{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:43:17Z","timestamp":1782402197654,"version":"3.54.5"},"reference-count":62,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T00:00:00Z","timestamp":1616198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>External root resorption (ERR) is a silent destructive phenomenon detrimental to dental health. ERR may have multiple etiologies such as infection, inflammation, traumatic injuries, pressure, mechanical stimulations, neoplastic conditions, systemic disorders, or idiopathic causes. Often, if undiagnosed and untreated, ERR can lead to the loss of the tooth or multiple teeth. Traditionally, clinicians have relied on radiographs and cone beam computed tomography (CBCT) images for the diagnosis of ERR; however, these techniques are not often precise or definitive and may require exposure of patients to more ionizing radiation than necessary. To overcome these shortcomings, there is an immense need to develop non-invasive approaches such as biomarker screening methods for rapid and precise diagnosis for ERR. In this review, we performed a literature survey for potential salivary or gingival crevicular fluid (GCF) proteomic biomarkers associated with ERR and analyzed the potential pathways leading to ERR. To the best of our knowledge, this is the first proteomics biomarker survey that connects ERR to body biofluids which represents a novel approach to diagnose and even monitor treatment progress for ERR.<\/jats:p>","DOI":"10.3390\/ijms22063181","type":"journal-article","created":{"date-parts":[[2021,3,21]],"date-time":"2021-03-21T22:00:37Z","timestamp":1616364037000},"page":"3181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Bioinformatics Systems Biology Analysis of the Current Oral Proteomic Biomarkers and Implications for Diagnosis and Treatment of External Root Resorption"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2626-8318","authenticated-orcid":false,"given":"Mahmoud","family":"Mona","sequence":"first","affiliation":[{"name":"Department of Endodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zunnaira","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Department of Endodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5008-6944","authenticated-orcid":false,"given":"Firas","family":"Kobeissy","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman","family":"Chahbandar","sequence":"additional","affiliation":[{"name":"Department of Endodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Pileggi","sequence":"additional","affiliation":[{"name":"Department of Endodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0011-8532(22)02509-5","article-title":"Root resorption","volume":"36","author":"Bakland","year":"1992","journal-title":"Dent. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1590\/S2176-94512013000300004","article-title":"The four mechanisms of dental resorption initiation","volume":"18","author":"Consolaro","year":"2013","journal-title":"Dent. Press J. Orthod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/iej.12450","article-title":"A novel multimodular methodology to investigate external cervical tooth resorption","volume":"49","author":"Mavridou","year":"2016","journal-title":"Int. Endod. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/j.joen.2018.07.020","article-title":"Invasive Cervical Resorption: Clinical Management in the Anterior Zone","volume":"44","author":"Espona","year":"2018","journal-title":"J. Endod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/iej.12824","article-title":"External cervical resorption: A three-dimensional classification","volume":"51","author":"Patel","year":"2018","journal-title":"Int. Endod. J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Patel, S., Kanagasingam, S., and Pitt Ford, T. (2009). External cervical resorption: A review. J. Endod., 616\u2013625.","DOI":"10.1016\/j.joen.2009.01.015"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/cpph.19","article-title":"Biomarkers-A General Review","volume":"76","author":"Aronson","year":"2017","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bonnet, A., Lagarrigue, S., Liaubet, L., Robert-Grani\u00e9, C., Sancristobal, M., and Tosser-Klopp, G. (2009). Pathway results from the chicken data set using GOTM, Pathway Studio and Ingenuity softwares. BMC Proc., 3.","DOI":"10.1186\/1753-6561-3-S4-S11"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1517\/17460440903413488","article-title":"Ariadne\u2019s ChemEffect and Pathway Studio knowledge base","volume":"4","author":"Yuryev","year":"2009","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ajodo.2009.06.021","article-title":"Root resorption associated with orthodontic tooth movement: A systematic review","volume":"137","author":"Weltman","year":"2010","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_11","first-page":"31","article-title":"Root resorption and orthodontic treatment. Review of the literature","volume":"56","author":"Pizzo","year":"2007","journal-title":"Minerva Stomatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s40510-014-0065-6","article-title":"Effect of orthodontic forces on cytokine and receptor levels in gingival crevicular fluid: A systematic review","volume":"15","author":"Kapoor","year":"2014","journal-title":"Prog. Orthod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1177\/154405910608500812","article-title":"RANKL increase in compressed periodontal ligament cells from root resorption","volume":"85","author":"Yamaguchi","year":"2006","journal-title":"J. Dent. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0002-9416(86)90108-9","article-title":"Idiopathic resorption of teeth. A report of three cases","volume":"89","author":"George","year":"1986","journal-title":"Am. J. Orthod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1034\/j.1600-051X.2002.290615.x","article-title":"Cervical external root resorption in vital teeth","volume":"29","author":"Bergmans","year":"2002","journal-title":"J. Clin. