{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:25:05Z","timestamp":1793147105873,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The enhanced osteoclastogenesis contributes to alveolar bone resorption in periodontitis, which increases the risk of tooth loss. To reduce bone destruction, the inhibition of osteoclast development is proposed as a feasible treatment. CD40L-CD40-TRAF6 signal transduction plays a crucial role in inflammation, but how it regulates osteoclast activity in periodontitis has not been elucidated. In this study, we showed the potential role of CD40L-CD40-TRAF6 signaling in periodontitis. CD40L obviously promoted osteoclast formation and bone resorption capacity <jats:italic>in vitro<\/jats:italic>. Mechanistically, we found that osteoclastogenesis was enhanced by the overexpression of NFATc1 and NF-\u03baB activation. Importantly, osteoclast activity was effectively suppressed by TRAF-STOP, a small molecular inhibitor of TRAF6. Furthermore, local injection of TRAF-STOP-loaded injectable PLGA-PEG-PLGA hydrogel could alleviate ligation-induced periodontitis <jats:italic>in vivo<\/jats:italic>. Taken together, TRAF-STOP shows promising clinical efficacy in periodontitis through alleviating osteoclastogenesis.<\/jats:p>","DOI":"10.3389\/fphar.2023.1119847","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T14:32:46Z","timestamp":1684161166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["TRAF-STOP alleviates osteoclastogenesis in periodontitis"],"prefix":"10.3389","volume":"14","author":[{"given":"Yaxian","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaocai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaguang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengmei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12974-017-0875-9","article-title":"Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation","volume":"14","author":"Aarts","year":"2017","journal-title":"J. neuroinflammation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.jim.2013.05.002","article-title":"Optimization of the ligature-induced periodontitis model in mice","volume":"394","author":"Abe","year":"2013","journal-title":"J. Immunol. methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/35046196","article-title":"Bone versus immune system","volume":"408","author":"Arron","year":"2000","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.canlet.2020.05.021","article-title":"Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis","volume":"488","author":"Bishop","year":"2020","journal-title":"Cancer Lett."},{"key":"B5","doi-asserted-by":"publisher","first-page":"674","DOI":"10.2174\/1568026618666180531092503","article-title":"Toward small-molecule inhibition of protein-protein interactions: General aspects and recent progress in targeting costimulatory and coinhibitory (immune checkpoint) interactions","volume":"18","author":"Bojadzic","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"g2645","DOI":"10.1136\/bmj.g2645","article-title":"Time to take periodontitis seriously","volume":"348","author":"Chapple","year":"2014","journal-title":"BMJ Clin. Res. ed)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nrm1368","article-title":"Shaping the nuclear action of NF-kappaB","volume":"5","author":"Chen","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.immunol.021908.132649","article-title":"Primary B cell immunodeficiencies: Comparisons and contrasts","volume":"27","author":"Conley","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"11385","DOI":"10.1021\/acs.chemrev.0c01177","article-title":"Translational applications of hydrogels","volume":"121","author":"Correa","year":"2021","journal-title":"Chem. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1126\/science.7689748","article-title":"Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40","volume":"261","author":"Durie","year":"1993","journal-title":"Sci. (New York, NY)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.smim.2009.06.004","article-title":"The immunobiology of CD154-CD40-TRAF interactions in atherosclerosis","volume":"21","author":"Engel","year":"2009","journal-title":"Seminars Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4097","DOI":"10.1038\/s41467-018-06470-0","article-title":"Structural properties of a haemophore facilitate targeted elimination of the pathogen Porphyromonas gingivalis","volume":"9","author":"Gao","year":"2018","journal-title":"Nat. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.3390\/molecules25112505","article-title":"Development of PLGA-PEG-PLGA hydrogel delivery system for enhanced immunoreaction and efficacy of newcastle disease virus DNA vaccine","volume":"25","author":"Gao","year":"2020","journal-title":"Mol. (Basel, Switz."},{"key":"B14","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.cmet.2008.07.001","article-title":"T cells potentiate PTH-induced cortical bone loss through CD40L signaling","volume":"8","author":"Gao","year":"2008","journal-title":"Cell metab."