{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:25:37Z","timestamp":1790270737884,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"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","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    The limited regenerative potential of periodontal tissue remains a challenge in orthodontic treatment, especially with respect to alveolar bone remodeling. The dynamic balance between the bone formation of osteoblasts and the bone resorption of osteoclasts controls bone homeostasis. The osteogenic effect of low-intensity pulsed ultrasound (LIPUS) is widely accepted, so LIPUS is expected to be a promising method for alveolar bone regeneration. Osteogenesis is regulated by the acoustic mechanical effect of LIPUS, while the cellular perception, transduction mode and response regulation mechanism of LIPUS stimuli are still unclear. This study aimed to explore the effects of LIPUS on osteogenesis by osteoblast-osteoclast crosstalk and the underlying regulation mechanism.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    The effects of LIPUS on orthodontic tooth movement (OTM) and alveolar bone remodeling were investigated via rat model by histomorphological analysis. Mouse bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs) were purified and used as BMSC-derived osteoblasts and BMM-derived osteoclasts, respectively. The osteoblast-osteoclast co-culture system was used to evaluate the effect of LIPUS on cell differentiation and intercellular crosstalk by Alkaline phosphatase (ALP), Alizarin Red S (ARS), tartrate-resistant acid phosphatase (TRAP) staining, real-time quantitative PCR, western blotting and immunofluorescence.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    LIPUS was found to improve OTM and alveolar bone remodeling\n                    <jats:italic>in vivo<\/jats:italic>\n                    , promote differentiation and EphB4 expression in BMSC-derived osteoblasts\n                    <jats:italic>in vitro<\/jats:italic>\n                    , particularly when cells were directly co-cultured with BMM-derived osteoclasts. LIPUS enhanced EphrinB2\/EphB4 interaction between osteoblasts and osteoclasts in alveolar bone, activated the EphB4 receptor on osteoblasts membrane, transduced LIPUS-related mechanical signals to the intracellular cytoskeleton, and gave rise to the nuclear translocation of YAP in Hippo signaling pathway, thus regulating cell migration and osteogenic differentiation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    This study shows that LIPUS modulates bone homeostasis by osteoblast-osteoclast crosstalk via EphrinB2\/EphB4 signaling, which benefits the balance between OTM and alveolar bone remodeling.\n                  <\/jats:p>","DOI":"10.3389\/fbioe.2023.1192720","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T11:18:29Z","timestamp":1687605509000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":34,"title":["Low-intensity pulsed ultrasound regulates osteoblast-osteoclast crosstalk via EphrinB2\/EphB4 signaling for orthodontic alveolar bone remodeling"],"prefix":"10.3389","volume":"11","author":[{"given":"Jie","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjiao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiru","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s40510-018-0208-2","article-title":"Effect of low level laser and low intensity pulsed ultrasound therapy on bone remodeling during orthodontic tooth movement in rats","volume":"19","author":"Alazzawi","year":"2018","journal-title":"Prog. Orthod."},{"key":"B2","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1111\/prd.12194","article-title":"Effect of orthodontic treatment on the periodontal tissues","volume":"74","author":"Antoun","year":"2017","journal-title":"Periodontol. 2000"},{"key":"B3","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.ajodo.2019.01.027","article-title":"Low-intensity pulsed ultrasound enhances the rate of lateral tooth movement and compensatory bone formation in rats","volume":"157","author":"Arai","year":"2020","journal-title":"Am. J. Orthod. Dentofac. Orthop. official Publ. Am. Assoc. Orthod. its Const. Soc. Am. Board Orthod."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0076-3","article-title":"Claudin 11 regulates bone homeostasis via bidirectional EphB4-EphrinB2 signaling","volume":"50","author":"Baek","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.actbio.2020.03.043","article-title":"Co-culture systems of osteoblasts and osteoclasts: Simulating in vitro bone remodeling in regenerative approaches","volume":"108","author":"Borciani","year":"2020","journal-title":"Acta biomater."