{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T21:29:26Z","timestamp":1786483766058,"version":"build-2736575974"},"reference-count":53,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["#23K15994"],"award-info":[{"award-number":["#23K15994"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Oral Biosciences"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.job.2026.100799","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:59:17Z","timestamp":1783133957000},"page":"100799","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin suppresses periapical bone resorption in a mouse model of apical periodontitis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro"],"prefix":"10.1016","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-0772","authenticated-orcid":false,"given":"Faisal","family":"Alghamdi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8565-3728","authenticated-orcid":false,"given":"Chunmei","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9725-6034","authenticated-orcid":false,"given":"Kento","family":"Tazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2641-5308","authenticated-orcid":false,"given":"Shuaichen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnosuke","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaharu","family":"Ishidori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6424-736X","authenticated-orcid":false,"given":"Risa","family":"Ohshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-0487","authenticated-orcid":false,"given":"Nobuyuki","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-4508","authenticated-orcid":false,"given":"Takashi","family":"Okiji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-0487","authenticated-orcid":false,"given":"Yoshio","family":"Yahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.job.2026.100799_bib1","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1177\/10454411980090040701","article-title":"Periapical inflammatory responses and their modulation","volume":"9","author":"Stashenko","year":"1998","journal-title":"Crit Rev Oral Biol Med"},{"key":"10.1016\/j.job.2026.100799_bib2","first-page":"148","article-title":"Apical periodontitis in vital and nonvital teeth: clinical and radiographic features","volume":"19","author":"Asgary","year":"2024","journal-title":"Iran Endod J"},{"key":"10.1016\/j.job.2026.100799_bib3","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1111\/iej.13467","article-title":"The global prevalence of apical periodontitis: a systematic review and meta-analysis","volume":"54","author":"Tib\u00farcio-Machado","year":"2021","journal-title":"Int Endod J"},{"key":"10.1016\/j.job.2026.100799_bib4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/j.1365-2591.2007.01323.x","article-title":"Outcome of primary root canal treatment: systematic review of the literature - part 2. influence of clinical factors","volume":"41","author":"Ng","year":"2008","journal-title":"Int Endod J"},{"key":"10.1016\/j.job.2026.100799_bib5","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.joen.2022.01.003","article-title":"Local immunomodulatory effects of intracanal medications in apical periodontitis","volume":"48","author":"Hussein","year":"2022","journal-title":"J Endod"},{"key":"10.1016\/j.job.2026.100799_bib6","article-title":"Pathogenesis of apical periodontitis: a literature review","volume":"2","author":"Graunaite","year":"2012","journal-title":"J Oral Maxillofac Res"},{"key":"10.1016\/j.job.2026.100799_bib7","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1111\/iej.14125","article-title":"The immune landscape in apical periodontitis: from mechanism to therapy","volume":"57","author":"Wen","year":"2024","journal-title":"Int Endod J"},{"key":"10.1016\/j.job.2026.100799_bib8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1365-2591.2012.02105.x","article-title":"The receptor activator of NF-\u03baB ligand-osteoprotegerin system in pulpal and periapical disease","volume":"46","author":"Belibasakis","year":"2013","journal-title":"Int Endod J"},{"key":"10.1016\/j.job.2026.100799_bib9","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nri2062","article-title":"Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems","volume":"7","author":"Takayanagi","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"10.1016\/j.job.2026.100799_bib10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"10.1016\/j.job.2026.100799_bib11","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/ar3379","article-title":"Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors","volume":"13","author":"Zhao","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.job.2026.100799_bib12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41421-025-00853-6","article-title":"Cell signaling and transcriptional regulation of osteoclast lineage commitment, differentiation, bone resorption and diseases","volume":"12","author":"Zhu","year":"2026","journal-title":"Cell Discov"},{"key":"10.1016\/j.job.2026.100799_bib13","first-page":"4648","article-title":"Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4","volume":"24","author":"Knowles","year":"2010","journal-title":"FASEB J"},{"key":"10.1016\/j.job.2026.100799_bib14","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1007\/s00784-023-04920-8","article-title":"Bacteria associated with apical periodontitis promotes in vitro the differentiation of macrophages to osteoclasts","volume":"27","author":"Torres-Monjar\u00e1s","year":"2023","journal-title":"Clin Oral Investig"},{"key":"10.1016\/j.job.2026.100799_bib15","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.3390\/ijms20143576","article-title":"Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases","volume":"20","author":"Agidigbi","year":"2019","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.job.2026.100799_bib16","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev