High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease
Identifieur interne : 000D67 ( Pmc/Corpus ); précédent : 000D66; suivant : 000D68High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease
Auteurs : Jinpan Liu ; Ronghui Li ; Tongjun Liu ; Xiaohui Rausch-Fan ; Mingguo WangSource :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Peri-implant disease is a chronic inflammation of the soft and hard tissues around a dental implant, resulting from bacterial infection. Recent evidence indicates that some pro-inflammatory cytokines and chemokines released by immunocytes are substantially responsible for the progress and consequence of inflammation. High mobility group box 1 (HMGB1) is released into the extracellular matrix and acts as a key pro-inflammatory factor during injury, necrosis and inflammation. A higher concentration of HMGB1 has been found in gingival crevicular fluid from inflammatory gingival tissue than from healthy sites. HMGB1 mRNA and protein are overexpressed in murine periodontal ligament fibroblasts stimulated with lipopolysaccharide (LPS) and IL-1β. Thus, this study sought to assess HMGB1 expression in peri-implant crevicular fluid (PICF) at each stage of peri-implant disease and to investigate the correlation between HMGB1 and peri-implant disease progress. The results demonstrated that the HMGB1 expression level in PICF is indicative of the progress of peri-implant disease and hence may be a useful diagnostic and prognostic biomarker for peri-implant tissue.
Url:
DOI: 10.1038/s41598-017-06937-y
PubMed: 28765610
PubMed Central: 5539157
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease</title><author><name sortKey="Liu, Jinpan" sort="Liu, Jinpan" uniqKey="Liu J" first="Jinpan" last="Liu">Jinpan Liu</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Li, Ronghui" sort="Li, Ronghui" uniqKey="Li R" first="Ronghui" last="Li">Ronghui Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Liu, Tongjun" sort="Liu, Tongjun" uniqKey="Liu T" first="Tongjun" last="Liu">Tongjun Liu</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Rausch Fan, Xiaohui" sort="Rausch Fan, Xiaohui" uniqKey="Rausch Fan X" first="Xiaohui" last="Rausch-Fan">Xiaohui Rausch-Fan</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9259 8492</institution-id><institution-id institution-id-type="GRID">grid.22937.3d</institution-id><institution>Division of Conservative Dentistry and Periodontology,</institution><institution>School of Dentistry, Medical University of Vienna,</institution></institution-wrap>Sensengasse 2a, 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Wang, Mingguo" sort="Wang, Mingguo" uniqKey="Wang M" first="Mingguo" last="Wang">Mingguo Wang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28765610</idno><idno type="pmc">5539157</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539157</idno><idno type="RBID">PMC:5539157</idno><idno type="doi">10.1038/s41598-017-06937-y</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000D67</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D67</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease</title><author><name sortKey="Liu, Jinpan" sort="Liu, Jinpan" uniqKey="Liu J" first="Jinpan" last="Liu">Jinpan Liu</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Li, Ronghui" sort="Li, Ronghui" uniqKey="Li R" first="Ronghui" last="Li">Ronghui Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Liu, Tongjun" sort="Liu, Tongjun" uniqKey="Liu T" first="Tongjun" last="Liu">Tongjun Liu</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author><author><name sortKey="Rausch Fan, Xiaohui" sort="Rausch Fan, Xiaohui" uniqKey="Rausch Fan X" first="Xiaohui" last="Rausch-Fan">Xiaohui Rausch-Fan</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9259 8492</institution-id><institution-id institution-id-type="GRID">grid.22937.3d</institution-id><institution>Division of Conservative Dentistry and Periodontology,</institution><institution>School of Dentistry, Medical University of Vienna,</institution></institution-wrap>Sensengasse 2a, 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Wang, Mingguo" sort="Wang, Mingguo" uniqKey="Wang M" first="Mingguo" last="Wang">Mingguo Wang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</nlm:aff></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Peri-implant disease is a chronic inflammation of the soft and hard tissues around a dental implant, resulting from bacterial infection. Recent evidence indicates that some pro-inflammatory cytokines and chemokines released by immunocytes are substantially responsible for the progress and consequence of inflammation. High mobility group box 1 (HMGB1) is released into the extracellular matrix and acts as a key pro-inflammatory factor during injury, necrosis and inflammation. A higher concentration of HMGB1 has been found in gingival crevicular fluid from inflammatory gingival tissue than from healthy sites. HMGB1 mRNA and protein are overexpressed in murine periodontal ligament fibroblasts stimulated with lipopolysaccharide (LPS) and IL-1β. Thus, this study sought to assess HMGB1 expression in peri-implant crevicular fluid (PICF) at each stage of peri-implant disease and to investigate the correlation between HMGB1 and peri-implant disease progress. