{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:56:58Z","timestamp":1786114618256,"version":"build-2736575974"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173643"],"award-info":[{"award-number":["82173643"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Long-term excessive fluoride ingestion may lead to skeletal fluorosis, a disease characterized by unclear pathogenesis and lack of effective cure. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSCs-EVs) exert a crucial regulatory effect on bone remodeling and have broad clinical application prospects. Whether BMSCs-EVs can participate in the occurrence and development of skeletal fluorosis by transferring miRNAs is a scientific question worth exploring. In this study, miRNA sequencing was used to screen for differentially expressed miRNAs in fluoride-exposed rBMSCs-EVs (F-EVs). The top 15 differentially expressed miRNAs were subjected to target gene prediction, and GO and KEGG analyses as well as PPI network construction were performed. On this basis, miR-320-3p was selected for in-depth study. First, our data revealed that miR-320-3p was upregulated in fluoride-exposed osteoblasts and was involved in the enhancement of fluoride-induced osteogenic differentiation. Subsequently, a tracing experiment confirmed that rBMSCs-EVs and their miR-320-3p could be successfully taken up by fluoride-exposed osteoblasts. Then, elevated levels of miR-320-3p in F-EVs could further promote the enhancement of fluoride-induced osteogenic differentiation, while EVs with inhibited miR-320-3p exerted a significant inhibitory effect. Mechanism studies revealed that under fluoride exposure, rBMSCs-EVs could regulate Igf1r\/ERK1\/2\/MAPK by transferring miR-320-3p, thereby affecting osteogenic differentiation. This study is the first to elucidate the pathogenesis of skeletal fluorosis from the rBMSCs-EVs miRNAs and provides new ideas for the clinical management of skeletal fluorosis.<\/jats:p>","DOI":"10.1093\/stcltm\/szag064","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:20:27Z","timestamp":1781695227000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential miRNA profiles in fluoride-exposed\u00a0rBMSCs-EVs and the influence of miR-320-3p transfer on osteogenic differentiation"],"prefix":"10.1093","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2905-9850","authenticated-orcid":false,"given":"Mingyue","family":"Yin","sequence":"first","affiliation":[{"name":"School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University , Gui\u2019an New Area 561113,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University , Gui\u2019an New Area 561113,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University , Gui\u2019an New Area 561113,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University , Gui\u2019an New Area 561113,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueli","family":"Pan","sequence":"additional","affiliation":[{"name":"School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University , Gui\u2019an New Area 561113,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"2026080517164861200_szag064-B1","doi-asserted-by":"publisher","first-page":"2566","DOI":"10.1007\/s11356-019-06938-6","article-title":"Fluorosis and cognitive development among children (6-14 years of age) in the endemic areas of the world: a review and critical analysis","volume":"27","author":"Saeed","year":"2020","journal-title":"Environ Sci Pollut Res Int"},{"key":"2026080517164861200_szag064-B2","doi-asserted-by":"crossref","first-page":"e2200342","DOI":"10.9745\/GHSP-D-22-00342","article-title":"Prevalence of skeletal fluorosis in Northern Tanzania: a follow-up study","volume":"11","author":"Foat","year":"2023","journal-title":"Glob Health Sci Pract"},{"key":"2026080517164861200_szag064-B3","first-page":"31","author":"Xiang","year":"2021"},{"key":"2026080517164861200_szag064-B4","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1007\/s12011-017-0930-5","article-title":"Micromolar levels of sodium fluoride promote osteoblast differentiation through Runx2 signaling","volume":"178","author":"Lee","year":"2017","journal-title":"Biol Trace Elem Res"},{"key":"2026080517164861200_szag064-B5","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s12933-024-02252-9","article-title":"Roles of non-coding RNA in diabetic