{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T06:19:21Z","timestamp":1762064361670,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771053","82001029","81772873","81970920"],"award-info":[{"award-number":["81771053","82001029","81772873","81970920"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation mediated by long non-coding (lnc)RNAs in CCD remain to be elucidated. Here, a novel osteoclast-specific lncRNA (OC-lncRNA) was identified during the osteoclast differentiation of RAW 264.7 cells transfected with a RUNX2 mutation expression cassette. We further confirmed that OC-lncRNA positively regulated osteoclastogenesis and bone resorption. The OC-lncRNA promoted the expression of CXC chemokine receptor type 3 (CXCR3) by competitively binding to microRNA (miR)-221-5p. The CXCR3\u2013CXC-motif chemokine ligand 10 (CXCL10) interaction and nuclear factor-\u03baB constituted a positive feedback that positively regulated osteoclastogenesis and bone resorption. These results demonstrate that OC-lncRNA-mediated osteoclast dysfunction via the OC-lncRNA\u2013miR-221-5p\u2013CXCR3 axis, which is involved in the process of delayed tooth eruption of CCD.<\/jats:p>","DOI":"10.3390\/cells11172729","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T21:27:17Z","timestamp":1662067637000},"page":"2729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel lncRNA Mediates the Delayed Tooth Eruption of Cleidocranial Dysplasia"],"prefix":"10.3390","volume":"11","author":[{"given":"Yuejiao","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"},{"name":"Department of Periodontics, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5291-9826","authenticated-orcid":false,"given":"Yixiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuguo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology and National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1259\/dmfr\/63490079","article-title":"Dentomaxillofacial variability of cleidocranial dysplasia: Clinicoradiological presentation and systematic review","volume":"32","author":"Golan","year":"2003","journal-title":"Dentomaxillofac. Radiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6591414","DOI":"10.1155\/2018\/6591414","article-title":"Delayed Eruption of Permanent Dentition and Maxillary Contraction in Patients with Cleidocranial Dysplasia: Review and Report of a Family","volume":"2018","author":"Impellizzeri","year":"2018","journal-title":"Int. J. Dent."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/mutage\/geq044","article-title":"Mutational analysis of RUNX2 gene in Chinese patients with cleidocranial dysplasia","volume":"25","author":"Zhang","year":"2010","journal-title":"Mutagenesis"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, X., Liu, Y., Wang, X., Sun, X., Zhang, C., and Zheng, S. (2017). Analysis of novel RUNX2 mutations in Chinese patients with cleidocranial dysplasia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181653"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1177\/154411130201300403","article-title":"Cellular, molecular, and genetic determinants of tooth eruption","volume":"13","author":"Wise","year":"2002","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0003-9969(84)90105-5","article-title":"Experimental study in the dog of the non-active role of the tooth in the eruptive process","volume":"29","author":"Marks","year":"1984","journal-title":"Arch. Oral Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/ocr.12000","article-title":"Tooth eruption: Altered gene expression in the dental follicle of patients with cleidocranial dysplasia","volume":"16","author":"Dorotheou","year":"2013","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.coms.2007.08.001","article-title":"Genetic disorders and bone affecting the craniofacial skeleton","volume":"19","author":"Chacon","year":"2007","journal-title":"Oral Maxillofac. Surg. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s00223-020-00666-7","article-title":"New Function of RUNX2 in Regulating Osteoclast Differentiation via the AKT\/NFATc1\/CTSK Axis","volume":"106","author":"Xin","year":"2020","journal-title":"Calcif. Tissue Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1073\/pnas.97.4.1566","article-title":"RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism","volume":"97","author":"Li","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S8756-3282(99)00278-1","article-title":"The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc\/oc) mutants","volume":"26","author":"Scimeca","year":"2000","journal-title":"Bone"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.archoralbio.2004.01.010","article-title":"Delayed tooth eruption and suppressed osteoclast number in the eruption pathway of heterozygous Runx2\/Cbfa1 knockout mice","volume":"49","author":"Yoda","year":"2004","journal-title":"Arch. Oral Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1601-6343.2009.01438.x","article-title":"Mechanism and control of tooth eruption: Overview and clinical implications","volume":"12","author":"Proffit","year":"2009","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_14","first-page":"211","article-title":"Genetic analysis of Runx2 function during intramembranous ossification","volume":"143","author":"Takarada","year":"2016","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00441-009-0832-8","article-title":"Regulation of bone development and extracellular matrix protein genes by RUNX2","volume":"339","author":"Komori","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E1587","DOI":"10.1002\/humu.21298","article-title":"Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia","volume":"31","author":"Ott","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1177\/00220345000790120301","article-title":"Osteoprotegerin and osteoclast differentiation factor in tooth eruption","volume":"79","author":"Wise","year":"2000","journal-title":"J. Dent. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23971","DOI":"10.1074\/jbc.M302457200","article-title":"Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-\/- mice by RANKL transgene","volume":"278","author":"Enomoto","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/j.1600-0722.2006.00406.x","article-title":"Regional differences of expression of bone morphogenetic protein-2 and RANKL in the rat dental follicle","volume":"114","author":"Wise","year":"2006","journal-title":"Eur. J. Oral Sci."