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28765610</article-id><article-id pub-id-type="pmc">5539157</article-id><article-id pub-id-type="publisher-id">6937</article-id><article-id pub-id-type="doi">10.1038/s41598-017-06937-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jinpan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Ronghui</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Tongjun</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rausch-Fan</surname><given-names>Xiaohui</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Wang</surname><given-names>Mingguo</given-names></name><address><email>2563309609@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1761 1174</institution-id><institution-id institution-id-type="GRID">grid.27255.37</institution-id><institution>Department of Stomatology, Jinan Central Hospital,</institution><institution>Shandong University,</institution></institution-wrap>Jinan, 250013 P.R. China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9259 8492</institution-id><institution-id institution-id-type="GRID">grid.22937.3d</institution-id><institution>Division of Conservative Dentistry and Periodontology,</institution><institution>School of Dentistry, Medical University of Vienna,</institution></institution-wrap>Sensengasse 2a, 1090 Vienna, Austria</aff></contrib-group><pub-date pub-type="epub"><day>1</day><month>8</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>8</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>7027</elocation-id><history><date date-type="received"><day>27</day><month>3</month><year>2017</year></date><date date-type="accepted"><day>21</day><month>6</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s) 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Peri-implant disease is a chronic inflammation of the soft and hard tissues around a dental implant, resulting from bacterial infection. Recent evidence indicates that some pro-inflammatory cytokines and chemokines released by immunocytes are substantially responsible for the progress and consequence of inflammation. High mobility group box 1 (HMGB1) is released into the extracellular matrix and acts as a key pro-inflammatory factor during injury, necrosis and inflammation. A higher concentration of HMGB1 has been found in gingival crevicular fluid from inflammatory gingival tissue than from healthy sites. HMGB1 mRNA and protein are overexpressed in murine periodontal ligament fibroblasts stimulated with lipopolysaccharide (LPS) and IL-1β. Thus, this study sought to assess HMGB1 expression in peri-implant crevicular fluid (PICF) at each stage of peri-implant disease and to investigate the correlation between HMGB1 and peri-implant disease progress. The results demonstrated that the HMGB1 expression level in PICF is indicative of the progress of peri-implant disease and hence may be a useful diagnostic and prognostic biomarker for peri-implant tissue.</p></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">Peri-implant disease is a chronic inflammation of soft and hard tissue around a dental implant, resulting from a bacterial infection. This disease is classified into peri-implant mucositis (MU) and peri-implantitis (PI)<sup><xref ref-type="bibr" rid="CR1">1</xref></sup>, depending on the severity of the lesion. MU is a reversible inflammation restricted to the mucosa, whereas PI is an irreversible inflammation associated with the loss of the supporting marginal bone<sup><xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref></sup>. If MU is untreated or is not treated in a timely manner, it may develop into PI, and severe effects on the implant may result if PI induces rapid bone loss and causes implant failure.</p><p id="Par3">Contemporary peri-implant pathological models use immunobiology concepts to explain the disease development process, which is similar to that of gingivitis and periodontitis<sup><xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref></sup>. Plaque is the agent initiating inflammation. Bacterial products, such as lipopolysaccharide (LPS) and endotoxin, recruit neutrophils to the peri-implant pocket, which act as phagocytes and remove bacteria. However, if there is an overload of microbial plaque, the toxic enzymes released from the neutrophils will damage.</p><p id="Par4">Recent evidence has indicated that some pro-inflammatory cytokines and chemokines released by immunocytes are substantially responsible for the progress and consequences of inflammation. High mobility group box 1 (HMGB1) is a nonhistone DNA-binding nuclear protein that plays a crucial role in DNA binding, transcription and repair. HMGB1 is released into the extracellular matrix and act as a key pro-inflammatory factor during injury, necrosis and inflammation<sup><xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR6">6</xref></sup>. Extracellular HMGB1 mediates the inflammatory response by binding to receptor for advanced glycation end-products (RAGE), toll-like receptor (TLR)-2, TLR-4 and TLR-9, which have been implicated in inflammatory processes<sup><xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR8">8</xref></sup>. HMGB1 plays an important role in many acute and chronic inflammatory conditions, such as rheumatoid arthritis, osteoarthritis, cancer, lupus and periodontitis<sup><xref ref-type="bibr" rid="CR9">9</xref>–<xref ref-type="bibr" rid="CR13">13</xref></sup>.