cardiomyopathy","volume":"23","author":"Yao","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"2026080517164861200_szag064-B6","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.tox.2017.11.009","article-title":"The role of TGF\u03b2 receptor 1-smad3 signaling in regulating the osteoclastic mode affected by fluoride","volume":"393","author":"Yu","year":"2018","journal-title":"Toxicology"},{"key":"2026080517164861200_szag064-B7","first-page":"359","article-title":"Preliminary screening of fluorine-stained osteoblastic apoptosis-related microRNA","volume":"35","author":"Deng","year":"2021","journal-title":"Anat Rec"},{"key":"2026080517164861200_szag064-B8","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s12011-016-0833-x","article-title":"Preliminary analysis of microRNAs expression profiling in MC3T3-E1 cells exposed to fluoride","volume":"176","author":"Wang","year":"2017","journal-title":"Biol Trace Elem Res"},{"key":"2026080517164861200_szag064-B9","doi-asserted-by":"publisher","first-page":"111876","DOI":"10.1016\/j.ecoenv.2020.111876","article-title":"Altered miRNA expression profiling in enamel organ of fluoride affected rat embryos","volume":"210","author":"Weng","year":"2021","journal-title":"Ecotoxicol Environ Saf"},{"key":"2026080517164861200_szag064-B10","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1007\/s00128-019-02660-8","article-title":"Analysis of the microRNA profile of coal-burning endemic fluorosis using deep sequencing and bioinformatic approaches","volume":"103","author":"Wang","year":"2019","journal-title":"Bull Environ Contam Toxicol"},{"key":"2026080517164861200_szag064-B11","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1007\/s12011-020-02239-z","article-title":"miR-122-5p mediates fluoride-induced osteoblast activation by targeting CDK4","volume":"199","author":"Li","year":"2021","journal-title":"Biol Trace Elem Res"},{"key":"2026080517164861200_szag064-B12","doi-asserted-by":"publisher","first-page":"126626","DOI":"10.1016\/j.jtemb.2020.126626","article-title":"Downregulation of miR-4755-5p promotes fluoride-induced osteoblast activation via tageting cyclin D1","volume":"62","author":"Gao","year":"2020","journal-title":"J Trace Elem Med Biol"},{"key":"2026080517164861200_szag064-B13","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1002\/tox.23302","article-title":"miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation","volume":"36","author":"Ouyang","year":"2021","journal-title":"Environ Toxicol"},{"key":"2026080517164861200_szag064-B14","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1093\/toxsci\/kfab054","article-title":"Let-7c-5p regulates CyclinD1 in fluoride-mediated osteoblast proliferation and activation","volume":"182","author":"Luo","year":"2021","journal-title":"Toxicol Sci"},{"key":"2026080517164861200_szag064-B15","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.biomaterials.2019.01.016","article-title":"Mesenchymal stem cell-derived extracellular vesicles and retinal ischemia-reperfusion","volume":"197","author":"Mathew","year":"2019","journal-title":"Biomaterials"},{"key":"2026080517164861200_szag064-B16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/s41586-021-04234-3","article-title":"MicroRNA sequence codes for small extracellular vesicle release and cellular retention","volume":"601","author":"Martin","year":"2022","journal-title":"Nature"},{"key":"2026080517164861200_szag064-B17","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat Cell Biol"},{"key":"2026080517164861200_szag064-B18","doi-asserted-by":"crossref","first-page":"8570","DOI":"10.1002\/jcp.27833","article-title":"Prospect of mesenchymal stem cells in therapy of osteoporosis: a review","volume":"234","author":"Maleki","year":"2019","journal-title":"J Cell Physiol"},{"key":"2026080517164861200_szag064-B19","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1186\/s12967-020-02530-6","article-title":"Phase II multicenter randomized controlled clinical trial on the efficacy of intra-articular injection of autologous bone marrow mesenchymal stem cells with platelet rich plasma for the treatment of knee osteoarthritis","volume":"18","author":"Lamo-Espinosa","year":"2020","journal-title":"J Transl Med"},{"key":"2026080517164861200_szag064-B20","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s00264-020-04571-4","article-title":"Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up","volume":"45","author":"Hernigou","year":"2021","journal-title":"Int