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1056\/NEJM197105132841906","article-title":"Periodontal disease","volume":"284","author":"Glickman","year":"1971","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1038\/sj.emboj.7600564","article-title":"RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis","volume":"24","author":"Gohda","year":"2005","journal-title":"EMBO J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"61638","DOI":"10.1021\/acsami.1c18701","article-title":"Injectable and self-healing hydrogels with double-dynamic bond tunable mechanical, gel-sol transition and drug delivery properties for promoting periodontium regeneration in periodontitis","volume":"13","author":"Guo","year":"2021","journal-title":"ACS Appl. Mater. interfaces"},{"key":"B18","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nri3785","article-title":"Periodontitis: From microbial immune subversion to systemic inflammation","volume":"15","author":"Hajishengallis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/prd.12368","article-title":"Maintaining homeostatic control of periodontal bone tissue","volume":"86","author":"Hathaway-Schrader","year":"2021","journal-title":"Periodontology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5925","DOI":"10.1038\/s41467-022-33492-6","article-title":"Nanoparticulate cell-free DNA scavenger for treating inflammatory bone loss in periodontitis","volume":"13","author":"Huang","year":"2022","journal-title":"Nat. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1038\/nm1197-1285","article-title":"Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2","volume":"3","author":"Iotsova","year":"1997","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.tim.2013.12.005","article-title":"Emerging roles of immunostimulatory oral bacteria in periodontitis development","volume":"22","author":"Jiao","year":"2014","journal-title":"Trends Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/nm1054","article-title":"Selective inhibition of NF-kappa B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo","volume":"10","author":"Jimi","year":"2004","journal-title":"Nat. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1111\/j.0105-2896.2005.00329.x","article-title":"Role of nuclear factor-kappaB in the immune system and bone","volume":"208","author":"Jimi","year":"2005","journal-title":"Immunol. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/sj.embor.7400345","article-title":"Strength of TRAF6 signalling determines osteoclastogenesis","volume":"6","author":"Kadono","year":"2005","journal-title":"EMBO Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3646","DOI":"10.3390\/ijms21103646","article-title":"The role of Ca(2+)-NFATc1 signaling and its modulation on osteoclastogenesis","volume":"21","author":"Kang","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1177\/0022034514552491","article-title":"Global burden of severe periodontitis in 1990-2010: A systematic review and meta-regression","volume":"93","author":"Kassebaum","year":"2014","journal-title":"J. Dent. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1111\/jre.12615","article-title":"A novel IkB kinase inhibitor attenuates ligature-induced periodontal disease in mice","volume":"54","author":"Kure","year":"2019","journal-title":"J. periodontal Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/prd.12146","article-title":"Molecular basis for immunohistochemical and inflammatory changes during progression of gingivitis to periodontitis","volume":"76","author":"Kurgan","year":"2018","journal-title":"Periodontology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"788","DOI":"10.4049\/jimmunol.138.3.788","article-title":"Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen BP50 (CDW40)","volume":"138","author":"Ledbetter","year":"1987","journal-title":"J. Immunol. Baltim. Md 1950)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.3390\/ijms21031056","article-title":"Regulation of osteoclast differentiation at multiple stages by protein kinase D family kinases","volume":"21","author":"Leightner","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1073\/pnas.1013492108","article-title":"Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand","volume":"108","author":"Li","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/s41569-018-0024-x","article-title":"Nanoimmunotherapy targeting CD40-TRAF6 signalling to reduce atherosclerosis","volume":"15","author":"Lim","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1101\/gad.13.8.1015","article-title":"TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling","volume":"13","author":"Lomaga","year":"1999","journal-title":"Genes & Dev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"8723","DOI":"10.1016\/j.biomaterials.2014.06.045","article-title":"PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment","volume":"35","author":"Ma","year":"2014","journal-title":"Biomaterials"},{"key":"B36","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1177\/154405910408300706","article-title":"Monocyte activation by Porphyromonas gingivalis LPS in aggressive periodontitis with the use of whole-blood cultures","volume":"83","author":"Mahanonda","year":"2004","journal-title":"J. Dent. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1038\/s41596-018-0035-4","article-title":"An experimental murine model to study periodontitis","volume":"13","author":"Marchesan","year":"2018","journal-title":"Nat. Protoc."},{"key":"B38","doi-asserted-by":"publisher","first-page":"114869","DOI":"10.1016\/j.bcp.2021.114869","article-title":"Anti-inflammatory, but not osteoprotective, effect of the TRAF6\/CD40 inhibitor 6877002 in rodent models of local and systemic osteolysis","volume":"195","author":"Marino","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/978-94-007-0763-4_7","article-title":"Macrophage fusion and multinucleated giant cells of inflammation","volume":"713","author":"McNally","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/j.1600-065X.2009.00821.x","article-title":"Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation","volume":"231","author":"Negishi-Koga","year":"2009","journal-title":"Immunol. Rev."},{"key":"B41","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/j.1600-065X.2009.00821.x","article-title":"Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation","volume":"231","author":"Negishi-Koga","year":"2009","journal-title":"Immunol. Rev."