</p><p id="Par5">Only a few studies have investigated the role of HMGB1 in the pathological process of periodontitis. A higher concentration of HMGB1 has been found in gingival crevicular fluid from inflammatory gingival tissue compared with healthy sites<sup><xref ref-type="bibr" rid="CR14">14</xref></sup>. Additionally, HMGB1 mRNA and protein are overexpressed in murine periodontal ligament fibroblasts stimulated with LPS and interleukin (IL)-1β<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>. These observations suggest that HMGB1 plays a role in periodontitis. However, the mechanism by which HMGB1 participates in periodontitis and peri-implant disease is still unclear.</p><p id="Par6">Several pro-inflammatory factors have been found to be related to the progress of periodontitis<sup><xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR16">16</xref></sup>, such as IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF)-α. In experimental models, the higher expression of HMGB1 combined with IL-1β and TNF-α results in alveolar bone loss in periodontitis<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>.</p><p id="Par7">Although there have been numerous studies on the role of inflammation in periodontitis, fewer studies have investigated the role of HMGB1 in the progress of peri-implant disease, and no studies have been conducted on the association between HMGB1 and clinical parameters, such as plaque index, bleeding index, pocket probing depth, and gingival index. Furthermore, the correlation between HMGB1 and other pro-inflammatory cytokines also remains to be evaluated.</p><p id="Par8">Thus, the aim of the present study was to investigate the association between the expression of HMGB1 and the progress of peri-implant disease and clinical parameters. In addition, the study also evaluated the correlation between HMGB1 and levels of IL-1β, IL-6, IL-8, and TNF-α.</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Materials and Methods</title><sec id="Sec3"><title>Study population and specimen collection</title><p id="Par9">The study population included 79 implant sites from 47 healthy adult volunteers (26 females and 21 males), 18–59 years of age (mean age 43 ± 11.7 years). Patients were treated with endosseous titanium implants with a platform-switching design (DIO-IFN, DongSeo Inc., Korea). From those selected 79 dental implants, 20 dental implants were placed at maxillary premolar and 15 were placed at maxillary molar regions, whereas 25 dental implants were placed at mandibular premolar and 19 were placed at mandibular molar regions.The implants were 3.8–5.0 mm in diameter and 8.5–13.0 mm in length and were inserted into type II or type III bone. The mean time in function was 65.2 ± 4.7 months (range, 57 to 71 months).</p><p id="Par10">A thorough medical and dental history was taken for each patient. The criteria for inclusion were as follows: (i) the absence of allergies or metabolic bone disorder; (ii) do not have autoimmune diseases and systematic disease; (iii) nonsmoking status and not drug or alcohol abuse; (iv) not-pregnant; (v) had not used antibiotics within the previous 6 months; (vi) not having undergone any type of peri-implant therapy in the last 6 months. Exclusion criteria included inadequate oral hygiene, periodontal disease.</p><p id="Par11">All procedures were approved by the Ethics Committee of the College of Stomatology, Shandong University (SDU, Jinan, China), registered by number LW201400101. All methods were carried out in accordance with the Declaration of Helsinki. Prior to the study, all volunteers were informed and then signed a consent form authorizing the examinations.</p></sec><sec id="Sec4"><title>Clinical examination and grouping</title><p id="Par12">Clinical examinations were performed by two trained examiners, and results were calibrated among the two examiners. The clinical examinations included an assessment of the modified Sulcus Bleeding Index (mBI) (0, 1, 2, or 3), simplified gingival index (sGI) (0, 1, 2, or 3), probing depth (PD), and modified plaque index (mPI) (0, 1, 2, or 3). Clinical measurements were taken at four sites around the implants (mid-mesial, mid-distal, mid-buccal, and mid-lingual).</p><p id="Par13">The PD was measured by using a pressure-sensitive probe with a probing force of 0.25 N (Hu-Friedy PCPUNC 15 Mfg Co. Inc., Chicago IL). The clinical examination was performed one week before peri-implant crevicular fluid (PICF) collection.