{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:26:13Z","timestamp":1793406373398,"version":"4.5.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81873711"],"award-info":[{"award-number":["81873711"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Orthop Surg Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Medication-related osteonecrosis of the jaw (MRONJ), caused by long-term anti-resorptive therapy, leads to bone necrosis and impaired healing. This study developed a miR-21-loaded mesoporous silica nanoparticles (MSN) hydrogel to promote local bone regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptome sequencing of zoledronic acid (ZOL)-treated osteoclasts (OCs) revealed PDCD4 upregulation and NF-\u03baB (p65) phosphorylation inhibition. miR-21, identified as a regulator of PDCD4, was validated in vitro. Amino-modified mesoporous silica nanoparticles (MSN-NH\u2082) were synthesized to carry miR-21, and embedded in a dynamic Schiff base-crosslinked hydrogel. The hydrogel's biocompatibility, sustained release, and therapeutic effect were evaluated in a rat MRONJ model via micro-CT, histology, TRAP staining, and RNA in situ hybridization (RISH).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>miR-21 reversed ZOL-induced suppression of NF-\u03baB\/p65 phosphorylation by targeting PDCD4, thereby restoring osteoclast differentiation and resorption activity. The miR-21-loaded MSN hydrogel promoted bone regeneration, increased TRAP\u207a osteoclast numbers, and elevated local miR-21 expression, while maintaining systemic safety. These findings suggest that the miR-21-loaded MSN hydrogel system exerts its therapeutic effect primarily through the miR-21\/PDCD4\/NF-\u03baB signaling pathway, facilitating coordinated regulation of osteoclast-mediated bone remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The miR-21-loaded MSN hydrogel effectively restored bone remodeling and healed MRONJ defects without systemic toxicity, offering a promising localized adjunct to anti-resorptive therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13018-025-06503-7","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:37:55Z","timestamp":1766489875000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Localized therapeutic strategy based on microRNA-21-loaded mesoporous silica nanoparticles hydrogel improves bone repair in medication-related osteonecrosis of the jaw"],"prefix":"10.1186","volume":"20","author":[{"given":"Ye","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuofan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"issue":"4","key":"6503_CR1","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1111\/odi.15198","volume":"31","author":"K Lee","year":"2025","unstructured":"Lee K, Kim K, Kim JY, et al. Mechanisms underlying medication-related osteonecrosis of the jaw. Oral Dis. 2025;31(4):1073\u201383.","journal-title":"Oral Dis"},{"issue":"6","key":"6503_CR2","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.bjoms.2020.03.010","volume":"58","author":"J Murphy","year":"2020","unstructured":"Murphy J, Mannion CJ. Medication-related osteonecrosis of the jaws and quality of life: review and structured analysis. Br J Oral Maxillofac Surg. 2020;58(6):619\u201324.","journal-title":"Br J Oral Maxillofac Surg"},{"issue":"9","key":"6503_CR3","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/S0278-2391(03)00720-1","volume":"61","author":"RE Marx","year":"2003","unstructured":"Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115\u20137.","journal-title":"J Oral Maxillofac Surg"},{"issue":"10","key":"6503_CR4","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.bjoms.2024.08.008","volume":"62","author":"N Patel","year":"2024","unstructured":"Patel N, Seoudi N. Management of medication-related osteonecrosis of the jaw: an overview of national and international guidelines. Br J Oral Maxillofac Surg. 2024;62(10):899\u2013908.","journal-title":"Br J Oral Maxillofac Surg"},{"key":"6503_CR5","doi-asserted-by":"publisher","DOI":"10.1177\/03008916251363754","author":"M Stellato","year":"2025","unstructured":"Stellato M, Zecca E, Bracchi P, et al. Medication-related jaw osteonecrosis in metastatic RCC treated with VEGFR-TKIs \u00b1 IO and bone agents: a real-world analysis. Tumori. 