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1902\/jop.2015.150536","article-title":"A Familial Pattern of Multiple Idiopathic Cervical Root Resorption With a 30-Year Follow-Up","volume":"87","author":"Neely","year":"2016","journal-title":"J. Periodontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1902\/jop.2007.060155","article-title":"A familial pattern of multiple idiopathic cervical root resorption in a father and son: A 22-year follow-up","volume":"78","author":"Neely","year":"2007","journal-title":"J. Periodontol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/sj.ebd.6400308","article-title":"Multiple idiopathic cervical root resorption most frequently seen in younger females","volume":"6","year":"2005","journal-title":"Evid. Based Dent."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/edt.12316","article-title":"Effect of bisphosphonates on root resorption after tooth replantation\u2014A systematic review","volume":"33","author":"Najeeb","year":"2017","journal-title":"Dent. Traumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.tripleo.2004.11.047","article-title":"A case of multiple idiopathic external root resorption: A 6-year follow-up study","volume":"100","author":"Yamamoto","year":"2005","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.joen.2018.12.012","article-title":"Multiple Cervical Root Resorption in a Young Adult Female Previously Treated with Chemotherapy: A Case Report","volume":"45","author":"Llavayol","year":"2019","journal-title":"J. Endod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1016\/j.joen.2018.06.017","article-title":"Multiple Idiopathic Cervical Root Resorptions in Patients with Hepatitis B Virus Infection","volume":"44","author":"Kumar","year":"2018","journal-title":"J. Endod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"972","DOI":"10.12968\/denu.2015.42.10.972","article-title":"Idiopathic Radiographic Apical Root Resorption in Wind Instrument Players","volume":"42","author":"Shafi","year":"2015","journal-title":"Dent. Update"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.joen.2015.02.014","article-title":"Varicella Zoster Virus and Internal Root Resorption: A Case Report","volume":"41","author":"Talebzadeh","year":"2015","journal-title":"J. Endod."},{"key":"ref_25","first-page":"693240","article-title":"Regional aggressive root resorption caused by neuronal virus infection","volume":"2012","author":"Worsaae","year":"2012","journal-title":"Case. Rep. Dent."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.joen.2009.03.044","article-title":"Human and feline invasive cervical resorptions: The missing link?\u2014Presentation of four cases","volume":"35","author":"Schawalder","year":"2009","journal-title":"J. Endod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/scd.12539","article-title":"Multiple idiopathic cervical root resorption: Case report of an unusual presentation","volume":"41","author":"Samara","year":"2021","journal-title":"Spec. Care Dent."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/aej.12398","article-title":"Multiple idiopathic cervical root resorption involving all permanent teeth","volume":"46","author":"Chen","year":"2020","journal-title":"Aust. Endod. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1365-2591.2010.01820.x","article-title":"Multiple idiopathic cervical resorption: Case report and discussion of management options","volume":"44","author":"Yu","year":"2011","journal-title":"Int. Endod. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.5177\/ntvt.2018.02.17203","article-title":"External cervical root resorption","volume":"125","author":"Warnsinck","year":"2018","journal-title":"Ned. Tijdschr. Tandheelkd."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1590\/2176-9451.19.6.062-069.oar","article-title":"Protein biomarkers of external root resorption: A new protein extraction protocol. Are we going in the right direction?","volume":"19","author":"Vieira","year":"2014","journal-title":"Dent. Press J. Orthod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/j.1601-6343.2009.01457.x","article-title":"Detection of root resorption using dentin and bone markers","volume":"12","author":"George","year":"2009","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cellbi.2009.05.001","article-title":"Tissue-specific expression of dentin sialophosphoprotein (DSPP) and its polymorphisms in mouse tissues","volume":"33","author":"Yuan","year":"2009","journal-title":"Cell Biol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/ejo\/26.1.25","article-title":"Dentine phosphoproteins in gingival crevicular fluid during root resorption","volume":"26","author":"Mah","year":"2004","journal-title":"Eur. J. Orthod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/iej.12001","article-title":"Dentine sialoprotein expression in gingival crevicular fluid during trauma-induced root resorption","volume":"46","author":"Kumar","year":"2013","journal-title":"Int. Endod. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41368-018-0035-9","article-title":"The functional significance of dentin sialoprotein-phosphophoryn and dentin sialoprotein","volume":"10","author":"Ritchie","year":"2018","journal-title":"Int. J. Oral Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Alyahya, L., and Myers, G.L. (2020). Denosumab Use as a Predictor Variable for External Cervical Resorption: A Case-Control Study. J. Endod.","DOI":"10.1016\/j.joen.2020.12.011"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1034\/j.1600-0722.2003.00051.x","article-title":"Expression and role of RANKL in periodontal ligament cells during physiological root-resorption in human deciduous teeth","volume":"111","author":"Fukushima","year":"2003","journal-title":"Eur. J. Oral Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ajodo.2004.03.038","article-title":"Expression of mRNA for osteoprotegerin and receptor activator of nuclear factor kappa beta ligand (RANKL) during root resorption induced by the application of heavy orthodontic forces on rat molars","volume":"128","author":"Low","year":"2005","journal-title":"Am. J. Orthod. Dentofacial. Orthop."