</p><p id="Par14">The height of the alveolar bone around the implant was determined by periapical radiograph examination. Radiographs were digitized at 600 dpi using a flatbed scanner and crest bone loss measurements were performed based on these digitized images. Peri-implant bone loss was measured by comparing the bone observed in the radiograph examination with that observed immediately after surgery. Crest bone loss at the mesial and distal aspects of each dental implant was determined by using the implant thread dimensions provided by the implant system manufactures, and bone loss larger than one thread was considered a sign of bone loss.</p><p id="Par15">The implant sites were classified into three groups according to the PD and sGI: a healthy gingival group (HG group), a peri-implant mucositis group (MU group) and a peri-implantitis group (PI group). Dental implant sites with no sign of inflammation (PD < 3, sGI ≤ 1) were placed in the HG group, whereas sites exhibiting signs of inflammation (PD ≥ 3, sGI > 1) without a radiographic sign of bone loss were included in the MU group. Those sites with PD ≥ 3, GI > 1 and a radiographic sign of bone loss composed the PI group.</p></sec><sec id="Sec5"><title>Sample collection</title><p id="Par16">PICF samples were obtained from each implant by using sterile standardized paper strips<sup><xref ref-type="bibr" rid="CR17">17</xref></sup> (PerioPaper, Periocal, Oraflow Inc., Aintyville, NY, USA). Patients were scheduled for PICF collection from 8 am to 10 am to avoid diurnal variations (food, drink, saliva and soft mucinous deposits) that might affect the results. Before collection, the volunteers were restrained for breakfast, and to perform the regular brushing. The samples were collected after delivery of the suprastructure, and all sites had the supragingival plaque were cleaned with sterile cotton rolls. Then the sites were isolated with sterile cotton rolls, and were gently dried in order to reduce contamination with plaque or saliva. Regardless of the PD, paper strips were inserted to a standardized 1-mm depth in a given site for a standard sampling time of 30 seconds without traumatizing the tissues. Strips contaminated with blood or saliva were discarded, and corresponding samples were taken 24 h later in order to reduce deviation, and the results came from the combination of two batches. After collection, paper strips were transported immediately to a Periotron which was calibrated,turned on, and allowed to warm up before PICF sampling. Firstly, a blank paper strip was placed in the device to adjust the reading to zero, then PICF samples were measured with the device, and the units were converted to microliters by a software program.</p></sec><sec id="Sec6"><title>Laboratory testing</title><p id="Par17">The concentration of HMGB1, IL-1β, IL-6, IL-8 and TNF-α in PICF was assessed by using commercially available high-sensitivity multiplex map human cytokine immunoassay (R&D, SAD, USA) according to the manufacturer’s instructions. Firstly, a 96-well plate was coated by microsphere beads that carring monoclonal antibodies against target analytes. Secondly, samples and standard fluid were pipetted into the wells and incubated overnight at 4 °C. Then washed the wells with a vacuum manifold, and a mixture of biotinylated secondary antibodies was added. After incubation at 37 °C for 1 h, streptavidin conjugated to the fluorescent protein, R-phycoerythrin was added to the beads and incubated at 37 °C for 30 min. Finally washed the wells in order to remove unbound reagents, sheath fluid was added to the wells and the beads were analyzed in the bead analyzer. Levels of cytokines as low as 0.1 pg/ml could be detected with this technique.</p></sec><sec id="Sec7"><title>Statistical analysis</title><p id="Par18">The demographic data were compared with a χ<sup><italic>2</italic></sup><italic>-</italic>test, and the comparisons of numerical data were performed with a one-way ANOVA and least significant difference (LSD) multiple comparison. The concentrations of HMGB1 in the different stages of peri-implant disease were compared with a one-way ANOVA. Spearman rank correlation coefficients were used to assess the correlation between HMGB1 and the clinical parameters of peri-implant disease, and the correlations between HMGB1 and IL-1β, IL-6, IL-8, and TNF-α in PICF were calculated by Pearson correlation. Differences were considered statistically significant at the level of p < 0.05. All statistical analyses were carried out using the statistical software package SPSS version 13.0.</p></sec></sec><sec id="Sec8" sec-type="results"><title>Results</title><sec id="Sec9"><title>Patient characteristics and clinical results</title><p id="Par19">All of the recalled patients met the inclusion criteria and were included in the study. Among 79 implants, 24 implants showed signs of MU, 16 implants showed signs of PI, and 39 implants were classified in the HG group. The demographic and behavioral data including sex, age, and clinical parameters are summarized in Table <xref rid="Tab1" ref-type="table">1</xref>.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Comparison of the general demographic characteristics and clinical parameters in different stages of peri-implant disease.