2025. https:\/\/doi.org\/10.1177\/03008916251363754.","journal-title":"Tumori"},{"issue":"3","key":"6503_CR6","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s00109-024-02425-9","volume":"102","author":"G Bassan Marinho Maciel","year":"2024","unstructured":"Bassan Marinho Maciel G, Marinho Maciel R, Linhares Ferrazzo K, Cademartori Danesi C. Etiopathogenesis of medication-related osteonecrosis of the jaws: a review. J Mol Med. 2024;102(3):353\u201364.","journal-title":"J Mol Med"},{"issue":"1","key":"6503_CR7","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1186\/s13018-024-05320-8","volume":"19","author":"F Huang","year":"2024","unstructured":"Huang F, Wang Y, Liu J, Cheng Y, Zhang X, Jiang H. Asperuloside alleviates osteoporosis by promoting autophagy and regulating Nrf2 activation. J Orthop Surg Res. 2024;19(1):855.","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"6503_CR8","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1186\/s13018-024-05295-6","volume":"19","author":"L Shen","year":"2024","unstructured":"Shen L, Yang H, Zhou F, Jiang T, Jiang Z. Risk factors of short-term residual low back pain after PKP for the first thoracolumbar osteoporotic vertebral compression fracture. J Orthop Surg Res. 2024;19(1):792.","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"6503_CR9","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1186\/s13018-024-05287-6","volume":"19","author":"J Leeyaphan","year":"2024","unstructured":"Leeyaphan J, Rojjananukulpong K, Intarasompun P, Peerakul Y. Simple clinical predictors for making directive decisions in osteoporosis screening for women: a cross-sectional study. J Orthop Surg Res. 2024;19(1):789.","journal-title":"J Orthop Surg Res"},{"issue":"8","key":"6503_CR10","doi-asserted-by":"publisher","first-page":"2753","DOI":"10.1039\/D4TB02256D","volume":"13","author":"D Zhang","year":"2025","unstructured":"Zhang D, Zuo M, Zhou J, et al. A facile combined therapy of chemotherapeutic agent and microRNA for hepatocellular carcinoma using non-cationic nanogel. J Mater Chem B. 2025;13(8):2753\u201366.","journal-title":"J Mater Chem B"},{"issue":"1","key":"6503_CR11","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1093\/bmb\/ldaa002","volume":"133","author":"L Giordano","year":"2020","unstructured":"Giordano L, Porta GD, Peretti GM, Maffulli N. Therapeutic potential of microrna in tendon injuries. Br Med Bull. 2020;133(1):79\u201394.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR12","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1093\/bmb\/ldaa040","volume":"138","author":"G Gargano","year":"2021","unstructured":"Gargano G, Oliviero A, Oliva F, Maffulli N. Small interfering RNAs in tendon homeostasis. Br Med Bull. 2021;138(1):58\u201367.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1093\/bmb\/ldz015","volume":"130","author":"A Oliviero","year":"2019","unstructured":"Oliviero A, Della Porta G, Peretti GM, Maffulli N. Microrna in osteoarthritis: physiopathology, diagnosis and therapeutic challenge. Br Med Bull. 2019;130(1):137\u201347.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR14","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1093\/bmb\/ldac012","volume":"142","author":"G Gargano","year":"2022","unstructured":"Gargano G, Oliva F, Oliviero A, Maffulli N. Small interfering RNAs in the management of human rheumatoid arthritis. Br Med Bull. 2022;142(1):34\u201343.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR15","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1093\/bmb\/ldad023","volume":"148","author":"G Gargano","year":"2023","unstructured":"Gargano G, Asparago G, Spiezia F, Oliva F, Maffulli N. Small interfering RNAs in the management of human osteoporosis. Br Med Bull. 2023;148(1):58\u201369.