{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:14:59Z","timestamp":1790792099695,"version":"4.1.0"},"reference-count":37,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T00:00:00Z","timestamp":1728691200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100009976","name":"Chongqing Postdoctoral Science Special Foundation","doi-asserted-by":"publisher","award":["2021XM1031"],"award-info":[{"award-number":["2021XM1031"]}],"id":[{"id":"10.13039\/501100009976","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022M720599"],"award-info":[{"award-number":["2022M720599"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing Municipality","doi-asserted-by":"publisher","award":["#cstc2021jcyjmsxmX0560"],"award-info":[{"award-number":["#cstc2021jcyjmsxmX0560"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201059"],"award-info":[{"award-number":["82201059"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82220108019"],"award-info":[{"award-number":["82220108019"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chongqing Traditional Chinese Medicine scientific research project","award":["#2024ZYYB005"],"award-info":[{"award-number":["#2024ZYYB005"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>Nonresolving inflammation causes irreversible damage to periodontal ligament stem cells (PDLSCs) and impedes alveolar bone restoration. The impaired tissue regeneration ability of stem cells is associated with abnormal mitochondrial metabolism. However, the impact of specific metabolic alterations on the differentiation process of PDLSCs remains to be understood. In this study, we found that inflammation altered the metabolic flux of the tricarboxylic acid cycle and induced the accumulation of fumarate through metabolic testing and metabolic flux analysis. Transcriptome sequencing revealed the potential of fumarate in modulating epigenetics. Specifically, histone methylation typically suppresses the expression of genes related to osteogenesis. Fumarate was found to impede the osteogenic differentiation of PDLSCs that exhibited high levels of H3K9me3. Various techniques, including assay for transposase-accessible chromatin with high-throughput sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing, were used to identify the target genes regulated by H3K9me3. Mechanistically, accumulated fumarate inhibited lysine-specific demethylase 4B (KDM4B) activity and increased H3K9 methylation, thus silencing asporin gene transcription. Preventing fumarate from binding to the histone demethylase KDM4B with \u03b1-ketoglutarate effectively restored the impaired osteogenic capacity of PDLSCs and improved alveolar bone recovery. Collectively, our research has revealed the significant impact of accumulated fumarate on the regulation of osteogenesis in stem cells, suggesting that inhibiting fumarate production could be a viable therapeutic approach for treating periodontal diseases.<\/jats:p>","DOI":"10.1177\/00220345241279555","type":"journal-article","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T03:16:08Z","timestamp":1728702968000},"page":"1302-1312","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Fumarate Restrains Alveolar Bone Restoration via Regulating H3K9 Methylation"],"prefix":"10.1177","volume":"103","author":[{"given":"Y.Y.","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.Y.","family":"He","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-322X","authenticated-orcid":false,"given":"H.Y.","family":"Ye","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.L.","family":"Bai","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"},{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.M.","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.Z.","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6859-7411","authenticated-orcid":false,"given":"Q.M.","family":"Zhai","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Ji","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Medical University, Chongqing, China"},{"name":"Chongqing Key Laboratory of Oral Diseases, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-2066","authenticated-orcid":false,"given":"R.D.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,10,12]]},"reference":[{"key":"bibr1-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04475-w"},{"key":"bibr2-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.76"},{"key":"bibr3-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.12.037"},{"key":"bibr4-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2015.11.001"},{"key":"bibr5-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00506-6"},{"key":"bibr6-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.11.006"},{"issue":"4","key":"bibr7-00220345241279555","volume":"10","author":"Cai W","year":"2023","journal-title":"Adv Science (Weinh)"},{"key":"bibr8-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.02.011"},{"key":"bibr9-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.04.017"},{"key":"bibr10-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.01.010"},{"key":"bibr11-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000032490"},{"key":"bibr12-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1111\/jre.12616"},{"key":"bibr13-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2016.12.001"},{"key":"bibr14-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161087"},{"issue":"3","key":"bibr15-00220345241279555","first-page":"162","volume":"14","author":"Guo D","year":"2022","journal-title":"Protein Cell"},{"key":"bibr16-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1177\/00220345211059418"},{"key":"bibr17-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05720-6"},{"key":"bibr18-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3209"},{"key":"bibr19-00220345241279555","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242115989"},{"key":"bibr20-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13078-5"},{"key":"bibr21-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221116031"},{"key":"bibr22-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4897"},{"key":"bibr23-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.02.032"},{"key":"bibr24-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31146-8"},{"key":"bibr25-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.11.012"},{"key":"bibr26-00220345241279555","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.725043"},{"key":"bibr27-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2019.05.002"},{"key":"bibr28-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/nature19353"},{"key":"bibr29-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13962"},{"key":"bibr30-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2363-0"},{"key":"bibr31-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19360-1"},{"key":"bibr32-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1177\/0022034519858063"},{"key":"bibr33-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1101\/gad.191056.112"},{"key":"bibr34-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.02.011"},{"key":"bibr35-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05770-w"},{"key":"bibr36-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4MR0421-750R"},{"key":"bibr37-00220345241279555","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh2548"}],"container-title":["Journal of Dental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00220345241279555","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/00220345241279555","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00220345241279555","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:08:58Z","timestamp":1777496938000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/00220345241279555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,12]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1177\/00220345241279555"],"URL":"https:\/\/doi.org\/10.1177\/00220345241279555","relation":{},"ISSN":["0022-0345","1544-0591"],"issn-type":[{"value":"0022-0345","type":"print"},{"value":"1544-0591","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,12]]}}}