Cell"},{"key":"10.1016\/j.job.2026.100799_bib17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.11005\/jbm.2014.21.4.233","article-title":"Regulation of NFATc1 in osteoclast differentiation","volume":"21","author":"Kim","year":"2014","journal-title":"J Bone Metab"},{"key":"10.1016\/j.job.2026.100799_bib18","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s12276-024-01157-7","article-title":"Unraveling the intricacies of osteoclast differentiation and maturation: insight into novel therapeutic strategies for bone-destructive diseases","volume":"56","author":"Takegahara","year":"2024","journal-title":"Exp Mol Med"},{"key":"10.1016\/j.job.2026.100799_bib19","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"10.1016\/j.job.2026.100799_bib20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cmet.2020.04.001","article-title":"Benefits of metformin in attenuating the hallmarks of aging","volume":"32","author":"Kulkarni","year":"2020","journal-title":"Cell Metab"},{"key":"10.1016\/j.job.2026.100799_bib21","doi-asserted-by":"crossref","first-page":"20348","DOI":"10.1074\/jbc.M115.662114","article-title":"Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1\u03b2 (IL-1\u03b2) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages","volume":"290","author":"Kelly","year":"2015","journal-title":"J Biol Chem"},{"key":"10.1016\/j.job.2026.100799_bib22","doi-asserted-by":"crossref","first-page":"904","DOI":"10.2337\/dci22-0047","article-title":"Metformin and cancer: solutions to a real-world evidence failure","volume":"46","author":"Yu","year":"2023","journal-title":"Diabetes Care"},{"key":"10.1016\/j.job.2026.100799_bib23","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41419-021-04235-0","article-title":"Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt","volume":"12","author":"Xiong","year":"2021","journal-title":"Cell Death Dis"},{"key":"10.1016\/j.job.2026.100799_bib24","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1016\/j.biopha.2018.11.032","article-title":"Metformin; an old antidiabetic drug with new potentials in bone disorders","volume":"109","author":"Bahrambeigi","year":"2019","journal-title":"Biomed Pharmacother"},{"key":"10.1016\/j.job.2026.100799_bib25","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1643676","article-title":"Metformin attenuates alveolar bone destruction in mice with apical periodontitis and inhibits pro-inflammatory cytokine synthesis in lipopolysaccharide-stimulated RAW264.7 through the AMPK-mTOR-NF-\u03baB pathway","volume":"16","author":"Ren","year":"2025","journal-title":"Front Immunol"},{"key":"10.1016\/j.job.2026.100799_bib26","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.joen.2023.07.005","article-title":"Metformin reduces bone resorption in apical periodontitis through regulation of osteoblast and osteoclast differentiation","volume":"49","author":"Hong","year":"2023","journal-title":"J Endod"},{"key":"10.1016\/j.job.2026.100799_bib27","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3390\/bioengineering10040488","article-title":"Recent advances in apical periodontitis treatment: a narrative review","volume":"10","author":"Arias","year":"2023","journal-title":"Bioengineered"},{"key":"10.1016\/j.job.2026.100799_bib28","doi-asserted-by":"crossref","DOI":"10.1080\/20002297.2023.2184924","article-title":"Role of Enterococcus faecalis in refractory apical periodontitis: from pathogenicity to host cell response","volume":"15","author":"Deng","year":"2023","journal-title":"J Oral Microbiol"},{"key":"10.1016\/j.job.2026.100799_bib29","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.joen.2019.10.001","article-title":"Intracanal metformin promotes healing of apical periodontitis via suppressing inducible nitric oxide synthase expression and monocyte recruitment","volume":"46","author":"Wang","year":"2020","journal-title":"J Endod"},{"key":"10.1016\/j.job.2026.100799_bib30","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.gendis.2021.06.003","article-title":"Metformin ameliorates HMGB1-mediated oxidative stress through mTOR pathway in experimental periodontitis","volume":"10","author":"Sun","year":"2023","journal-title":"Genes Dis"},{"key":"10.1016\/j.job.2026.100799_bib31","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.job.2022.12.003","article-title":"Three-dimensional cellular visualization in mouse apical periodontitis using combined whole-mount staining and optical tissue clearing","volume":"65","author":"Tazawa","year":"2023","journal-title":"J Oral Biosci"},{"key":"10.1016\/j.job.2026.100799_bib32","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.jpain.2023.01.013","article-title":"Modulation of the inflammatory response by pre-emptive administration of IMT504 reduces postoperative pain in rats and has opioid-sparing effects","volume":"24","author":"Rubione","year":"2023","journal-title":"J Pain"},{"key":"10.1016\/j.job.2026.100799_bib33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and molecular mechanisms of metformin action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr Rev"},{"key":"10.1016\/j.job.2026.100799_bib34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.3390\/cells10030671","article-title":"A mouse model for studying the development of apical periodontitis with age","volume":"10","author":"Goldman","year":"2021","journal-title":"Cells"},{"key":"10.1016\/j.job.2026.100799_bib35","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.biocel.2009.12.018","article-title":"NFATc1: functions in osteoclasts","volume":"42","author":"Zhao","year":"2010","journal-title":"Int J Biochem Cell Biol"},{"key":"10.1016\/j.job.2026.100799_bib36","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2021.641162","article-title":"Role of OSCAR signaling in osteoclastogenesis and bone disease","volume":"9","author":"Nedeva","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"10.1016\/j.job.2026.100799_bib37","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0128275","article-title":"Studies