{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:36:38Z","timestamp":1780623398679,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research (KAKENHI)","award":["20K18750"],"award-info":[{"award-number":["20K18750"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI)","award":["21BA100275"],"award-info":[{"award-number":["21BA100275"]}]},{"name":"AnGes, Inc. and Hosokawa Micron Corporation","award":["20K18750"],"award-info":[{"award-number":["20K18750"]}]},{"name":"AnGes, Inc. and Hosokawa Micron Corporation","award":["21BA100275"],"award-info":[{"award-number":["21BA100275"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-\u03baB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following the bilateral extraction of maxillary first molars in a controlled experiment involving forty rats of OTM model with ethics approved. The decreased tendency of the OTM distance and inclination angle with increased bone volume and improved trabecular bone structure indicated minimized alveolar bone destruction. Reverse transcription-quantitative polymerase chain reaction and histomorphometric analysis demonstrated the suppression of inflammation and bone resorption by downregulating the expression of tartrate-resistant acid phosphatase, tumor necrosis factor-\u03b1, interleukin-1\u03b2, cathepsin K, NF-\u03baB p65, and receptor activator of NF-\u03baB ligand while provoking periodontal regeneration by upregulating the expression of alkaline phosphatase, transforming growth factor-\u03b21, osteopontin, and fibroblast growth factor-2. Importantly, relative gene expression over the maxillary second molar compression side in proximity to the alveolus highlighted the pharmacological effect of intra-socket PLGA-NfD administration, as evidenced by elevated osteocalcin expression, indicative of enhanced osteocytogenesis. These findings emphasize that locally administered PLGA-NfD serves as an effective inflammatory suppressor and yields periodontal regenerative responses following tooth extraction.<\/jats:p>","DOI":"10.3390\/ijms25105223","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:03:08Z","timestamp":1715673788000},"page":"5223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NF-\u03baB Decoy Oligodeoxynucleotide-Loaded Poly Lactic-co-glycolic Acid Nanospheres Facilitate Socket Healing in Orthodontic Tooth Movement"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4710-032X","authenticated-orcid":false,"given":"Albert chun-shuo","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4973-8762","authenticated-orcid":false,"given":"Yuji","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasumi","family":"Hatano-sato","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Oishi","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hosomichi","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Usumi-fujita","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3754-6723","authenticated-orcid":false,"given":"Hiroyuki","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-3914","authenticated-orcid":false,"given":"Hiroyuki","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Pharmaceutical\/Beauty Science Research Center, Material Business Division, Hosokawa Micron Corporation, Osaka 573-1132, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiko","family":"Sasai","sequence":"additional","affiliation":[{"name":"Pharmaceutical\/Beauty Science Research Center, Material Business Division, Hosokawa Micron Corporation, Osaka 573-1132, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Ochi","sequence":"additional","affiliation":[{"name":"Pharmaceutical\/Beauty Science Research Center, Material Business Division, Hosokawa Micron Corporation, Osaka 573-1132, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8043-660X","authenticated-orcid":false,"given":"Takashi","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1100\/2011\/761768","article-title":"Cellular and molecular changes in orthodontic tooth movement","volume":"11","author":"Ariffin","year":"2011","journal-title":"Sci. World J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tsai, M.H., Megat Abdul Wahab, R., and Yazid, F. (2021). Timing of orthodontic tooth movement in bone defects repaired with synthetic scaffolds: A scoping review of animal studies. Arch. Oral Biol., 132.","DOI":"10.1016\/j.archoralbio.2021.105278"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.2319\/062017-407","article-title":"Effects of bone regeneration materials and tooth movement timing on canine experimental orthodontic treatment","volume":"88","author":"Machibya","year":"2018","journal-title":"Angle Orthod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.ajodo.2015.09.027","article-title":"BoneCeramic graft regenerates alveolar defects but slows orthodontic tooth movement with less root resorption","volume":"149","author":"Ru","year":"2016","journal-title":"Am. J. Orthod. Dentofacial Orthop."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/JPER.17-0550","article-title":"Bone regeneration with bovine bone impairs orthodontic tooth movement despite proper osseous wound healing in a novel mouse model","volume":"90","author":"Klein","year":"2019","journal-title":"J. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1002\/JPER.19-0145","article-title":"The impact of alloplast and allograft on bone homeostasis: Orthodontic tooth movement into regenerated bone","volume":"91","author":"Klein","year":"2020","journal-title":"J. Periodontol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1111\/j.1600-051X.2005.00726.x","article-title":"Ridge alterations following implant placement in fresh extraction sockets: An experimental study in the dog","volume":"32","author":"Sukekava","year":"2005","journal-title":"J. Clin. Periodontol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1111\/jcpe.13528","article-title":"The effect of timing of orthodontic therapy on the outcomes of regenerative periodontal surgery in patients with stage IV periodontitis: A multicenter randomized trial","volume":"48","author":"Jepsen","year":"2021","journal-title":"J. Clin. Periodontol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1016\/j.jfma.2022.02.021","article-title":"Orthodontic treatment of periodontally compromised teeth after periodontal regeneration: A restrospective study","volume":"121","author":"Tu","year":"2022","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"419","DOI":"10.2174\/1389450043345416","article-title":"New trends in the development of transcription factor decoy (TFD) pharmacotherapy","volume":"5","author":"Gambari","year":"2004","journal-title":"Curr. Drug Targets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3389\/fphys.2017.00067","article-title":"The potential use of pharmacological agents to modulate orthodontic tooth movement (OTM)","volume":"8","author":"Kouskoura","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41368-021-00125-5","article-title":"Biomechanical and biological responses of periodontium in orthodontic tooth movement: Up-date in a new decade","volume":"13","author":"Li","year":"2021","journal-title":"Int. J. Oral Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1177\/1087057115617456","article-title":"Modulation of NF-\u03baB signaling as a therapeutic target in autoimmunity","volume":"21","author":"Herrington","year":"2016","journal-title":"J. Biomol. Screen."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/sj.gt.3302711","article-title":"NF-\u03baB decoy oligodeoxynucleotides ameliorates osteoporosis through inhibition of activation and differentiation of osteoclasts","volume":"13","author":"Shimizu","year":"2006","journal-title":"Gene Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1093\/rheumatology\/39.7.749","article-title":"Transcription factor decoy for NF-kB inhibits cytokine and adhesion molecule expressions in synovial cells derived from rheumatoid arthritis","volume":"39","author":"Tomita","year":"2000","journal-title":"Rheumatology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Huang, A.C.S., Ishida, Y., Li, K., Rintanalert, D., Hatano-Sato, K., Oishi, S., Hosomichi, J., Usumi-Fujita, R., Yamaguchi, H., and Tsujimoto, H. (2023). NF-\u03baB decoy ODN-loaded poly(lactic-co-glycolic acid) nanospheres inhibit alveolar ridge resorption. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043699"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/jgm.724","article-title":"Enhanced intracellular uptake and inhibition of NF-\u03baB activation by decoy oligonucleotide released from PLGA microspheres","volume":"7","author":"Maiuri","year":"2005","journal-title":"J. Gene Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.phrs.2009.03.012","article-title":"Oligonucleotide decoy to NF-\u03baB slowly released from PLGA microspheres reduces chronic inflammation in rat","volume":"60","author":"Maiuri","year":"2009","journal-title":"Pharmacol. Res."},{"key":"ref_20","first-page":"306","article-title":"Orthodontic extraction space closure with and without socket preservation: A comparative case analysis","volume":"50","author":"Zere","year":"2019","journal-title":"Quintessence Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"302.e10","DOI":"10.1016\/j.ajodo.2006.07.020","article-title":"Orthodontic movement in bone defects filled with xenogenic graft: An experimental study in minipigs","volume":"131","author":"Oltramari","year":"2007","journal-title":"Am. J. Orthod. Dentofacial Orthop."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.ajodo.2013.12.021","article-title":"Timing of force application affects the rate of tooth movement into surgical alveolar defects with grafts in beagles","volume":"145","author":"Ahn","year":"2014","journal-title":"Am. J. Orthod. Dentofacial Orthop."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1902\/jop.2004.75.2.316","article-title":"Combined bone grafting and orthodontic treatment of an iatrogenic periodontal defect: A case report with clinical reentry","volume":"75","author":"Naaman","year":"2004","journal-title":"J. Periodontol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1177\/154405910708600613","article-title":"Nuclear factor \u03baB p65 phosphorylation in orthodontic tooth movement","volume":"86","author":"Zuo","year":"2007","journal-title":"J. Dent. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1089\/ten.tea.2014.0144","article-title":"NF-\u03baB decoy oligodeoxynucleotide enhanced osteogenesis in mesenchymal stem cells exposed to polyethylene particle","volume":"21","author":"Lin","year":"2015","journal-title":"Tissue Eng. Part A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1002\/jbm.a.36169","article-title":"Orthopaedic wear particle-induced bone loss and exogenous macrophage infiltration is mitigated by local infusion of NF-\u03baB decoy oligodeoxynucleotide","volume":"105","author":"Lin","year":"2017","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1002\/jbm.a.37175","article-title":"Suppression of NF-\u03baB-induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model","volume":"109","author":"Utsunomiya","year":"2021","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2147\/JIR.S140188","article-title":"Mechanisms of NF-\u03baB p65 and strategies for therapeutic