},{"key":"ref_20","first-page":"177","article-title":"Cleidocranial dysplasia: Clinical and molecular genetics","volume":"36","author":"Mundlos","year":"1999","journal-title":"J. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1093\/nar\/gkt006","article-title":"CPAT: Coding-Potential Assessment Tool using an alignment-free logistic regression model","volume":"41","author":"Wang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-1-4939-1369-5_3","article-title":"A biochemical approach to identify direct microRNA targets","volume":"1206","author":"Subramanian","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1359\/JBMR.041213","article-title":"Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1","volume":"20","author":"Takatsuna","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e295","DOI":"10.1038\/emm.2016.148","article-title":"NF-kappaB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells","volume":"49","author":"Jin","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1177\/154405910808700509","article-title":"Mechanisms of tooth eruption and orthodontic tooth movement","volume":"87","author":"Wise","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/ar.1091640105","article-title":"Eruption pathway formation in the presence of experimental tooth impaction in puppies","volume":"164","author":"Cahill","year":"1969","journal-title":"Anat. Rec."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115507","DOI":"10.1016\/j.bone.2020.115507","article-title":"Epigenetic and transcriptional regulation of osteoclastogenesis in the pathogenesis of skeletal diseases: A systematic review","volume":"138","author":"Sharma","year":"2020","journal-title":"Bone"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.cell.2011.03.014","article-title":"No-nonsense functions for long noncoding RNAs","volume":"145","author":"Nagano","year":"2011","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1007\/s00335-008-9136-7","article-title":"Noncoding RNA in development","volume":"19","author":"Amaral","year":"2008","journal-title":"Mamm. Genome"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9786","DOI":"10.1111\/jcmm.15560","article-title":"LncRNA-mRNA expression profiles and functional networks in osteoclast differentiation","volume":"24","author":"Liu","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21499","DOI":"10.1038\/srep21499","article-title":"Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis","volume":"6","author":"Dou","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature12986","article-title":"The multilayered complexity of ceRNA crosstalk and competition","volume":"505","author":"Tay","year":"2014","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3843","DOI":"10.1111\/jcmm.14228","article-title":"EPC-derived exosomes promote osteoclastogenesis through LncRNA-MALAT1","volume":"23","author":"Cui","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_34","first-page":"10195","article-title":"Long noncoding RNA MIRG induces osteoclastogenesis and bone resorption in osteoporosis through negative regulation of miR-1897","volume":"23","author":"Ling","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/j.1749-6632.2009.04813.x","article-title":"CXCR3, inflammation, and autoimmune diseases","volume":"1173","author":"Lacotte","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6051","DOI":"10.1158\/1078-0432.CCR-20-1359","article-title":"CXCR3 and Cognate Ligands are Associated with Immune Cell Alteration and Aggressiveness of Pancreatic Ductal Adenocarcinoma","volume":"26","author":"Cannon","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.chom.2020.05.002","article-title":"During Aspergillus Infection, Monocyte-Derived DCs, Neutrophils, and Plasmacytoid DCs Enhance Innate Immune Defense through CXCR3-Dependent Crosstalk","volume":"28","author":"Guo","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.1038\/s41467-019-12980-2","article-title":"CXCR3 enables recruitment and site-specific bystander activation of memory CD8(+) T cells","volume":"10","author":"Maurice","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1002\/art.23372","article-title":"Reciprocal cross-talk between RANKL and interferon-gamma-inducible protein 10 is responsible for bone-erosive experimental arthritis","volume":"58","author":"Kwak","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1158\/0008-5472.CAN-12-0481","article-title":"CXCL10 promotes osteolytic bone metastasis by enhancing cancer outgrowth and osteoclastogenesis","volume":"72","author":"Lee","year":"2012","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","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":"ref_42","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1172\/JCI10530","article-title":"IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB","volume":"107","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2018.01.037","article-title":"JN-2, a C-X-C motif chemokine receptor 3 antagonist, ameliorates arthritis progression in an animal model","volume":"823","author":"Kim","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"697837","DOI":"10.1155\/2014\/697837","article-title":"Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity","volume":"2014","author":"Zhang","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"30731","DOI":"10.1074\/jbc.M110.128124","article-title":"TNFalpha-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines","volume":"285","author":"Shin","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3936257","DOI":"10.1155\/2018\/3936257","article-title":"FNDC4 Inhibits RANKL-Induced Osteoclast Formation by Suppressing NF-kappaB Activation and CXCL10 Expression","volume":"2018","author":"Lv","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s13075-017-1353-6","article-title":"Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: Relevance for arthritis","volume":"19","author":"Lee","year":"2017","journal-title":"Arthritis Res. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/17\/2729\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:22:00Z","timestamp":1760142120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/17\/2729"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,1]]},"references-count":47,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cells11172729"],"URL":"https:\/\/doi.org\/10.3390\/cells11172729","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2022,9,1]]}}}