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2334\/josnusd.50.367","article-title":"Root resorption and the OPG\/RANKL\/RANK system: A mini review","volume":"50","author":"Tyrovola","year":"2008","journal-title":"J. Oral Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1600-0722.2006.00400.x","article-title":"Interleukin-1alpha and tumor necrosis factor-alpha expression during the early phases of orthodontic tooth movement in rats","volume":"114","author":"Bletsa","year":"2006","journal-title":"Eur. J. Oral Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.bbrc.2012.02.099","article-title":"Mechanical loading prevents the stimulating effect of IL-1\u03b2 on osteocyte-modulated osteoclastogenesis","volume":"420","author":"Kulkarni","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9917","DOI":"10.1074\/jbc.M706415200","article-title":"Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism","volume":"283","author":"Yao","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/ejo\/cjn024","article-title":"Identification of dentine sialoprotein in gingival crevicular fluid during physiological root resorption and orthodontic tooth movement","volume":"30","author":"Kereshanan","year":"2008","journal-title":"Eur. J. Orthod."},{"key":"ref_45","first-page":"132","article-title":"Quantitive evaluation of dentin sialoprotein (DSP) using microbeads\u2014A potential early marker of root resorption","volume":"9","author":"Lombardo","year":"2016","journal-title":"Oral Implantol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1177\/154405910508400114","article-title":"Macrophages and mast cells control the neutrophil migration induced by dentin proteins","volume":"84","author":"Silva","year":"2005","journal-title":"J. Dent. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Atsawasuwan, P., Lazari, P., Chen, Y., Zhou, X., Viana, G., and Evans, C.A. (2018). Secretory microRNA-29 expression in gingival crevicular fluid during orthodontic tooth movement. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194238"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.archoralbio.2006.08.018","article-title":"Biological markers for evaluation of root resorption","volume":"52","author":"Balducci","year":"2007","journal-title":"Arch. Oral Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.kjms.2018.01.007","article-title":"Orthodontic tooth movement: The biology and clinical implications","volume":"34","author":"Li","year":"2018","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/jre.12017","article-title":"Expression profiling of microRNAs in RAW264.7 cells treated with a combination of tumor necrosis factor alpha and RANKL during osteoclast differentiation","volume":"48","author":"Kagiya","year":"2013","journal-title":"J. Periodontal. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tcm.2013.05.002","article-title":"MicroRNA-29b regulation of abdominal aortic aneurysm development","volume":"24","author":"Maegdefessel","year":"2014","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.archoralbio.2011.11.010","article-title":"Long term effect of low intensity pulsed ultrasound on a human tooth slice organ culture","volume":"57","author":"Doschak","year":"2012","journal-title":"Arch. Oral Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s00441-012-1418-4","article-title":"Immunohistochemical localization of the NH(2)-terminal and COOH-terminal fragments of dentin sialoprotein in mouse teeth","volume":"349","author":"Yuan","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.archoralbio.2013.02.014","article-title":"Nanohydroxyapatite increases BMP-2 expression via a p38 MAP kinase dependent pathway in periodontal ligament cells","volume":"58","author":"Suto","year":"2013","journal-title":"Arch. Oral Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0003-9969(03)00173-0","article-title":"Immunocompetent cells in the pulp of human deciduous teeth","volume":"49","author":"Angelova","year":"2004","journal-title":"Arch. Oral Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1177\/0022034508329451","article-title":"In vivo application of amelogenin suppresses root resorption","volume":"88","author":"Yagi","year":"2009","journal-title":"J. Dent. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1600-9657.2011.01070.x","article-title":"Effect of platelet-derived grwth factor-BB on root resorption after reimplantation of partially denuded tooth in dog","volume":"28","author":"Noda","year":"2012","journal-title":"Dent. Traumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3109\/00016357.2012.680906","article-title":"Effect of basic fibroblast growth factor (FGF-2) in combination with beta tricalcium phosphate on root coverage in dog","volume":"71","author":"Ishii","year":"2013","journal-title":"Acta. Odontol. Scand."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1016\/j.oooo.2011.09.012","article-title":"Effect of basic fibroblast growth factor on root resorption after delayed autotransplantation of tooth in dogs","volume":"114","author":"Shiratani","year":"2012","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_60","unstructured":"Hargreaves, K., Cohen, S., and Berman, L. (2011). Cohen\u2019s Pathways of the Pulp, Mosby Elsevier."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4103\/JCD.JCD_445_18","article-title":"Multiple idiopathic cervical root resorption: Diagnosis, clinical\/radiographical\/histological presentation, and rehabilitation\u2014A 7-year follow-up case report","volume":"22","author":"Sharma","year":"2019","journal-title":"J. Conserv. Dent."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/iej.12440","article-title":"Multiple idiopathic cervical root resorption: A case report","volume":"49","author":"Wu","year":"2016","journal-title":"Int. Endod. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/3181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:38:37Z","timestamp":1760161117000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/3181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,20]]},"references-count":62,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22063181"],"URL":"https:\/\/doi.org\/10.3390\/ijms22063181","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,20]]}}}