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Variable</th><th>HG (n = 39) <inline-formula id="IEq1"><alternatives><tex-math id="M1">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M2"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq1.gif"></inline-graphic></alternatives></inline-formula></th><th>MU (n = 24) <inline-formula id="IEq2"><alternatives><tex-math id="M3">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M4"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq2.gif"></inline-graphic></alternatives></inline-formula></th><th>PI (n = 16) <inline-formula id="IEq3"><alternatives><tex-math id="M5">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M6"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq3.gif"></inline-graphic></alternatives></inline-formula></th><th><italic>P1</italic></th><th><italic>P2</italic></th><th><italic>P3</italic></th></tr></thead><tbody><tr><td>Age</td><td>39.3 ± 9.4</td><td>41.9 ± 12.8</td><td>45.8 ± 13.2</td><td></td><td></td><td></td></tr><tr><td>Sex (M/F)</td><td>6/16</td><td>27/15</td><td>7/9</td><td></td><td></td><td></td></tr><tr><td>sGI</td><td>0.47 ± 0.09</td><td>2.11 ± 0.33</td><td>2.47 ± 0.51</td><td>*</td><td>*</td><td></td></tr><tr><td>mPI</td><td>1.17 ± 0.04</td><td>1.76 ± 0.63</td><td>2.11 ± 0.41</td><td>*</td><td>*</td><td></td></tr><tr><td>mBI</td><td>0.11 ± 0.27</td><td>1.58 ± 0.31</td><td>2.29 ± 0.43</td><td>*</td><td>*</td><td>*</td></tr><tr><td>PD</td><td>1.94 ± 0.42</td><td>3.66 ± 0.93</td><td>5.54 ± 1.13</td><td>*</td><td>*</td><td>*</td></tr></tbody></table><table-wrap-foot><p><italic>P1</italic>: HG vs. MU, <italic>P2</italic>: HG vs. PI, <italic>P3</italic>: MU vs. PI; *<italic>p</italic>-value ≤ 0.05.</p><p>The demographic data were compared with a <italic>χ</italic><sup><italic>2</italic></sup><italic>-</italic>test, and the numerical data were compared with a one-way ANOVA and LSD multiple comparison.</p></table-wrap-foot></table-wrap></p><p id="Par20">These data showed an increasing tendency of sGI, mPI, mBI and PD accompanied by the progress of inflammation. These parameters were significantly different between the HG and MU groups as well as between the MU and PI groups. Interestingly, there were no significant differences in the sGI or mPI between the MU and PI groups.</p></sec><sec id="Sec10"><title>The association between HMGB1 and peri-implant disease progression</title><p id="Par21">Comparison of the HMGB1 concentrations in the PICF from the different groups revealed a significant increase in the HMGB1 concentration as the peri-implant disease progressed (Tables <xref rid="Tab2" ref-type="table">2</xref> and <xref rid="Tab3" ref-type="table">3</xref>). In addition, Pearson correlation coefficients were calculated to investigate the relationship between HMGB1 and the clinical parameters of peri-implant disease, including sGI, mPI, mBI and PD (Table <xref rid="Tab4" ref-type="table">4</xref>), thus revealing a positive correlation between HMGB1 and these clinical parameters. The strongest correlations were between the HMGB1 concentration and PD and sGI, and a moderate correlation was observed between the HMGB1 concentration and mBI. However, the correlation between the HMGB1 concentration and mPI was not significant. Comparison of HMGB1 concentrations in the different mPI groups showed that the differences between the HG group and MU group and between HG group and PI group were significant, whereas the difference between the MU group and PI group was not significant (Table <xref rid="Tab5" ref-type="table">5</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Comparison of the concentration of HMGB1 (pg/ml) in different stages of peri-implant disease.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Group</th><th>X</th><th>SD</th><th>Med</th><th>SE</th><th>N</th><th>F</th><th>P</th></tr></thead><tbody><tr><td>HG</td><td>167.3</td><td>18.9</td><td>167.4</td><td>3.1</td><td>39</td><td>2770.2</td><td><0.05</td></tr><tr><td>MU</td><td>309.4</td><td>45.4</td><td>316.6</td><td>7.5</td><td>24</td><td></td><td></td></tr><tr><td>PI</td><td>962. 2</td><td>82.5</td><td>987.4</td><td>16. 1</td><td>16</td><td></td><td></td></tr></tbody></table><table-wrap-foot><p><italic>X</italic>, mean; <italic>SD</italic>, standard deviation; <italic>Med</italic>, median; <italic>SE</italic>, standard error; <italic>N</italic>, number; <italic>F, f</italic> value.</p><p>The concentrations of HMGB1 in different stages of peri-implant disease were compared with a one-way ANOVA.</p></table-wrap-foot></table-wrap><table-wrap id="Tab3"><label>Table 3</label><caption><p>Comparison of the concentration of HMGB1, IL-1β, IL-6, IL-8 and TNF-α in PICF (pg/ml) in different stages of peri-implant disease.