},{"key":"B6","doi-asserted-by":"publisher","first-page":"932","DOI":"10.3390\/biom11070932","article-title":"In vitro compression model for orthodontic tooth movement modulates human periodontal ligament fibroblast proliferation, apoptosis and cell cycle","volume":"11","author":"Brockhaus","year":"2021","journal-title":"Biomolecules"},{"key":"B7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1111\/jcpe.12505","article-title":"Effects of facial tooth movement on the periodontium in rats: A comparison between conventional and low force","volume":"43","author":"Danz","year":"2016","journal-title":"J. Clin. periodontology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.jphotobiol.2016.02.037","article-title":"Efficiency of low-level laser therapy within induced dental movement: A systematic review and meta-analysis","volume":"158","author":"de Almeida","year":"2016","journal-title":"J. Photochem. Photobiol. B, Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"7792","DOI":"10.1002\/jcp.30388","article-title":"Roles and mechanisms of YAP\/TAZ in orthodontic tooth movement","volume":"236","author":"Deng","year":"2021","journal-title":"J. Cell. physiology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"37651","DOI":"10.1074\/jbc.M110.166900","article-title":"Strain-dependent up-regulation of ephrin-B2 protein in periodontal ligament fibroblasts contributes to osteogenesis during tooth movement","volume":"286","author":"Diercke","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1177\/00220345211007855","article-title":"Role of mechanotransduction in periodontal homeostasis and disease","volume":"100","author":"Dieterle","year":"2021","journal-title":"J. Dent. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"151699","DOI":"10.1016\/j.aanat.2021.151699","article-title":"Analysis of alveolar ridge width in an area of central lower incisor using cone-beam computed tomography in vivo","volume":"236","author":"Dominiak","year":"2021","journal-title":"Ann. Anat. = Anatomischer Anzeiger official organ Anatomische Gesellschaft"},{"key":"B13","doi-asserted-by":"publisher","first-page":"804","DOI":"10.3390\/jcm9030804","article-title":"Effect of low intensity pulsed ultrasound (LIPUS) on tooth movement and root resorption: A prospective multi-center randomized controlled trial","volume":"9","author":"El-Bialy","year":"2020","journal-title":"J. Clin. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.archoralbio.2016.06.007","article-title":"Effect of low-intensity pulsed ultrasound on the activity of osteoclasts: An in vitro study","volume":"70","author":"Feres","year":"2016","journal-title":"Archives oral Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"803","DOI":"10.3390\/biology10080803","article-title":"The significance of utilizing A corticotomy on periodontal and orthodontic outcomes: A systematic review and meta-analysis","volume":"10","author":"Gao","year":"2021","journal-title":"Biology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/1404915","article-title":"The recombinant protein EphB4-fc changes the Ti particle-mediated imbalance of OPG\/RANKL via EphrinB2\/EphB4 signaling pathway and inhibits the release of proinflammatory factors in vivo","volume":"2020","author":"Ge","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/prd.12368","article-title":"Maintaining homeostatic control of periodontal bone tissue","volume":"86","author":"Hathaway-Schrader","year":"2021","journal-title":"Periodontology 2000"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s10103-021-03352-8","article-title":"Effects of photobiomodulation on bone remodeling in an osteoblast-osteoclast co-culture system","volume":"37","author":"Hong","year":"2022","journal-title":"Lasers Med. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1177\/0022034515626102","article-title":"Mechanoresponsive properties of the periodontal ligament","volume":"95","author":"Huang","year":"2016","journal-title":"J. Dent. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1093\/ejo\/cjx012","article-title":"Orthodontic strain affects the Hippo-pathway effector YAP concomitant with proliferation in human periodontal ligament fibroblasts","volume":"39","author":"Huelter-Hassler","year":"2017","journal-title":"Eur. J. Orthod."