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR16","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1186\/s13018-021-02474-7","volume":"16","author":"F Migliorini","year":"2021","unstructured":"Migliorini F, Maffulli N, Spiezia F, Tingart M, Maria PG, Riccardo G. Biomarkers as therapy monitoring for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021;16(1):318.","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"6503_CR17","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1186\/s13018-021-02497-0","volume":"16","author":"F Migliorini","year":"2021","unstructured":"Migliorini F, Maffulli N, Spiezia F, Peretti GM, Tingart M, Giorgino R. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021;16(1):351.","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"6503_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/ncrna11010014","volume":"11","author":"BI Yalaev","year":"2025","unstructured":"Yalaev BI, Kaletnik EI, Karpova YS, et al. The role of microRNA in the regulation of differentiation and the functionality of osteoblasts, osteoclasts, and their precursors in osteoporosis. Non-coding RNA. 2025;11(1):14.","journal-title":"Non-coding RNA"},{"key":"6503_CR19","doi-asserted-by":"publisher","first-page":"1021429","DOI":"10.3389\/fphys.2023.1021429","volume":"14","author":"SS Mohd Yunus","year":"2023","unstructured":"Mohd Yunus SS, Soh HY, Abdul Rahman M, Peng X, Guo C, Ramli R. MicroRNA in medication related osteonecrosis of the jaw: a review. Front Physiol. 2023;14:1021429.","journal-title":"Front Physiol"},{"issue":"8","key":"6503_CR20","first-page":"2893","volume":"9","author":"D Santini","year":"2003","unstructured":"Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Canc Res: Off J Am Associat Canc Res. 2003;9(8):2893\u20137.","journal-title":"Clin Canc Res: Off J Am Associat Canc Res"},{"issue":"2","key":"6503_CR21","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1159\/000313787","volume":"124","author":"A Allegra","year":"2010","unstructured":"Allegra A, Alonci A, Penna G, et al. Bisphosphonates induce apoptosis of circulating endothelial cells in multiple myeloma patients and in subjects with bisphosphonate-induced osteonecrosis of the jaws. Acta Haematol. 2010;124(2):79\u201385.","journal-title":"Acta Haematol"},{"issue":"2","key":"6503_CR22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.cyto.2008.05.010","volume":"43","author":"G Oteri","year":"2008","unstructured":"Oteri G, Allegra A, Bellomo G, et al. Reduced serum levels of interleukin 17 in patients with osteonecrosis of the jaw and in multiple myeloma subjects after bisphosphonates administration. Cytokine. 2008;43(2):103\u20134.","journal-title":"Cytokine"},{"key":"6503_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.722804","volume":"12","author":"C Chen","year":"2021","unstructured":"Chen C, Liu YM, Fu BL, Xu LL, Wang B. Microrna-21: an emerging player in bone diseases. Front Pharmacol. 2021;12:722804.","journal-title":"Front Pharmacol"},{"key":"6503_CR24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252312883","author":"SK Niazi","year":"2024","unstructured":"Niazi SK, Magoola M. MicroRNA Nobel Prize: Timely Recognition and High Anticipation of Future Products-A Prospective Analysis. Int J Mol Sci. 2024. https:\/\/doi.org\/10.3390\/ijms252312883.","journal-title":"Int J Mol Sci"},{"key":"6503_CR25","doi-asserted-by":"crossref","unstructured":"Cha W, Fan R, Miao Y, et al. Mesoporous Silica Nanoparticles as Carriers for Intracellular Delivery of Nucleic Acids and Subsequent Therapeutic Applications. Molecules (Basel, Switzerland) 2017, 22(5).","DOI":"10.3390\/molecules22050782"},{"issue":"11","key":"6503_CR26","doi-asserted-by":"publisher","first-page":"3703","DOI":"10.1002\/jbm.a.35504","volume":"103","author":"N Shadjou","year":"2015","unstructured":"Shadjou N, Hasanzadeh M. Silica-based mesoporous nanobiomaterials as promoter of bone regeneration process. J Biomed Mater Res A. 2015;103(11):3703\u201316.","journal-title":"J Biomed Mater Res A"},{"issue":"1","key":"6503_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-024-05301-x","volume":"19","author":"M Andersen","year":"2024","unstructured":"Andersen M, Andresen AK, Hartvigsen J, Hermann AP, S\u00f8rensen J, Carreon LY. Vertebroplasty for painful osteoporotic vertebral compression fractures: a protocol for a single-center