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>variable</th><th>HG (n = 39) <inline-formula id="IEq4"><alternatives><tex-math id="M7">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M8"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq4.gif"></inline-graphic></alternatives></inline-formula></th><th>MU(n = 24) <inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M10"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq5.gif"></inline-graphic></alternatives></inline-formula></th><th>PI(n = 16) <inline-formula id="IEq6"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{{\boldsymbol{X}}}\pm {\boldsymbol{S}}$$\end{document}</tex-math><mml:math id="M12"><mml:mover accent="true"><mml:mi mathvariant="bold-italic">X</mml:mi><mml:mo mathvariant="bold-italic">¯</mml:mo></mml:mover><mml:mo>±</mml:mo><mml:mi mathvariant="bold-italic">S</mml:mi></mml:math><inline-graphic xlink:href="41598_2017_6937_Article_IEq6.gif"></inline-graphic></alternatives></inline-formula></th><th>P1</th><th>P2</th><th>P3</th></tr></thead><tbody><tr><td>HMGB1</td><td>167.3 ± 18.9</td><td>309.4 ± 45.4</td><td>962.6 ± 82.5</td><td>*</td><td>*</td><td>*</td></tr><tr><td>IL-1β</td><td>227.7 ± 18.5</td><td>483.3 ± 65.9</td><td>872.2 ± 114.3</td><td>*</td><td>*</td><td>*</td></tr><tr><td>IL-6</td><td>144.3 ± 33.1</td><td>288.7 ± 45.9</td><td>537.2 ± 151.4</td><td>*</td><td></td><td></td></tr><tr><td>IL-8</td><td>45.3 ± 5.9</td><td>117.4 ± 16.4</td><td>178.26 ± 162.5</td><td>*</td><td>*</td><td></td></tr><tr><td>TNF-α</td><td>178.3 ± 11.9</td><td>289.4 ± 7.4</td><td>402.6 ± 24.5</td><td>*</td><td>*</td><td>*</td></tr></tbody></table><table-wrap-foot><p>values are presented as the mean ± standard deviation; P <italic>P1</italic>: HG vs. MU, <italic>P2</italic>: HG vs. PI, <italic>P3:</italic> MU vs. PI; *<italic>p</italic>-value ≤ 0.05.</p><p>The means in the different groups were compared using one-way ANOVA and LSD multiple comparison.</p></table-wrap-foot></table-wrap><table-wrap id="Tab4"><label>Table 4</label><caption><p>Correlation between the concentration of HMGB1 and the clinical parameters of peri-implant disease.</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th>N</th><th>R</th><th>P</th></tr></thead><tbody><tr><td>PD</td><td>79</td><td>0.859</td><td><0.05</td></tr><tr><td>sGI</td><td>79</td><td>0.804</td><td><0.05</td></tr><tr><td>mBI</td><td>79</td><td>0.649</td><td><0.05</td></tr><tr><td>mPI</td><td>79</td><td>0.448</td><td><0.05</td></tr></tbody></table><table-wrap-foot><p>Spearman rank correlation coefficients were used to assess the correlation between the HMGB1 concentration and the clinical parameters of peri-implant disease.</p></table-wrap-foot></table-wrap><table-wrap id="Tab5"><label>Table 5</label><caption><p>Comparison of the concentrations of HMGB1 in different mPI groups.</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th></th><th>X</th><th>SD</th><th>N</th><th>P</th></tr></thead><tbody><tr><td rowspan="4">HG vs. MU</td><td>mPI = 0</td><td>177.3</td><td>19.4</td><td>17</td><td rowspan="4">0.01</td></tr><tr><td>mPI = 1</td><td>186.5</td><td>19.6</td><td>23</td></tr><tr><td>mPI = 2</td><td>299.3</td><td>30.1</td><td>19</td></tr><tr><td>mPI = 3</td><td>330.9</td><td>27.8</td><td>2</td></tr><tr><td rowspan="4">HG vs. PI</td><td>mPI = 0</td><td>168.4</td><td>17.9</td><td>13</td><td rowspan="4">0.03</td></tr><tr><td>mPI = 1</td><td>455.4</td><td>31.7</td><td>21</td></tr><tr><td>mPI = 2</td><td>717.2</td><td>39.8</td><td>22</td></tr><tr><td>mPI = 3</td><td>933.6</td><td>117.9</td><td>7</td></tr><tr><td rowspan="4">MU vs. PI</td><td>mPI = 0</td><td>0</td><td>0</td><td>0</td><td rowspan="4">0.222</td></tr><tr><td>mPI = 1</td><td>691.7</td><td>97.1</td><td>6</td></tr><tr><td>mPI = 2</td><td>815.3</td><td>108.2</td><td>25</td></tr><tr><td>mPI = 3</td><td>951.2</td><td>115.6</td><td>8</td></tr></tbody></table><table-wrap-foot><p>The differences in the concentration of HMGB1 in the different groups were compared with a one-way ANOVA.</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec11"><title>Association between HMGB1 concentration and IL-1β, IL-6, IL-8, and TNF-α levels</title><p id="Par22">To explore the potential association between HMGB1 and the other pro-inflammatory factors in PICF, the correlation coefficients of the association between HMGB1 concentration and IL-1β, IL-6, IL-8, and TNF-α levels in those three groups were calculated (Table <xref rid="Tab6" ref-type="table">6</xref>). There was a high correlation between the HMGB1 level and the expression of IL-1β and TNF-α and a moderate correlation between the HMGB1 level and the expression of IL-6 and IL-8.<table-wrap id="Tab6"><label>Table 6</label><caption><p>Correlation coefficients between HMGB1, IL-1β, IL-6, IL-8 and TNF-α in PICF (pg/ml).</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th>HMGB-1</th><th>IL-1</th><th>IL-6</th><th>IL-8</th><th>TNF-α</th></tr></thead><tbody><tr><td>HMGB-1</td><td>1.000</td><td>0.757*</td><td>0.690*</td><td>0.685*</td><td>0.793*</td></tr><tr><td>IL-1</td><td>0.757*</td><td>1.000</td><td>0.551</td><td>0.716*</td><td>0.858*</td></tr><tr><td>IL-6</td><td>0.790*</td><td>0.551</td><td>1.000</td><td>0.784*</td><td>0.690*</td></tr><tr><td>IL-8</td><td>0.685*</td><td>0.716*</td><td>0.784*</td><td>1.000</td><td>0.588</td></tr><tr><td>TNF-α</td><td>0.793*</td><td>0.858*</td><td>0.690*</td><td>0.588</td><td>1.000</td></tr></tbody></table><table-wrap-foot><p><sup>*</sup>p-value ≤ 0.05.