},{"key":"B42","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/BF00199769","article-title":"A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes","volume":"20","author":"Paulie","year":"1985","journal-title":"CII"},{"key":"B43","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.smim.2009.05.012","article-title":"CD40 and autoimmunity: The dark side of a great activator","volume":"21","author":"Peters","year":"2009","journal-title":"Seminars Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3114","DOI":"10.1182\/blood-2005-02-0759","article-title":"LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia","volume":"106","author":"Qin","year":"2005","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","first-page":"671","DOI":"10.3390\/pharmaceutics11120671","article-title":"Poloxamer hydrogels for biomedical applications","volume":"11","author":"Russo","year":"2019","journal-title":"Pharmaceutics"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1161\/hh2401.101272","article-title":"CD40 signaling and plaque instability","volume":"89","author":"Sch\u00f6nbeck","year":"2001","journal-title":"Circulation Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/pl00000776","article-title":"The CD40\/CD154 receptor\/ligand dyad","volume":"58","author":"Sch\u00f6nbeck","year":"2001","journal-title":"Cell. Mol. life Sci. CMLS"},{"key":"B48","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.jacc.2017.11.055","article-title":"Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis","volume":"71","author":"Seijkens","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1016\/j.bioactmat.2020.07.002","article-title":"Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism","volume":"5","author":"Shen","year":"2020","journal-title":"Bioact. Mater."},{"key":"B50","doi-asserted-by":"publisher","first-page":"995061","DOI":"10.3389\/fphar.2022.995061","article-title":"Role of CD40(L)-TRAF signaling in inflammation and resolution-a double-edged sword","volume":"13","author":"Strohm","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"107709","DOI":"10.1016\/j.pharmthera.2020.107709","article-title":"Molecular basis and therapeutic implications of CD40\/CD40L immune checkpoint","volume":"219","author":"Tang","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"B52","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/imr.12302","article-title":"Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system","volume":"266","author":"Walsh","year":"2015","journal-title":"Immunol. Rev."},{"key":"B53","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.actbio.2020.09.018","article-title":"Antimicrobial and anti-inflammatory thermo-reversible hydrogel for periodontal delivery","volume":"116","author":"Wang","year":"2020","journal-title":"Acta biomater."},{"key":"B54","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1177\/0885328216680343","article-title":"Thermo-sensitive hydrogel PLGA-PEG-PLGA as a vaccine delivery system for intramuscular immunization","volume":"31","author":"Wang","year":"2017","journal-title":"J. biomaterials Appl."},{"key":"B55","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.cmet.2010.04.015","article-title":"PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss","volume":"11","author":"Wei","year":"2010","journal-title":"Cell metab."},{"key":"B56","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.jconrel.2021.03.041","article-title":"Local drug delivery systems as therapeutic strategies against periodontitis: A systematic review","volume":"333","author":"Wei","year":"2021","journal-title":"J. Control. release official J. Control. Release Soc."},{"key":"B57","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41368-022-00177-1","article-title":"Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system","volume":"14","author":"Xin","year":"2022","journal-title":"Int. J. oral Sci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.actbio.2019.01.001","article-title":"An injectable and thermosensitive hydrogel: Promoting periodontal regeneration by controlled-release of aspirin and erythropoietin","volume":"86","author":"Xu","year":"2019","journal-title":"Acta biomater."},{"key":"B59","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/nature00888","article-title":"Distinct molecular mechanism for initiating TRAF6 signalling","volume":"418","author":"Ye","year":"2002","journal-title":"Nature"},{"key":"B60","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1021\/ci500631e","article-title":"Discovery of small molecule CD40-TRAF6 inhibitors","volume":"55","author":"Zarzycka","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"B61","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.jconrel.2014.03.026","article-title":"PEG-PLGA copolymers: Their structure and structure-influenced drug delivery applications","volume":"183","author":"Zhang","year":"2014","journal-title":"J. Control. release official J. Control. Release Soc."},{"key":"B62","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.cis.2017.04.008","article-title":"Engineering and delivery of nanocolloids of hydrophobic drugs","volume":"249","author":"Zhao","year":"2017","journal-title":"Adv. colloid interface Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1119847\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T18:49:39Z","timestamp":1684262979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1119847\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,15]]},"references-count":62,"alternative-id":["10.3389\/fphar.2023.1119847"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1119847","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,15]]},"article-number":"1119847"}}