{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:02:14Z","timestamp":1790744534948,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite three decades of research efforts, no significant improvement in patient survival rates has been achieved, highlighting the urgent need for in-depth investigation into its pathogenesis to develop novel therapeutic strategies and more effective drugs. FOXD2-AS1, a long non-coding RNA, has been implicated in the prognosis and survival of various cancers, but its role in OS remains underexplored. This study therefore aimed to investigate the functional involvement of FOXD2-AS1 in OS progression and to evaluate a biocompatible delivery system for its in vitro and in vivo application.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We synthesized mPEG-PDPA hydrogel via free radical polymerization of 2-(diisopropylamino)ethyl methacrylate (PDA) and polyethylene glycol monomethyl ether acrylate (mPEG-AC), and employed this hydrogel as a delivery vehicle for FOXD2-AS1. The biocompatibility and safety of the empty hydrogel were first validated through both\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell assays and\n                      <jats:italic>in vivo<\/jats:italic>\n                      animal experiments. To explore the mechanistic actions of FOXD2-AS1, we performed real-time quantitative PCR and Western blot analyses, and conducted transcriptome profiling to identify downstream pathways and associated genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>Our results demonstrated that the mPEG-PDPA hydrogel itself was non-toxic and reliable as a delivery vehicle. Functionally, FOXD2-AS1 promoted alkaline phosphatase (ALP) release and exacerbated the inflammatory response, thereby accelerating the development and deterioration of OS. Mechanistically, FOXD2-AS1 activated the F-box protein Coronatine Insensitive 1 homolog (COI-1)\/OCN\/Runx-2 signaling pathway, as confirmed by qPCR and Western blot. Transcriptome analysis further revealed that this process involved changes in cell migration, apoptosis, and cell cycle regulation, with CPS1-IT1, ANKRD10-IT1, TBC1D3P1-DHX40P1, and RGS5 identified as key associated genes. Collectively, our findings provide new insights into the pathological mechanisms of OS and offer valuable data support for future therapeutic strategy development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1664094","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:51:26Z","timestamp":1790743886000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathological mechanisms of long non-coding RNA FOXD2-AS1 promoting osteosarcoma mediated by the COI-1\/OCN\/Runx-2 signaling pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhipeng","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Tianjin Hospital","place":["Tianjin, China"]},{"name":"Department of Orthopaedics, Tianjin Hospital, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liandong","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Tianjin Hospital","place":["Tianjin, China"]},{"name":"Department of Orthopaedics, Tianjin Hospital, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Tianjin Hospital","place":["Tianjin, China"]},{"name":"Department of Orthopaedics, Tianjin Hospital, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hejun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Tianjin First Central Hospital","place":["Tianjin, China"]},{"name":"Department of Endocrinology and Metabolism, Tianjin First Central Hospital, Affiliated Hospital of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41571-021-00519-8","article-title":"Advancing therapy for osteosarcoma","volume":"18","author":"Gill","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","article-title":"Osteosarcoma","volume":"8","author":"Beird","year":"2022","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1056\/NEJMra2103423","article-title":"New horizons in the treatment of osteosarcoma","volume":"385","author":"Meltzer","year":"2021","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41413-023-00246-z","article-title":"Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment","volume":"11","author":"Tian","year":"2023","journal-title":"Bone Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7207","DOI":"10.1038\/s41467-022-34689-5","article-title":"Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment","volume":"13","author":"Jiang","year":"2022","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0248984","DOI":"10.1371\/journal.pone.0248984","article-title":"High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs","volume":"16","author":"Kafita","year":"2021","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"12742","DOI":"10.1038\/s41598-023-39608-2","article-title":"Mutational landscape of cancer-driver genes across human cancers","volume":"13","author":"Sinkala","year":"2023","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"130729","DOI":"10.1016\/j.ijbiomac.2024.130729","article-title":"Co-delivery