Orthop"},{"key":"2026080517164861200_szag064-B21","doi-asserted-by":"publisher","first-page":"9636897241303275","DOI":"10.1177\/09636897241303275","article-title":"Intra-articular injection of human bone marrow-derived mesenchymal stem cells in knee osteoarthritis: a randomized, double-blind, controlled trial","volume":"34","author":"Lee","year":"2025","journal-title":"Cell Transplant"},{"key":"2026080517164861200_szag064-B22","first-page":"618","article-title":"Effects of transplanting autologous bone marrow mesenchymal stem cells via articular cavity on skeletal fluorosis rabbits","volume":"37","author":"Pan","year":"2018","journal-title":"Chin J Endemiol"},{"key":"2026080517164861200_szag064-B23","first-page":"114","article-title":"Effects of transplantation of autologous bone marrow mesenchymal stem cells via ear vein injection on rabbits with skeletal fluorosis","volume":"35","author":"Li","year":"2018","journal-title":"Chin J Environ Health"},{"key":"2026080517164861200_szag064-B24","first-page":"2887","article-title":"Melatonin improves therapeutic potential of mesenchymal stem cells derived exosomes against renal ischemia-reperfusion injury in rats","volume":"11","author":"Alzahrani","year":"2019","journal-title":"Am J Transl Res"},{"key":"2026080517164861200_szag064-B25","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.3923\/ijp.2018.1128.1135","article-title":"Ameliorative effect of mesenchymal stem cells-derived exosomes on diethylnitrosamine-induced liver injury in albino rats","volume":"14","author":"Alzahrani","year":"2018","journal-title":"Int J Pharmacol"},{"key":"2026080517164861200_szag064-B26","doi-asserted-by":"publisher","first-page":"121931","DOI":"10.1016\/j.envpol.2023.121931","article-title":"Screening of differentially methylated genes in skeletal fluorosis of rats with different types and involvement of aberrant methylation of Cthrc1","volume":"332","author":"Ding","year":"2023","journal-title":"Environ Pollut"},{"key":"2026080517164861200_szag064-B27","doi-asserted-by":"publisher","first-page":"962","DOI":"10.3390\/ijms23020962","article-title":"Biphasic functions of sodium fluoride (NaF) in soft and in hard periodontal tissues","volume":"23","author":"Wang","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026080517164861200_szag064-B28","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/s41419-020-2574-1","article-title":"Bone-targeted lncRNA OGRU alleviates unloading induced bone loss via miR-320-3p\/Hoxa10 axis","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis"},{"key":"2026080517164861200_szag064-B29","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.7150\/ijbs.46627","article-title":"The role of autophagy and mitophagy in bone metabolic disorders","volume":"16","author":"Wang","year":"2020","journal-title":"Int J Biol Sci"},{"key":"2026080517164861200_szag064-B30","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1002\/jbmr.2510","article-title":"Osteoblast-specific loss of IGF1R signaling results in impaired endochondral bone formation during fracture healing","volume":"30","author":"Wang","year":"2015","journal-title":"J Bone Miner Res"},{"key":"2026080517164861200_szag064-B31","doi-asserted-by":"crossref","first-page":"eabo7868","DOI":"10.1126\/sciadv.abo7868","article-title":"Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression","volume":"9","author":"Zhang","year":"2023","journal-title":"Sci Adv"},{"key":"2026080517164861200_szag064-B32","doi-asserted-by":"publisher","first-page":"2404080","DOI":"10.1002\/advs.202404080","article-title":"PP2Ac regulates autophagy via mediating mTORC1 and ULK1 during osteoclastogenesis in the subchondral bone of osteoarthritis","volume":"11","author":"Zhang","year":"2024","journal-title":"Adv Sci"},{"key":"2026080517164861200_szag064-B33","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1080\/15548627.2021.2017587","article-title":"Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis","volume":"18","author":"Yoshida","year":"2022","journal-title":"Autophagy"},{"key":"2026080517164861200_szag064-B34","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1080\/15548627.2020.1822097","article-title":"Mitophagy in degenerative joint