</p><p>The correlations between HMGB1, IL-1β, IL-6, IL-8 and TNF-α in PICF were calculated with Pearson correlation.</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec12" sec-type="discussion"><title>Discussion</title><p id="Par23">Peri-implant disease, similarly to periodontitis, may have a multi-factorial background. Page <italic>et al</italic>. have hypothesized that the progress of periodontitis is dependent on a combination of several factors, including the effects of bacteria and their production, overexpression of pro-inflammatory factors (cytokines and chemokines) in the local microenvironment, lower expression of inflammation inhibitors, and the susceptibility of the host<sup><xref ref-type="bibr" rid="CR18">18</xref></sup>. Thus, the balance of cytokines determines whether inflammation occurs and homeostasis is maintained. Investigators are searching for valid biological diagnostic markers with high sensitivity that can indicate the presence of inflammation before clinical damage occurs.</p><p id="Par24">The biochemical content of PICF, similar to that of gingival crevicular fluid (GCF), is considered to accurately reflect the processes occurring in peri-implant tissue<sup><xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR19">19</xref></sup>. Therefore, assessing the expression of cytokines in PICF from different disease stages can reveal essential information regarding the disease progress.</p><p id="Par25">HMGB1 is a mediator factor newly identified to be related to the onset and progress of periodontitis. In the present study, we assessed the levels of HMGB1 in PICF of patients with HG, MU and PI. The HMGB1 levels were significantly different between different groups (HG group vs. MU group, HG group vs. PI group, MU group vs. PI group), showing a significant increase as peri-implant disease progressed. Additionally, we assessed the correlation between the HMGB1 level and clinical parameters indicating the severity of the peri-implant disease, such as sGI, mBI, PD, and mPI. There was a close correlation between the HMGB1 concentration and sGI and PD, a moderate correlation between the HMGB1 concentration and mBI, and an insignificant correlation between HMGB1 and mPI, thus suggesting that HMGB1 may play a role in the development of peri-implant disease, especially in the destruction of soft and hard tissue.</p><p id="Par26">Interestingly, the present study demonstrated that there was no significant difference in mPI between the MU group and PI group. This result is consistent with findings from a study by Bhardwaj <italic>et al</italic>., which has compared the clinical parameters between HG, MU, and PI groups<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. In the present study, the comparison of the concentration of HMGB1 in the different mPI groups revealed significant differences between the HG group and MU group as well as the HG group and PI group but not between the MU group and PI group. Although plaque accumulation is the initial inflammatory factor, these data suggested that the amount of plaque is less correlated with the level of HMGB1 and the tissue destruction, such as bone loss, observed in the late stage of the disease</p><p id="Par27">Several studies have investigated the role of HMGB1 in the dental area; however, most of them have investigated its role in periodontitis rather than in peri-implant disease. In periodontitis, a higher concentration of HMGB1 and more HMGB1-positive cells have been observed in GCF and inflammatory gingival epithelial cells, respectively, than in controls <italic>in vitro</italic><sup><xref ref-type="bibr" rid="CR14">14</xref></sup>. Moreover, the expression of HMGB1 is higher in GCF and gingival tissue of chronic periodontitis and generalized aggressive periodontitis patients than in controls<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>. The protein expression of HMGB1 has been shown to be up-regulated after stimulation with LPS or IL-1β in murine periodontal ligament fibroblasts, with LPS and IL-1β in human gingival fibroblasts, and with TNF-α and IL-1β in human gingival epithelial cells<sup><xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR23">23</xref></sup>. In addition, two studies have demonstrated that the inflammatory signal for periodontitis contributes to the translocation of HMGB1 from the nucleus to the cytoplasm and extracellular matrix in gingival epithelial cells<sup><xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR14">14</xref></sup>. These data demonstrate that HMGB1 is expressed and released by cells residing in the periodontium and consequently responds to inflammatory signals and participates in the progress of periodontitis.</p><p id="Par28">To our knowledge, no studies have been conducted regarding the role of HMGB1 in the progress of peri-implant disease and the correlation of HMGB1 with clinical parameters of peri-implant disease.