of siAEG-1 and doxorubicin to treat osteosarcoma via nanomicelles for azide\u2212alkyne \u201cclick\u201d conjugation of poly(l-lysine) dendrons onto Zein","volume":"264","author":"Pang","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/s41586-020-1996-3","article-title":"Loss of p53 drives neuron reprogramming in head and neck cancer","volume":"578","author":"Amit","year":"2020","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.pcad.2024.01.016","article-title":"RNA In cardiovascular disease: a new frontier of personalized medicine","volume":"85","author":"Abdul-Rahman","year":"2024","journal-title":"Prog Cardiovasc Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41392-024-01777-5","article-title":"RNA Modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy","volume":"9","author":"Liu","year":"2024","journal-title":"Signal Transduction Targeted Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"115890","DOI":"10.1016\/j.bcp.2023.115890","article-title":"Macrophage lncRNAs in cancer development: long-awaited therapeutic targets","volume":"218","author":"Arab","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"5340240","DOI":"10.1155\/2021\/5340240","article-title":"Identification of epithelial-mesenchymal transition- (EMT-) related LncRNA for prognostic prediction and risk stratification in esophageal squamous cell carcinoma","volume":"2021","author":"Wang","year":"2021","journal-title":"Dis Markers"},{"key":"B14","doi-asserted-by":"publisher","first-page":"100491","DOI":"10.1016\/j.jbo.2023.100491","article-title":"LncRNA SATB2-AS1 promotes tumor growth and metastasis and affects the tumor immune microenvironment in osteosarcoma by regulating SATB2","volume":"41","author":"Wang","year":"2023","journal-title":"J Bone Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41419-020-2232-7","article-title":"Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"155101","DOI":"10.1016\/j.prp.2024.155101","article-title":"A review on the role of FOXD2-AS1 in human disorders","volume":"254","author":"Ghafouri-Fard","year":"2024","journal-title":"Pathol Res Pract"},{"key":"B17","doi-asserted-by":"publisher","first-page":"109104","DOI":"10.1016\/j.biopha.2019.109104","article-title":"HIF-1\u03b1 induced long noncoding RNA FOXD2-AS1 promotes the osteosarcoma through repressing p21","volume":"117","author":"Ren","year":"2019","journal-title":"Biomed Pharmacother"},{"key":"B18","doi-asserted-by":"publisher","first-page":"115325","DOI":"10.1016\/j.addr.2024.115325","article-title":"Advances in local drug delivery technologies for improved rheumatoid arthritis therapy","volume":"209","author":"An","year":"2024","journal-title":"Adv Drug Delivery Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"104753","DOI":"10.1016\/j.jddst.2023.104753","article-title":"Advanced nanoparticles, the hallmark of targeted drug delivery for osteosarcoma-an updated review","volume":"87","author":"Ashique","year":"2023","journal-title":"J Drug Delivery Sci Technol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1021\/acsmacrolett.3c00265","article-title":"UV Irradiation-Induced cyclic-to-linear topological changes of a light\/pH dual-sensitive cyclic copolymer for enhanced drug delivery","volume":"12","author":"Liu","year":"2023","journal-title":"ACS Macro Lett"},{"key":"B21","doi-asserted-by":"publisher","first-page":"103591","DOI":"10.1016\/j.jddst.2022.103591","article-title":"Ranella, pH responsive biohybrid BSA-poly(DPA) nanoparticles for interlysosomal drug delivery","volume":"75","author":"Papadimitriou","year":"2022","journal-title":"J Drug Delivery Sci Technol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2000143","DOI":"10.1002\/mabi.202000143","article-title":"Comb-like amphiphilic polycarbonates with different lengths of cationic branches for enhanced siRNA delivery","volume":"20","author":"Dong","year":"2020","journal-title":"Macromol Biosci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5608","DOI":"10.1039\/C6TB01556E","article-title":"Guanidinylated cationic nanoparticles as robust protein antigen delivery systems and adjuvants for promoting antigen-specific immune responses in vivo","volume":"4","author":"Li","year":"2016","journal-title":"J Mater Chem B"},{"key":"B24","doi-asserted-by":"publisher","first-page":"7963","DOI":"10.1080\/21655979.2021.2008218","article-title":"N6-methyladenosine methyltransferase WTAP-stabilized FOXD2-AS1 promotes the osteosarcoma progression through m6A\/FOXM1 axis","volume":"13","author":"Ren","year":"2022","journal-title":"Bioengineered"},{"key":"B25","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1146\/annurev.bioeng.4.111901.093336","article-title":"Advances in in vivo bioluminescence imaging of gene expression","volume":"4","author":"Contag","year":"2002","journal-title":"Annu Rev Biomed Eng"},{"key":"B26","doi-asserted-by":"publisher","first-page":"9835","DOI":"10.3390\/ijms24129835","article-title":"Curcumin attenuates periodontal injury via inhibiting ferroptosis of ligature-induced