doubled-blind randomized sham-controlled clinical trial. VOPE2. J Orthop Surg Res. 2024;19(1):813.","journal-title":"J Orthop Surg Res"},{"key":"6503_CR28","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd6740","author":"Y Li","year":"2021","unstructured":"Li Y, Chen X, Jin R, et al. Injectable hydrogel with MSNs\/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs. Sci Adv. 2021. https:\/\/doi.org\/10.1126\/sciadv.abd6740.","journal-title":"Sci Adv"},{"key":"6503_CR29","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.actbio.2022.10.038","volume":"154","author":"W Zhu","year":"2022","unstructured":"Zhu W, Dong Y, Xu P, et al. A composite hydrogel containing resveratrol-laden nanoparticles and platelet-derived extracellular vesicles promotes wound healing in diabetic mice. Acta Biomater. 2022;154:212\u201330.","journal-title":"Acta Biomater"},{"key":"6503_CR30","first-page":"61","volume":"41","author":"H Li","year":"2024","unstructured":"Li H, Zhao T, Yuan Z, et al. Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration. Bioact Mater. 2024;41:61\u201382.","journal-title":"Bioact Mater"},{"issue":"Database issue","key":"6503_CR31","doi-asserted-by":"publisher","first-page":"D92","DOI":"10.1093\/nar\/gkt1248","volume":"42","author":"JH Li","year":"2014","unstructured":"Li JH, Liu S, Zhou H, Qu LH, Yang JH. StarBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92-97.","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"6503_CR32","doi-asserted-by":"publisher","first-page":"436","DOI":"10.3892\/etm.2023.12135","volume":"26","author":"Y Liu","year":"2023","unstructured":"Liu Y, Wang W, Zeng Y, Zeng H. Transcriptome analysis of hydrogen inhibits osteoclastogenesis of mouse bone marrow mononuclear cells. Exp Ther Med. 2023;26(3):436.","journal-title":"Exp Ther Med"},{"key":"6503_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156755","volume":"142","author":"S Xu","year":"2025","unstructured":"Xu S, Zhang Z, Zhou X, et al. Gouqi-derived nanovesicles (GqDNVs) promoted MC3T3-E1 cells proliferation and improve fracture healing. Phytomedicine. 2025;142:156755.","journal-title":"Phytomedicine"},{"key":"6503_CR34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10010054","author":"ANM Mamun-Or-Rashid","year":"2021","unstructured":"Mamun-Or-Rashid ANM, Lucy TT, Yagi M, Yonei Y. Inhibitory effects of astaxanthin on CML-HSA-induced inflammatory and RANKL-induced osteoclastogenic gene expression in RAW 264.7 cells. Biomedicines. 2021. https:\/\/doi.org\/10.3390\/biomedicines10010054.","journal-title":"Biomedicines"},{"key":"6503_CR35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.817281","volume":"13","author":"D Eckert","year":"2022","unstructured":"Eckert D, Rapp F, Tsedeke AT, et al. Modulation of differentiation and bone resorbing activity of human (pre-) osteoclasts after X-ray exposure. Front Immunol. 2022;13:817281.","journal-title":"Front Immunol"},{"issue":"Pt A","key":"6503_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115887","volume":"302","author":"MS Ren","year":"2023","unstructured":"Ren MS, Xie HH, Ding Y, Li ZH, Liu B. Er-xian decoction drug-containing serum promotes Mc3t3-e1 cell proliferation and osteogenic differentiation via regulating BK channel. J Ethnopharmacol. 2023;302(Pt A):115887.","journal-title":"J Ethnopharmacol"},{"issue":"3","key":"6503_CR37","first-page":"71","volume":"3","author":"X Rao","year":"2013","unstructured":"Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2\u02c6(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostatistics, bioinformatics and biomathematics. 2013;3(3):71\u201385.","journal-title":"Biostatistics, bioinformatics and biomathematics"},{"issue":"Pt 2","key":"6503_CR38","doi-asserted-by":"publisher","first-page":"113432","DOI":"10.1016\/j.intimp.2024.113432","volume":"143","author":"N Mao","year":"2024","unstructured":"Mao N, Yu Y, Lu X, Yang Y, Liu Z, Wang D. Preventive effects of matrine on LPS-induced inflammation in RAW 2647 cells and intestinal damage in mice through the TLR4\/NF-\u03baB\/MAPK pathway. Int Immunopharmacol. 