},{"key":"B21","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.ultrasmedbio.2015.10.022","article-title":"High-frequency, low-intensity pulsed ultrasound enhances alveolar bone healing of extraction sockets in rats: A pilot study","volume":"42","author":"Kang","year":"2016","journal-title":"Ultrasound Med. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.3390\/jcm9051303","article-title":"Shortening of overall orthodontic treatment duration with low-intensity pulsed ultrasound (LIPUS)","volume":"9","author":"Kaur","year":"2020","journal-title":"J. Clin. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.3390\/cells9092073","article-title":"Osteoblast-osteoclast communication and bone homeostasis","volume":"9","author":"Kim","year":"2020","journal-title":"Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1016\/j.arthro.2021.02.019","article-title":"Low-intensity pulsed ultrasound augments tendon, ligament, and bone-soft tissue healing in preclinical animal models: A systematic review","volume":"37","author":"Lai","year":"2021","journal-title":"Arthrosc. J. Arthrosc. Relat. Surg. official Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc."},{"key":"B25","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1177\/0022034514566431","article-title":"Erythropoietin promotes bone formation through EphrinB2\/EphB4 signaling","volume":"94","author":"Li","year":"2015","journal-title":"J. Dent. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1186\/s13287-020-01732-5","article-title":"Low-intensity pulsed ultrasound upregulates osteogenesis under inflammatory conditions in periodontal ligament stem cells through unfolded protein response","volume":"11","author":"Li","year":"2020","journal-title":"Stem Cell. Res. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1111\/odi.13875","article-title":"Lipopolysaccharides affect compressed periodontal ligament cells via Eph-ephrin signaling","volume":"28","author":"Li","year":"2021","journal-title":"Oral Dis."},{"key":"B28","doi-asserted-by":"publisher","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":"B29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1089\/ten.TEB.2020.0212","article-title":"Bone graft materials for alveolar bone defects in orthodontic tooth movement","volume":"28","author":"Lu","year":"2022","journal-title":"Reviews"},{"key":"B30","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/bmb\/ldr006","article-title":"The evidence of low-intensity pulsed ultrasound for in vitro, animal and human fracture healing","volume":"100","author":"Martinez de Albornoz","year":"2011","journal-title":"Br. Med. Bull."},{"key":"B31","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1093\/ejo\/cjt066","article-title":"A preliminary study of the effects of low-intensity pulsed ultrasound exposure on the stability of orthodontic miniscrews in growing rats","volume":"36","author":"Miura","year":"2014","journal-title":"Eur. J. Orthod."},{"key":"B32","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1083\/jcb.201604097","article-title":"Unidirectional Eph\/ephrin signaling creates a cortical actomyosin differential to drive cell segregation","volume":"215","author":"O'Neill","year":"2016","journal-title":"J. Cell. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s10544-017-0229-5","article-title":"Characterisation of human induced pluripotent stem cell-derived endothelial cells under shear stress using an easy-to-use microfluidic cell culture system","volume":"19","author":"Ohtani-Kaneko","year":"2017","journal-title":"Biomed. microdevices"},{"key":"B34","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/nrendo.2016.71","article-title":"Osteocytic signalling pathways as therapeutic targets for bone fragility","volume":"12","author":"Plotkin","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1177\/0022034514567197","article-title":"Compression induces Ephrin-A2 in PDL fibroblasts via c-fos","volume":"94","author":"Sen","year":"2015","journal-title":"J. Dent. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00056-019-00196-4","article-title":"Dehiscence and fenestration in anterior teeth: Comparison before and after orthodontic treatment","volume":"81","author":"Sheng","year":"2020","journal-title":"J. Orofac. Orthop. = Fortschritte der Kieferorthopadie Organ\/official J. Deutsche Gesellschaft fur Kieferorthopadie."