periodontitis in mice","volume":"24","author":"Wang","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1007\/s00432-022-03967-6","article-title":"Regulatory network identified by pulmonary transcriptome and proteome profiling reveals extensive change of tumor-related genes in microRNA-21 knockout mice","volume":"148","author":"Luan","year":"2022","journal-title":"J Cancer Res Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"16740","DOI":"10.1038\/s41598-021-95568-5","article-title":"A simple and fast spectroscopy-based technique for COVID-19 diagnosis","volume":"11","author":"Kitane","year":"2021","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/s41563-023-01472-w","article-title":"Hydrogels for RNA delivery","volume":"22","author":"Zhong","year":"2023","journal-title":"Nat Mater"},{"key":"B30","doi-asserted-by":"publisher","first-page":"9106","DOI":"10.1016\/j.biomaterials.2010.08.016","article-title":"Incorporation of active DNA\/cationic polymer polyplexes into hydrogel scaffolds","volume":"31","author":"Lei","year":"2010","journal-title":"Biomaterials"},{"key":"B31","doi-asserted-by":"publisher","first-page":"30","DOI":"10.53350\/pjmhs2216330","article-title":"Alkaline phosphatase as serum tumor marker in osteosarcoma","volume":"16","author":"Bhatti","year":"2022","journal-title":"Pak J Med Health Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1177\/03009858221083035","article-title":"The use of alkaline phosphatase and runx2 to distinguish osteosarcoma from other common malignant primary bone tumors in dogs","volume":"59","author":"Barger","year":"2022","journal-title":"Vet Pathol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2147\/pgpm.s396866","article-title":"LncRNA FOXD2-AS1 increased proliferation and invasion of lung adenocarcinoma via cell-cycle regulation","volume":"16","author":"Yuan","year":"2023","journal-title":"Pharmgenomics Pers Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"bbab504","DOI":"10.1093\/bib\/bbab504","article-title":"Tumor immune microenvironment lncRNAs","volume":"23","author":"Park","year":"2022","journal-title":"Brief Bioinform"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1111\/jcmm.17268","article-title":"Overexpression of FOXD2-AS1 enhances proliferation and impairs differentiation of glioma stem cells by activating the NOTCH pathway via TAF-1","volume":"26","author":"Wang","year":"2022","journal-title":"J Cell Mol Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.amjms.2021.01.020","article-title":"Long non-coding RNA FOXD2-AS1 serves as a potential prognostic biomarker for patients with cancer: a meta-analysis and database testing","volume":"362","author":"Duan","year":"2021","journal-title":"Am J Med Sci"},{"key":"B37","doi-asserted-by":"publisher","first-page":"678","DOI":"10.26355\/eurrev_202101_24629","article-title":"LncRNA FOXD2-AS1 knockdown inhibits the resistance of human osteosarcoma cells to cisplatin by inhibiting miR-143 expression","volume":"25","author":"Zhang","year":"2021","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"6064","DOI":"10.1021\/acsnano.1c11562","article-title":"Trauma-responsive scaffold synchronizing oncolysis immunization and inflammation alleviation for post-operative suppression of cancer metastasis","volume":"16","author":"Li","year":"2022","journal-title":"ACS Nano"},{"key":"B39","doi-asserted-by":"publisher","first-page":"6346409","DOI":"10.1155\/2018\/6346409","article-title":"The role of osteocalcin and alkaline phosphatase immunohistochemistry in osteosarcoma diagnosis","volume":"2018","author":"Agustina","year":"2018","journal-title":"Patholog Res Int"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e23317","DOI":"10.1002\/jcla.23317","article-title":"Long noncoding RNAs in osteosarcoma via various signaling pathways","volume":"34","author":"Han","year":"2020","journal-title":"J Clin Lab Anal"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.22034\/apjcp.2018.19.8.2279","article-title":"Comparative study of correlation between angiogenesis markers (CD31) and Ki67 marker with behavior of aggressive and nonaggressive central giant cell granuloma with immunohistochemistry technique","volume":"19","author":"Razavi","year":"2018","journal-title":"Asian Pac J Cancer Prev"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2304163","DOI":"10.1002\/adfm.202304163","article-title":"Self-adaptive MoO3\u2212x subnanometric wires incorporated scaffolds for osteosarcoma therapy and bone regeneration","volume":"33","author":"Fang","year":"2023","journal-title":"Adv Funct Mater"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1664094\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:51:32Z","timestamp":1790743892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1664094\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":42,"alternative-id":["10.3389\/fmed.2026.1664094"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1664094","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"article-number":"1664094"}}