2024;143(Pt 2):113432.","journal-title":"Int Immunopharmacol"},{"key":"6503_CR39","doi-asserted-by":"publisher","DOI":"10.3390\/biom10081185","author":"M Muhammad","year":"2020","unstructured":"Muhammad M, Willems C, Rodr\u00edguez-Fern\u00e1ndez J, Gallego-Ferrer G, Groth T. Synthesis and characterization of oxidized polysaccharides for in situ forming hydrogels. Biomolecules. 2020. https:\/\/doi.org\/10.3390\/biom10081185.","journal-title":"Biomolecules"},{"issue":"12","key":"6503_CR40","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1002\/open.202100227","volume":"10","author":"BM Estev\u00e3o","year":"2021","unstructured":"Estev\u00e3o BM, Miletto I, Hioka N, Marchese L, Gianotti E. Mesoporous silica nanoparticles functionalized with amino groups for biomedical applications. ChemistryOpen. 2021;10(12):1251\u20139.","journal-title":"ChemistryOpen"},{"key":"6503_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2023.116899","volume":"177","author":"R Kozutsumi","year":"2023","unstructured":"Kozutsumi R, Kuroshima S, Al-Omari FA, et al. Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice. Bone. 2023;177:116899.","journal-title":"Bone"},{"issue":"1","key":"6503_CR42","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1080\/17512433.2021.1851192","volume":"14","author":"F Migliorini","year":"2021","unstructured":"Migliorini F, Colarossi G, Baroncini A, Eschweiler J, Tingart M, Maffulli N. Pharmacological management of postmenopausal osteoporosis: a level I evidence based - expert opinion. Expert Rev Clin Pharmacol. 2021;14(1):105\u201319.","journal-title":"Expert Rev Clin Pharmacol"},{"key":"6503_CR43","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.2147\/DDDT.S417598","volume":"17","author":"X Zheng","year":"2023","unstructured":"Zheng X, Qiu J, Gao N, et al. Paroxetine attenuates chondrocyte pyroptosis and inhibits osteoclast formation by inhibiting NF-\u03baB pathway activation to delay osteoarthritis progression. Drug Des Dev Ther. 2023;17:2383\u201399.","journal-title":"Drug Des Dev Ther"},{"issue":"4","key":"6503_CR44","doi-asserted-by":"publisher","first-page":"235","DOI":"10.2144\/000113837","volume":"52","author":"JA Hanna","year":"2012","unstructured":"Hanna JA, Wimberly H, Kumar S, Slack F, Agarwal S, Rimm DL. Quantitative analysis of microRNAs in tissue microarrays by in situ hybridization. Biotechniques. 2012;52(4):235\u201345.","journal-title":"Biotechniques"},{"key":"6503_CR45","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2024.13333","author":"L Yu","year":"2024","unstructured":"Yu L, Yang Y, Wang J, et al. PDCD4 promotes inflammation\/fibrosis by activating the PPAR\u2011\u03b3\/NF\u2011\u03baB pathway in mouse atrial myocytes. Mol Med Rep. 2024. https:\/\/doi.org\/10.3892\/mmr.2024.13333.","journal-title":"Mol Med Rep"},{"issue":"7","key":"6503_CR46","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1093\/carcin\/bgu008","volume":"35","author":"SK Hwang","year":"2014","unstructured":"Hwang SK, Baker AR, Young MR, Colburn NH. Tumor suppressor PDCD4 inhibits NF-\u03baB-dependent transcription in human glioblastoma cells by direct interaction with p65. Carcinogenesis. 2014;35(7):1469\u201380.","journal-title":"Carcinogenesis"},{"key":"6503_CR47","doi-asserted-by":"publisher","first-page":"43191","DOI":"10.1038\/srep43191","volume":"7","author":"CH Hu","year":"2017","unstructured":"Hu CH, Sui BD, Du FY, et al. MiR-21 deficiency inhibits osteoclast function and prevents bone loss in mice. Sci Rep. 2017;7:43191.","journal-title":"Sci Rep"},{"issue":"11","key":"6503_CR48","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1002\/jor.22128","volume":"30","author":"Y Zhou","year":"2012","unstructured":"Zhou Y, Liu Y, Cheng L. Mir-21 expression is related to particle-induced osteolysis pathogenesis. J Orthop Res. 2012;30(11):1837\u201342.","journal-title":"J Orthop Res"},{"issue":"9","key":"6503_CR49","first-page":"205","volume":"12","author":"F Frutuoso","year":"2024","unstructured":"Frutuoso F, Freitas F, Vilares M, et al. Medication-related osteonecrosis of the jaw: a systematic review of case reports and case series. Diseases (Basel, Switzerland). 