},{"key":"B37","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1111\/jcpe.13197","article-title":"Periodontal tissue regeneration after low-intensity pulsed ultrasound stimulation with or without intra-marrow perforation in two-wall intra-bony defects-A pilot study in dogs","volume":"47","author":"Shirakata","year":"2020","journal-title":"J. Clin. periodontology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1111\/clr.13738","article-title":"Osteogenic effect of low-intensity pulsed ultrasound and whole-body vibration on peri-implant bone. An experimental in vivo study","volume":"32","author":"Shobara","year":"2021","journal-title":"Clin. oral implants Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s10735-017-9752-1","article-title":"Expression pattern of YAP and TAZ during orthodontic tooth movement in rats","volume":"49","author":"Sun","year":"2018","journal-title":"J. Mol. histology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4137","DOI":"10.1007\/s00784-022-04384-2","article-title":"Dehiscence and fenestration of class I individuals with normality patterns in the anterior region: A CBCT study","volume":"26","author":"Sun","year":"2022","journal-title":"Clin. oral Investig."},{"key":"B41","first-page":"176","article-title":"Effects of low-intensity pulsed ultrasound on bone formation after the expansion of the inter-premaxillary suture in rats: A histologic and immunohistochemical study","volume":"30","author":"Toy","year":"2014","journal-title":"Aust. Orthod. J."},{"key":"B42","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s13287-021-02220-0","article-title":"Osteoclastic effects of mBMMSCs under compressive pressure during orthodontic tooth movement","volume":"12","author":"Wang","year":"2021","journal-title":"Stem Cell. Res. Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41413-022-00190-4","article-title":"Mechanical regulation of bone remodeling","volume":"10","author":"Wang","year":"2022","journal-title":"Bone Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.ultras.2018.06.015","article-title":"Low-intensity pulsed ultrasound promotes alveolar bone regeneration in a periodontal injury model","volume":"90","author":"Wang","year":"2018","journal-title":"Ultrasonics"},{"key":"B45","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s13287-022-02887-z","article-title":"Advances in the application of low-intensity pulsed ultrasound to mesenchymal stem cells","volume":"13","author":"Xia","year":"2022","journal-title":"Stem Cell. Res. Ther."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.1016\/j.ultrasmedbio.2018.07.007","article-title":"Low-intensity pulsed ultrasound treatment accelerates angiogenesis by activating YAP\/TAZ in human umbilical vein endothelial cells","volume":"44","author":"Xu","year":"2018","journal-title":"Ultrasound Med. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e68926","DOI":"10.1371\/journal.pone.0068926","article-title":"Low-intensity pulsed ultrasound accelerates tooth movement via activation of the BMP-2 signaling pathway","volume":"8","author":"Xue","year":"2013","journal-title":"PloS one"},{"key":"B48","doi-asserted-by":"publisher","first-page":"9789","DOI":"10.7150\/thno.42508","article-title":"Low-intensity Pulsed Ultrasound regulates alveolar bone homeostasis in experimental Periodontitis by diminishing Oxidative Stress","volume":"10","author":"Ying","year":"2020","journal-title":"Theranostics"},{"key":"B49","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41413-020-00124-y","article-title":"Piezo1 channel activation in response to mechanobiological acoustic radiation force in osteoblastic cells","volume":"9","author":"Zhang","year":"2021","journal-title":"Bone Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1186\/s13287-022-03070-0","article-title":"How the mechanical microenvironment of stem cell growth affects their differentiation: A review","volume":"13","author":"Zhang","year":"2022","journal-title":"Stem Cell. Res. Ther."},{"key":"B51","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1111\/jre.12424","article-title":"Transgenic expression of ephrinB2 in periodontal ligament stem cells (PDLSCs) modulates osteogenic differentiation via signaling crosstalk between ephrinB2 and EphB4 in PDLSCs and between PDLSCs and pre-osteoblasts within co-culture","volume":"52","author":"Zhu","year":"2017","journal-title":"J. periodontal Res."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1192720\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T11:18:34Z","timestamp":1687605514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1192720\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,23]]},"references-count":51,"alternative-id":["10.3389\/fbioe.2023.1192720"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2023.1192720","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,23]]},"article-number":"1192720"}}