manipulation","volume":"11","author":"Giridharan","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.4049\/jimmunol.167.5.2911","article-title":"Methotrexate suppresses NF-\u03baB activation through inhibition of I\u03baB\u03b1 phosphorylation and degradation","volume":"167","author":"Majumdar","year":"2001","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6490","DOI":"10.4049\/jimmunol.169.11.6490","article-title":"Piceatannol inhibits TNF-induced NF-\u03baB activation and NF-\u03baB-mediated gene expression through suppression of I\u03baB\u03b1 kinase and p65 phosphorylation","volume":"169","author":"Ashikawa","year":"2002","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1055\/s-0038-1672075","article-title":"NSAIDs (non-steroidal anti-inflammatory drugs)-their effects and side effects in orthodontic therapy\u2014A review","volume":"5","author":"Gargya","year":"2017","journal-title":"Dent. J. Adv. Stud."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.coph.2003.10.008","article-title":"Molecular therapy to inhibit NF-\u03baB activation by transcription factor decoy oligonucleotides","volume":"4","author":"Morishita","year":"2004","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/ejo\/cjl001","article-title":"The tissue, cellular, and molecular regulation of orthodontic tooth movement: 100 years after Carl Sandstedt","volume":"28","author":"Meikle","year":"2006","journal-title":"Eur. J. Orthod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1053\/j.sodo.2008.07.006","article-title":"Thinking beyond the wire: Emerging biologic relationships in orthodontics and periodontology","volume":"14","author":"Masella","year":"2008","journal-title":"Semin. Orthod."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Krishnan, V., and Davidovich, Z. (2015). Biological Mechanisms of Tooth Movement, John Wiley & Sons, Ltd.","DOI":"10.1002\/9781118916148"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1016\/j.actbio.2014.04.034","article-title":"Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-\u03baB decoy oligodeoxynucleotide: A preliminary report","volume":"10","author":"Lin","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.archoralbio.2018.08.003","article-title":"Expression of biological mediators during orthodontic tooth movement: A systematic review","volume":"95","author":"Vansant","year":"2018","journal-title":"Arch. Oral Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jeon, H.H., Teixeira, H., and Tsai, A. (2021). Mechanistic insight into orthodontic tooth movement based on animal studies: A critical review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10081733"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.sjbs.2018.03.008","article-title":"Biological aspects of orthodontic tooth movement: A review of literature","volume":"25","author":"Asiry","year":"2018","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8172","DOI":"10.1038\/s41598-020-65089-8","article-title":"Immunorthodontics: In vivo gene expression of orthodontic tooth movement","volume":"10","author":"Klein","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1177\/0022034520911647","article-title":"Bovine bone promotes osseous protection via osteoclast activation","volume":"99","author":"Klein","year":"2020","journal-title":"J. Dent. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1002\/JPER.23-0081","article-title":"Long-term stability of regenerative periodontal surgery and orthodontic tooth movement in stage IV periodontitis: 10-year data of a retrospective study","volume":"94","author":"Tietmann","year":"2023","journal-title":"J. Periodontol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Dieterle, M.P., Husari, A., Steinberg, T., Wang, X., Ramminger, I., and Tomakidi, P. (2021). From the matrix to the nucleus and back: Mechanobiology in the light of health, pathologies, and regeneration of oral periodontal tissues. Biomolecules, 11.","DOI":"10.3390\/biom11060824"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Koh, J., Zaffagnini, S., Kuroda, R., Longo, U.G., and Amirouche, F. (2021). Orthopaedic Biomechanics in Sports Medicine, Springer International Publishing.","DOI":"10.1007\/978-3-030-81549-3"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, J., Dai, Q., Weir, M.D., Schneider, A., Zhang, C., Hack, G.D., Oates, T.W., Zhang, K., Li, A., and Xu, H.H.K. (2020). Biocompatible nanocomposite enhanced osteogenic and cementogenic differentiation of periodontal ligament stem cells in vitro for periodontal regeneration. Materials, 13.","DOI":"10.3390\/ma13214951"},{"key":"ref_46","first-page":"277","article-title":"Increasing the amount of corticotomy does not affect orthodontic tooth movement or root resorption, but accelerates alveolar bone resorption in rats","volume":"39","author":"Kurohama","year":"2017","journal-title":"Eur. J. Orthod."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1046\/j.1365-2818.1997.1340694.x","article-title":"A new method for the model-independent assessment of thickness in three-dimensional images","volume":"185","author":"Hildebrand","year":"1997","journal-title":"J. Microsc."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Carter, L.E., Kilroy, G., Gimble, J.M., and Floyd, Z.E. (2012). An improved method for isolation of RNA from bone. BMC Biotechnol., 12.","DOI":"10.1186\/1472-6750-12-5"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5223\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:57Z","timestamp":1760107437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25105223"],"URL":"https:\/\/doi.org\/10.3390\/ijms25105223","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]}}}