2024;12(9):205.","journal-title":"Diseases (Basel, Switzerland)"},{"issue":"10","key":"6503_CR50","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.3390\/medicina57101119","volume":"57","author":"F Migliorini","year":"2021","unstructured":"Migliorini F, Giorgino R, Hildebrand F, et al. Risk factors and management in the elderly. Medicina (Kaunas). 2021;57(10):1119.","journal-title":"Medicina (Kaunas)"},{"issue":"3","key":"6503_CR51","doi-asserted-by":"publisher","first-page":"5452","DOI":"10.3390\/ijms16035452","volume":"16","author":"V Conti","year":"2015","unstructured":"Conti V, Russomanno G, Corbi G, et al. A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy. Int J Mol Sci. 2015;16(3):5452\u201366.","journal-title":"Int J Mol Sci"},{"key":"6503_CR52","doi-asserted-by":"publisher","first-page":"1477274","DOI":"10.3389\/fdmed.2024.1477274","volume":"5","author":"M Morakotsriwan","year":"2024","unstructured":"Morakotsriwan M, Chanamuangkon T, Vacharaksa A, Limlawan P. Microrna-21-5p profile in the alveolar bone following tooth extraction in medication-related osteonecrosis of the jaw rat model. Front Dent Med. 2024;5:1477274.","journal-title":"Front Dent Med"},{"key":"6503_CR53","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2024.117323","volume":"190","author":"S Minami","year":"2025","unstructured":"Minami S, Fujii Y, Yoshioka Y, et al. Extracellular vesicles from mouse bone marrow macrophages-derived osteoclasts treated with zoledronic acid contain miR-146a-5p and miR-322-3p, which inhibit osteoclast function. Bone. 2025;190:117323.","journal-title":"Bone"},{"issue":"1","key":"6503_CR54","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1093\/bmb\/ldac017","volume":"143","author":"F Migliorini","year":"2022","unstructured":"Migliorini F, Colarossi G, Eschweiler J, Oliva F, Driessen A, Maffulli N. Antiresorptive treatments for corticosteroid-induced osteoporosis: a Bayesian network meta-analysis. Br Med Bull. 2022;143(1):46\u201356.","journal-title":"Br Med Bull"},{"key":"6503_CR55","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldae024","author":"G Gargano","year":"2025","unstructured":"Gargano G, Pagano SM, Maffulli N. Circular RNAs in the management of human osteoporosis. Br Med Bull. 2025. https:\/\/doi.org\/10.1093\/bmb\/ldae024.","journal-title":"Br Med Bull"},{"issue":"1","key":"6503_CR56","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1186\/s13018-024-05361-z","volume":"19","author":"X Bao","year":"2024","unstructured":"Bao X, Liu C, Liu H, Wang Y, Xue P, Li Y. Association between polymorphisms of glucagon-like peptide-1 receptor gene and susceptibility to osteoporosis in Chinese postmenopausal women. J Orthop Surg Res. 2024;19(1):869.","journal-title":"J Orthop Surg Res"},{"key":"6503_CR57","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020479","author":"A Smieszek","year":"2020","unstructured":"Smieszek A, Marcinkowska K, Pielok A, Sikora M, Valihrach L, Marycz K. The role of miR-21 in osteoblasts-osteoclasts coupling in vitro. Cells. 2020. https:\/\/doi.org\/10.3390\/cells9020479.","journal-title":"Cells"},{"key":"6503_CR58","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.2147\/CIA.S235197","volume":"15","author":"C Cong","year":"2020","unstructured":"Cong C, Tian J, Gao T, et al. LncRNA GAS5 Is upregulated in osteoporosis and downregulates miR-21 to promote apoptosis of osteoclasts. Clin Interv Aging. 2020;15:1163\u20139.","journal-title":"Clin Interv Aging"},{"key":"6503_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2020.110785","volume":"111","author":"Z Geng","year":"2020","unstructured":"Geng Z, Yu Y, Li Z, et al. Mir-21 promotes osseointegration and mineralization through enhancing both osteogenic and osteoclastic expression. Mater Sci Eng C Mater Biol Appl. 2020;111:110785.","journal-title":"Mater Sci Eng C Mater Biol Appl"},{"issue":"1","key":"6503_CR60","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1186\/s13018-021-02678-x","volume":"16","author":"F Migliorini","year":"2021","unstructured":"Migliorini F, Maffulli N, Colarossi G, Eschweiler J, Tingart M, Betsch M. Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis. J Orthop Surg Res. 2021;16(1):533.","journal-title":"J Orthop Surg Res"},{"key":"6503_CR61","volume":"262","author":"RU Syed","year":"2024","unstructured":"Syed RU, Banu H, Alshammrani A, et al. Microrna-21 (miR-21) in breast cancer: from apoptosis dysregulation to therapeutic opportunities. Pathology. 2024;262:155572.","journal-title":"Pathology"},{"issue":"20","key":"6503_CR62","doi-asserted-by":"publisher","first-page":"20285","DOI":"10.18632\/aging.103800","volume":"12","author":"Z He","year":"2020","unstructured":"He Z, Long J, Yang C, et al. LncRNA DGCR5 plays a tumor-suppressive role in glioma via the miR-21\/Smad7 and miR-23a\/PTEN axes. Aging. 2020;12(20):20285\u2013307.","journal-title":"Aging"},{"issue":"19","key":"6503_CR63","doi-asserted-by":"publisher","first-page":"2799","DOI":"10.1038\/sj.onc.1210083","volume":"26","author":"ML Si","year":"2007","unstructured":"Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. MiR-21-mediated tumor growth. Oncogene. 2007;26(19):2799\u2013803.","journal-title":"Oncogene"},{"issue":"7","key":"6503_CR64","doi-asserted-by":"publisher","first-page":"4795","DOI":"10.1245\/s10434-024-15453-z","volume":"31","author":"VK Singh","year":"2024","unstructured":"Singh VK, Rajak N, Singh Y, Singh AK, Giri R, Garg N. Role of microrna-21 in prostate cancer progression and metastasis: molecular mechanisms to therapeutic targets. Ann Surg Oncol. 2024;31(7):4795\u2013808.","journal-title":"Ann Surg Oncol"},{"key":"6503_CR65","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040888","author":"T Dan","year":"2021","unstructured":"Dan T, Shastri AA, Palagani A, et al. MiR-21 plays a dual role in tumor formation and cytotoxic response in breast tumors. Cancers (Basel). 2021. https:\/\/doi.org\/10.3390\/cancers13040888.","journal-title":"Cancers (Basel)"},{"issue":"23","key":"6503_CR66","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.2217\/epi-2023-0230","volume":"15","author":"S Qian","year":"2023","unstructured":"Qian S, Liu J, Liao W, Wang F. METTL3 promotes non-small-cell lung cancer growth and metastasis by inhibiting FDX1 through copper death-associated pri-miR-21-5p maturation. Epigenomics. 2023;15(23):1237\u201355.","journal-title":"Epigenomics"},{"issue":"2","key":"6503_CR67","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/ni.1828","volume":"11","author":"FJ Sheedy","year":"2010","unstructured":"Sheedy FJ, Palsson-McDermott E, Hennessy EJ, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11(2):141\u20137.","journal-title":"Nat Immunol"},{"issue":"8","key":"6503_CR68","doi-asserted-by":"publisher","first-page":"6025","DOI":"10.1002\/jcp.30288","volume":"236","author":"J Xue","year":"2021","unstructured":"Xue J, Xiao T, Wei S, et al. Mir-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells. J Cell Physiol. 2021;236(8):6025\u201341.","journal-title":"J Cell Physiol"},{"issue":"3","key":"6503_CR69","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.4049\/jimmunol.1300613","volume":"192","author":"A Das","year":"2014","unstructured":"Das A, Ganesh K, Khanna S, Sen CK, Roy S. Engulfment of apoptotic cells by macrophages: a role of microRNA-21 in the resolution of wound inflammation. J Immunol. 2014;192(3):1120\u20139.","journal-title":"J Immunol"},{"issue":"1","key":"6503_CR70","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41413-023-00299-0","volume":"12","author":"J Yang","year":"2024","unstructured":"Yang J, Shuai J, Siow L, et al. Microrna-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment. Bone Res. 2024;12(1):2.","journal-title":"Bone Res"},{"issue":"12","key":"6503_CR71","doi-asserted-by":"publisher","first-page":"6653","DOI":"10.1007\/s00784-021-03951-3","volume":"25","author":"CGJ Monteiro","year":"2021","unstructured":"Monteiro CGJ, Vieira EM, Emerick C, et al. Ozonated oil effect for prevention of medication-related osteonecrosis of the jaw (MRONJ) in rats undergoing zoledronic acid therapy. Clin Oral Invest. 