYJ20220530152204011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman ethics and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eGuanghua School of Stomatology, Sun Yat-sen University, No.74, Zhongshan Second Road, Guangzhou 510055, Guangdong Province, China. \u003csup\u003e2\u003c/sup\u003eStomatology Center, Shenzhen People\u0026apos;s Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, No.1017, Dongmen North Road, Shenzhen 518020, Guangdong Province, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSanz M, Herrera D, Kebschull M, Chapple I, Jepsen S, Beglundh T, Sculean A, Tonetti MS. 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Wiad Lek. 2021;73(11):2396\u0026ndash;402.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmalz G, Davarpanah I, J\u0026auml;ger J, Mausberg RF, Krohn-Grimberghe B, Schmidt J, Haak R, Sack U, Ziebolz D. MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression \u0026ndash; First results of a cross-sectional study. J Microbiol Immunol Infect. 2019;52(3):386\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoack B, Kipping T, Tervahartiala T, Sorsa T, Hoffmann T, Lorenz K. Association between serum and oral matrix metalloproteinase-8 levels and periodontal health status. J Periodontal Res. 2017;52(5):824\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNizam N, G\u0026uuml;m\u0026uuml;ş P, Pitk\u0026auml;nen J, Tervahartiala T, Sorsa T, Buduneli N. Serum and Salivary Matrix Metalloproteinases, Neutrophil Elastase, Myeloperoxidase in Patients with Chronic or Aggressive Periodontitis. Inflammation. 2014;37(5):1771\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eT\u0026uuml;rkoğlu O, Barış N, Tervahartiala T, Şenarslan \u0026Ouml;, Sorsa T, Atilla G. Evaluation of Systemic Levels of Neutrophilic Enzymes in Patients With Hypertension and Chronic Periodontitis. J Periodontol. 2014;85(7):908\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlfakry H, Sinisalo J, Paju S, Nieminen MS, Valtonen V, Tervahartiala T, Pussinen PJ, Sorsa T. The Association of Serum Neutrophil Markers and Acute Coronary Syndrome. Scand J Immunol. 2012;76(2):181\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Ouml;z\u0026ccedil;aka \u0026Ouml;, Bı\u0026ccedil;akcı N, Pussinen P, Sorsa T, K\u0026ouml;se T, Buduneli N. Smoking and matrix metalloproteinases, neutrophil elastase and myeloperoxidase in chronic periodontitis. Oral Dis. 2010;17(1):68\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRai B, Kaur J, Anand SC. Possible relationship between periodontitis and dementia in a North Indian old age population: a pilot study. Gerodontology. 2010;29(2):1741\u0026ndash;2358.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZalewska EA, Ławicka R, Grygorczuk P, Nowosielska M, Kicman A, Ławicki S. Importance of Metalloproteinase 8 (MMP-8) in the Diagnosis of Periodontitis. Int J Mol Sci. 2024;25(5):25052721.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Periodontitis, matrix metalloproteinase-8, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-5461775/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5461775/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e: To determine whether the serum matrix metalloproteinase-8 (MMP-8) level is elevated in periodontitis patients compared with that in periodontally healthy individuals, we conducted a meta-analysis to assess its diagnostic value. This study aims to provide insight into the increased prevalence and severity of systemic diseases in periodontitis patients, as well as the potential of serum MMP-8 in the rapid diagnosis of periodontitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A comprehensive search following the PECO criteria of PubMed, Embase and the Cochrane Library from their inception to October 8, 2024, was conducted to retrieve comprehensive relevant articles. The complete selection procedure was meticulously documented with transparency and was registered in PROSPERO CRD42024608648. The methodological qualities of the included articles were evaluated following the Newcastle‒Ottawa Scale (NOS) grading system. The level of serum MMP-8 was converted to a standard (mean ± standard deviation (SD)), and meta-analysis was conducted with Review Manager 5.4 software. Sensitivity analyses were performed with Stata 17.0 software.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 12 studies, including 10 case‒control studies and 2 cohort studies, were ultimately included, with a total of 871 participants. The results of the meta-analysis revealed higher serum MMP-8 levels in periodontitis patients than in healthy controls (SMD 0.64, 95% CI 0.27 to 1.01; 12 studies, 871 participants). High heterogeneity (I\u003csup\u003e2\u003c/sup\u003e = 86%) indicated variability in outcomes, possibly influenced by regional factors. Duval and Tweedie’s trim and fill procedure was conducted, and no evidence of a small study effect was found. Sensitivity analyses revealed great stability of the data included.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Our meta-analysis revealed that the serum MMP-8 level in periodontitis patients was likely greater than that in healthy subjects, but further studies on regional factors are needed to clarify this conclusion considering the degree of heterogeneity.\u003c/p\u003e","manuscriptTitle":"Relationship between Serum Matrix Metalloproteinase-8 and Periodontitis: A PRISMA-Compliant Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-19 11:28:26","doi":"10.21203/rs.3.rs-5461775/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d2cf01f2-10a9-4860-b41e-7b4d5f9ec63b","owner":[],"postedDate":"December 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-09T15:08:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-19 11:28:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5461775","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5461775","identity":"rs-5461775","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}