of OC-STAMP in osteoclast fusion: a new knockout mouse model, rescue of cell fusion, and transmembrane topology","volume":"10","author":"Witwicka","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.job.2026.100799_bib38","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00774-006-0697-9","article-title":"Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells","volume":"24","author":"Yagi","year":"2006","journal-title":"J Bone Miner Metabol"},{"key":"10.1016\/j.job.2026.100799_bib39","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1177\/002215540004800207","article-title":"Osteoclastic tartrate-resistant acid phosphatase (Acp 5): its localization to dendritic cells and diverse murine tissues","volume":"48","author":"Hayman","year":"2000","journal-title":"J Histochem Cytochem"},{"key":"10.1016\/j.job.2026.100799_bib40","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.818462","article-title":"Cathepsin K(+) non-osteoclast cells in the skeletal system: function, models, identity, and therapeutic implications","volume":"10","author":"Zou","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"10.1016\/j.job.2026.100799_bib41","article-title":"Matrix metalloproteinase-9 enhances osteoclastogenesis: insights from transgenic rabbit bone marrow models and in vitro studies","volume":"26","author":"Chen","year":"2025","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.job.2026.100799_bib42","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3390\/jdb8030012","article-title":"A synthetic peptide, CK2.3, inhibits RANKL-induced osteoclastogenesis through BMPRIa and ERK signaling pathway","volume":"8","author":"Nguyen","year":"2020","journal-title":"J Dev Biol"},{"key":"10.1016\/j.job.2026.100799_bib43","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.joen.2012.03.010","article-title":"Protective effect of metformin on periapical lesions in rats by decreasing the ratio of receptor activator of nuclear factor kappa B ligand\/osteoprotegerin","volume":"38","author":"Liu","year":"2012","journal-title":"J Endod"},{"key":"10.1016\/j.job.2026.100799_bib44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12964-022-00966-5","article-title":"Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1","volume":"20","author":"Xie","year":"2022","journal-title":"Cell Commun Signal"},{"key":"10.1016\/j.job.2026.100799_bib45","article-title":"Metformin switches cell death modes to soothe the apical periodontitis via ZBP1","volume":"38","author":"Liu","year":"2024","journal-title":"FASEB J"},{"key":"10.1016\/j.job.2026.100799_bib46","doi-asserted-by":"crossref","first-page":"2902","DOI":"10.1002\/jcb.23206","article-title":"Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats","volume":"112","author":"Mai","year":"2011","journal-title":"J Cell Biochem"},{"key":"10.1016\/j.job.2026.100799_bib47","article-title":"Experimental study on the inhibition of RANKL-induced osteoclast differentiation in vitro by metformin hydrochloride","volume":"2022","author":"Chen","year":"2022","journal-title":"Internet J Endocrinol"},{"key":"10.1016\/j.job.2026.100799_bib48","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s11914-023-00828-0","article-title":"The differential effect of metformin on osteocytes, osteoblasts, and osteoclasts","volume":"21","author":"de Vries","year":"2023","journal-title":"Curr Osteoporos Rep"},{"key":"10.1016\/j.job.2026.100799_bib49","article-title":"Diabetes medication metformin inhibits osteoclast formation and activity in in vitro models for periodontitis","volume":"9","author":"Tao","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"10.1016\/j.job.2026.100799_bib50","doi-asserted-by":"crossref","first-page":"4727","DOI":"10.18632\/aging.102796","article-title":"Metformin coordinates osteoblast\/osteoclast differentiation associated with ischemic osteonecrosis","volume":"12","author":"Park","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"10.1016\/j.job.2026.100799_bib51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jphs.2022.10.007","article-title":"IL-1\u03b2 promotes osteoclastogenesis by increasing the expression of IGF2 and chemokines in non-osteoclastic cells","volume":"151","author":"Otsuka","year":"2023","journal-title":"J Pharmacol Sci"},{"key":"10.1016\/j.job.2026.100799_bib52","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.3389\/fimmu.2019.02925","article-title":"TNF-\u03b1 directly enhances osteocyte RANKL expression and promotes osteoclast formation","volume":"10","author":"Marahleh","year":"2019","journal-title":"Front Immunol"},{"key":"10.1016\/j.job.2026.100799_bib53","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cytogfr.2003.10.005","article-title":"IL-6, RANKL, TNF-alpha\/IL-1: interrelations in bone resorption pathophysiology","volume":"15","author":"Kwan","year":"2004","journal-title":"Cytokine Growth Factor Rev"}],"container-title":["Journal of Oral Biosciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1349007926000678?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1349007926000678?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:47:46Z","timestamp":1786481266000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1349007926000678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":53,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["S1349007926000678"],"URL":"https:\/\/doi.org\/10.1016\/j.job.2026.100799","relation":{},"ISSN":["1349-0079"],"issn-type":[{"value":"1349-0079","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Metformin suppresses periapical bone resorption in a mouse model of apical periodontitis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro","name":"articletitle","label":"Article Title"},{"value":"Journal of Oral Biosciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.job.2026.100799","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"100799"}}