2021;25(12):6653\u20139.","journal-title":"Clin Oral Invest"},{"issue":"5","key":"6503_CR72","doi-asserted-by":"publisher","first-page":"2430","DOI":"10.1021\/acsbiomaterials.8b01468","volume":"5","author":"H Ning","year":"2019","unstructured":"Ning H, Wu X, Wu Q, et al. Microfiber-reinforced composite hydrogels loaded with rat adipose-derived stem cells and BMP-2 for the treatment of medication-related osteonecrosis of the jaw in a rat model. ACS Biomater Sci Eng. 2019;5(5):2430\u201343.","journal-title":"ACS Biomater Sci Eng"},{"issue":"3","key":"6503_CR73","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1016\/j.jds.2023.10.007","volume":"19","author":"K Suyama","year":"2024","unstructured":"Suyama K, Otsuru M, Nakamura N, et al. Bone resection methods in medication-related osteonecrosis of the jaw in the mandible: an investigation of 206 patients undergoing surgical treatment. J Dent Sci. 2024;19(3):1758\u201369.","journal-title":"J Dent Sci"},{"issue":"11","key":"6503_CR74","first-page":"6361","volume":"29","author":"S Soutome","year":"2021","unstructured":"Soutome S, Otsuru M, Hayashida S, et al. Periosteal reaction of medication-related osteonecrosis of the jaw (MRONJ): clinical significance and changes during conservative therapy. Support Care Cancer. 2021;29(11):6361\u20138.","journal-title":"Support Care Cancer"},{"issue":"Pt A","key":"6503_CR75","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.ijbiomac.2021.10.142","volume":"193","author":"Y Kuang","year":"2021","unstructured":"Kuang Y, Zhai J, Xiao Q, Zhao S, Li C. Polysaccharide\/mesoporous silica nanoparticle-based drug delivery systems: a review. Int J Biol Macromol. 2021;193(Pt A):457\u201373.","journal-title":"Int J Biol Macromol"},{"issue":"11","key":"6503_CR76","doi-asserted-by":"publisher","first-page":"976","DOI":"10.2174\/1389557516666160505114814","volume":"18","author":"X She","year":"2018","unstructured":"She X, Chen L, Yi Z, et al. Tailored mesoporous silica nanoparticles for controlled drug delivery: platform fabrication, targeted delivery, and computational design and analysis. Mini Rev Med Chem. 2018;18(11):976\u201389.","journal-title":"Mini Rev Med Chem"},{"issue":"4","key":"6503_CR77","first-page":"998","volume":"6","author":"W Wei","year":"2021","unstructured":"Wei W, Ma Y, Yao X, et al. Advanced hydrogels for the repair of cartilage defects and regeneration. Bioact Mater. 2021;6(4):998\u20131011.","journal-title":"Bioact Mater"},{"issue":"12","key":"6503_CR78","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1002\/adma.201104763","volume":"24","author":"F Tang","year":"2012","unstructured":"Tang F, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv Mater (Deerfield Beach, Fla). 2012;24(12):1504\u201334.","journal-title":"Adv Mater (Deerfield Beach, Fla)"},{"key":"6503_CR79","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041896","author":"T Christoforidou","year":"2021","unstructured":"Christoforidou T, Giasafaki D, Andriotis EG, et al. Oral drug delivery systems based on ordered mesoporous silica nanoparticles for modulating the release of aprepitant. Int J Mol Sci. 2021. https:\/\/doi.org\/10.3390\/ijms22041896.","journal-title":"Int J Mol Sci"},{"issue":"5","key":"6503_CR80","doi-asserted-by":"publisher","first-page":"e1373","DOI":"10.1210\/clinem\/dgad711","volume":"109","author":"KH Park-Min","year":"2024","unstructured":"Park-Min KH, Mun SH, Bockman R, McDonald MM. New horizons: translational aspects of osteomorphs. J Clin Endocrinol Metab. 2024;109(5):e1373\u20138.","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Journal of Orthopaedic Surgery and Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-025-06503-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13018-025-06503-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-025-06503-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:02:14Z","timestamp":1766491334000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13018-025-06503-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6503"],"URL":"https:\/\/doi.org\/10.1186\/s13018-025-06503-7","relation":{},"ISSN":["1749-799X"],"issn-type":[{"value":"1749-799X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"assertion":[{"value":"18 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1079"}}