</p><p id="Par29">The concentration of IL-1β, IL-6, IL-8 and TNF-α in GCF has been shown to be markedly elevated in periodontitis<sup><xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR16">16</xref></sup>. Our results demonstrated that higher expression of HMGB1 was accompanied by a higher concentration of IL-1β, IL-6, IL-8 and TNF-α. The close correlation between the levels of HMGB1 and these cytokines suggested that these cytokines may cooperatively promote inflammation in peri-implant disease.</p><p id="Par30">Previous studies have revealed that HMGB1 release from monocytes, macrophages, gingival fibroblasts, epithelial cells, and endothelial cells is stimulated by IL-1β and TNF-α. Consequently, HMGB1 activates the release of IL-1β and TNF-α from monocytes and macrophages<sup><xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR22">22</xref></sup>. Anti-IL-1β antibodies or the IL-1 receptor antagonist block the pro-inflammatory action of HMGB1 in cultured cells<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. Additionally, administration of anti-HMGB1 antibody has been found to protect mice against the lethality induced by LPS and to decrease the release of IL-1β and TNF-α<sup><xref ref-type="bibr" rid="CR25">25</xref>–<xref ref-type="bibr" rid="CR27">27</xref></sup>. An increased amount of HMGB1 has also been observed in the salivary glands of patients with Sjogren’s syndrome, and HMGB1 may act together with IL-1β and TNF-α in forming a feed-forward loop promoting inflammation<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. In agreement with findings from previous studies, our results revealed a strong correlation between the level of HMGB1 and IL-1β and TNF-α.</p><p id="Par31">IL-6 is a pro-inflammatory cytokine and a central mediator of the acute-phase response. This pleiotropic cytokine stimulates B cell differentiation and T cell activation as well as the production of acute-phase proteins, including c-reactive protein<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>. HMGB1 stimulates the release of IL-6 and IL-11 from human periodontal ligament cells<sup><xref ref-type="bibr" rid="CR30">30</xref></sup> and also induces the expression of IL-6 and TNF-α in the brain<sup><xref ref-type="bibr" rid="CR31">31</xref></sup>. In addition, HMGB1 is released by macrophages and cardiomyocytes, and this release is followed by an increase in TNF-α and IL-6 expression<sup><xref ref-type="bibr" rid="CR31">31</xref></sup>. In an experimental periodontitis model, the expression profile of HMGB1 has been shown to be similar to those of TNF-α and IL-6, with higher expression of those cytokines occurring at day 7 and 15 followed by a decrease on day 30<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>.</p><p id="Par32">IL-8 is a neutrophil chemotactic factor and an early mediator of periodontitis. Its increased concentration in the PICF of some patients with clinically healthy implants may indicate the onset of inflammation<sup><xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR29">29</xref></sup>. HMGB1 activates human umbilic vein endothelial cells, which then produce multiple inflammatory cytokines, such as IL-6 and IL-8<sup><xref ref-type="bibr" rid="CR32">32</xref></sup>. An intraperitoneal injection of HMGB1, which induces IL-1β and IL-8, provokes the accumulation of neutrophils in the lung<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>.</p><p id="Par33">Our results were consistent with these previous findings and indicated a close correlation between the cytokines IL-1β, IL-6, IL-8, TNF-α and the progress of peri-implant disease with HMGB1. The data suggested that the cytokines are connected in a network and expand the pro-inflammatory properties of themselves and other cytokines. Although HMGB1 itself has only minimal pro-inflammatory characteristics, it can acquire much greater activity through amplifying the response of other cytokines.</p><p id="Par34">In conclusion, the results obtained in this study indicated that HMGB1 in PICF is a key mediator of several pro-inflammatory cytokines and plays a crucial role in the advance of peri-implant disease. HMGB1 can be considered a new biomarker for the peri-implant condition. Future studies should investigate the mechanism of the interaction of pro-inflammatory and anti-inflammatory cytokines in peri-implant disease. Understanding the intricacies of peri-implant disease should enable novel treatment paradigms and perhaps the development of prevention strategies.</p></sec></body><back><fn-group><fn><p><bold>Publisher's note:</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group><notes notes-type="author-contribution"><title>Author Contributions</title><p>Jinpan Liu and Mingguo Wang designed the study; Jinpan Liu and Xiaohui Rausch-Fan collected and analyzed the data; Mingguo Wang, Jinpan Liu, Ronghui Li, Tongjun Liu, and Xiaohui Rausch-Fan conducted the study; Jinpan Liu and Ronghui Li wrote the first draft of the manuscript; Jinpan Liu, Ronghui Li and Mingguo Wang revised the manuscript; and Mingguo Wang gave final approval of the manuscript. 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