diseases","volume":"17","author":"Sun","year":"2021","journal-title":"Autophagy"},{"key":"2026080517164861200_szag064-B35","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1186\/s12951-024-02640-z","article-title":"Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy","volume":"22","author":"Lei","year":"2024","journal-title":"J Nanobiotechnology"},{"key":"2026080517164861200_szag064-B36","doi-asserted-by":"publisher","first-page":"115829","DOI":"10.1016\/j.bcp.2023.115829","article-title":"Extracellular vesicles from bone marrow mesenchymal stem cells alleviate osteoporosis in mice through USP7-mediated YAP1 protein stability and the Wnt\/\u03b2-catenin pathway","volume":"217","author":"Wang","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"2026080517164861200_szag064-B37","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.3892\/etm.2020.8454","article-title":"ERK\/MAPK signalling pathway and tumorigenesis (review)","volume":"19","author":"Guo","year":"2020","journal-title":"Exp Ther Med"},{"key":"2026080517164861200_szag064-B38","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1007\/s00109-019-01785-x","article-title":"Regulation of osteoblast behaviors via cross-talk between hippo\/YAP and MAPK signaling pathway under fluoride exposure","volume":"97","author":"Zhu","year":"2019","journal-title":"J Mol Med (Berl)"},{"key":"2026080517164861200_szag064-B39","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1177\/15353702231191117","article-title":"Fluoride induces osteoblast autophagy by inhibiting the PI3K\/AKT\/mTOR signaling pathway in vivo and in vitro","volume":"248","author":"Linghu","year":"2023","journal-title":"Exp Biol Med (Maywood)"},{"key":"2026080517164861200_szag064-B40","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s12038-021-00236-5","article-title":"17 \u03b2-Estradiol alleviates oxidative damage in osteoblasts by regulating miR-320\/RUNX2 signaling pathway","volume":"46","author":"Xu","year":"2021","journal-title":"J Biosci"},{"key":"2026080517164861200_szag064-B41","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1007\/s11914-019-00537-7","article-title":"Exosomes and extracellular RNA in muscle and bone aging and crosstalk","volume":"17","author":"Qin","year":"2019","journal-title":"Curr Osteoporos Rep"},{"key":"2026080517164861200_szag064-B42","doi-asserted-by":"publisher","first-page":"11021","DOI":"10.1074\/jbc.M116.770941","article-title":"Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: a novel mechanism in muscle-bone communication","volume":"292","author":"Qin","year":"2017","journal-title":"J Biol Chem"},{"key":"2026080517164861200_szag064-B43","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1186\/s12951-022-01655-8","article-title":"Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossifcation of the posterior longitudinal ligament","volume":"20","author":"Tang","year":"2022","journal-title":"J Nanobiotechnology"},{"key":"2026080517164861200_szag064-B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.11005\/jbm.2022.29.1.1","article-title":"The extracellular signal-regulated kinase mitogen-activated protein kinase pathway in osteoblasts","volume":"29","author":"Greenblatt","year":"2022","journal-title":"J Bone Metab"},{"key":"2026080517164861200_szag064-B45","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1007\/s12011-023-03869-9","article-title":"MiR-1a-3p inhibits apoptosis in fluoride\u2011exposed LS8 cells by targeting Map3k1","volume":"202","author":"Chen","year":"2023","journal-title":"Biol Trace Elem Res"},{"key":"2026080517164861200_szag064-B46","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.bbrc.2020.12.100","article-title":"MAP kinase phosphatase MKP-1 regulates p-ERK1\/2 signaling pathway with fluoride treatment","volume":"542","author":"Zhao","year":"2021","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/15\/8\/szag064\/70500240\/szag064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/15\/8\/szag064\/70500240\/szag064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T21:16:54Z","timestamp":1785964614000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/doi\/10.1093\/stcltm\/szag064\/8752876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,7,20]]}},"URL":"https:\/\/doi.org\/10.1093\/stcltm\/szag064","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,7,20]]},"article-number":"szag064"}}