{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T00:18:25Z","timestamp":1769300305828,"version":"3.49.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteoporosis has become an increasingly pressing global public health challenge. Monoclonal antibody romosozumab (ROMO), which targets sclerostin (SOST), a critical inhibitor of bone formation, demonstrates considerable therapeutic efficacy. However, its relatively high cost and potential cardiovascular risks may hinder broader clinical application. Current preventive measures remain inadequate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study presents a novel, cost-effective osteoporosis vaccine with dual preventive and therapeutic capabilities, derived from the high-affinity binding epitope of ROMO to SOST. ELISA screening determined that the SOST\n                      <jats:sub>131\u2013163<\/jats:sub>\n                      region within loop3 domain serves as the primary epitope for ROMO, suggesting a role in skeletal regulation with minimal impact on cardiovascular system. SOST\n                      <jats:sub>131\u2013163<\/jats:sub>\n                      was conjugated to the diphtheria toxin translocation domain (DTT) to create novel SOST-targeted vaccines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Immunogenicity assays demonstrated that both DDT-SOST\n                      <jats:sub>(131-163)3<\/jats:sub>\n                      (DS\n                      <jats:sub>3<\/jats:sub>\n                      ) and DDT-SOST\n                      <jats:sub>(131-163)5<\/jats:sub>\n                      (DS\n                      <jats:sub>5<\/jats:sub>\n                      ) elicited strong IgG2 antibody responses comparable to ROMO. Molecular docking studies indicated strong affinities of DS\n                      <jats:sub>3<\/jats:sub>\n                      and DS\n                      <jats:sub>5<\/jats:sub>\n                      for Toll-like receptor 2 (TLR2), enhancing TLR2-mediated humoral B-cell immunity and eliciting synergistic T-helper cell responses. Recombinant expression in Escherichia coli confirmed the successful production of DS\n                      <jats:sub>3<\/jats:sub>\n                      and DS\n                      <jats:sub>5<\/jats:sub>\n                      , with molecular weights of 31.8 kDa and 40.3 kDa, respectively.\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments showed that the vaccines effectively induced high-titer anti-SOST antibodies in mice, overcoming immune tolerance. Additionally, cell-based assays indicated that antiserum from vaccinated mice inhibited osteoclast differentiation and promoted osteoblast mineralization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The SOST-targeted vaccination strategy offers a promising and cost-effective approach for the early prevention and sustained management of osteoporosis, demonstrating substantial potential for clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1644437","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T05:16:12Z","timestamp":1764566172000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["In silico design of novel precision vaccine targeting sclerostin epitopes for osteoporosis prevention and treatment"],"prefix":"10.3389","volume":"16","author":[{"given":"Jianzhou","family":"Luo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tailin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zili","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiren","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/S2213-8587(17)30188-2","article-title":"Osteoporosis treatment: recent developments and ongoing challenges","volume":"5","author":"Khosla","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1186\/s13018-021-02821-8","article-title":"Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis","volume":"16","author":"Salari","year":"2021","journal-title":"J Orthop Surg Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s11657-014-0182-3","article-title":"Estimating prevalence of osteoporosis: examples from industrialized countries","volume":"9","author":"Wade","year":"2014","journal-title":"Arch Osteoporos"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1513724","article-title":"Clinical practice. Postmenopausal osteoporosis","volume":"374","author":"Black","year":"2016","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1186\/s12967-023-04563-z","article-title":"Romosozumab in osteoporosis: yesterday, today and tomorrow","volume":"21","author":"Wu","year":"2023","journal-title":"J Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab193","article-title":"Cardiovascular safety and sclerostin inhibition","volume":"106","author":"Langdahl","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-023-02319-2","article-title":"SOST gene suppression stimulates osteocyte Wnt\/\u03b2-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis","volume":"101","author":"Jiao","year":"2023","journal-title":"J Mol Med (Berl)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"R167","DOI":"10.1530\/JME-18-0176","article-title":"Novel actions of sclerostin on bone","volume":"62","author":"Holdsworth","year":"2019","journal-title":"J Mol Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/hta24290","article-title":"Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation","volume":"24","author":"Davis","year":"2020","journal-title":"Health Technol Assess"},{"key":"B10","doi-asserted-by":"publisher","first-page":"113610","DOI":"10.1016\/j.intimp.2024.113610","article-title":"In silicon desinging of RANKL-targeting vaccine for protection of osteoporosis based on the epitope of Denosumab","volume":"144","author":"Wu","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.03.205","article-title":"A new vaccine targeting RANKL, prepared by incorporation of an unnatural Amino acid into RANKL, prevents OVX-induced bone loss in mice","volume":"499","author":"Li","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2020.03.006","article-title":"Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches","volume":"25","author":"Parvizpour","year":"2020","journal-title":"Drug Discov Today"},{"key":"B13","doi-asserted-by":"publisher","first-page":"W322","DOI":"10.1093\/nar\/gkz397","article-title":"HawkDock: a web server to predict and analyze the protein-protein complex based on computational docking and MM\/GBSA","volume":"47","author":"Weng","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3289","article-title":"PDBsum: Structural summaries of PDB entries","volume":"27","author":"Laskowski","year":"2018","journal-title":"Protein Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"W449","DOI":"10.1093\/nar\/gkaa379","article-title":"NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data","volume":"48","author":"Reynisson","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1293706","article-title":"MHCII-peptide presentation: an assessment of the state-of-the-art prediction methods","volume":"15","author":"Yang","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"W24","DOI":"10.1093\/nar\/gkx346","article-title":"BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes","volume":"45","author":"Jespersen","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1186\/1471-2105-9-514","article-title":"ElliPro: a new structure-based tool for the prediction of antibody epitopes","volume":"9","author":"Ponomarenko","year":"2008","journal-title":"BMC Bioinf"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr335","article-title":"Immune system simulation online","volume":"27","author":"Rapin","year":"2011","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094751","article-title":"Sclerostin: from molecule to clinical biomarker","volume":"23","author":"Omran","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1007\/s00894-014-2278-5","article-title":"AllerTOP v.2\u2013a server for in silico prediction of allergens","volume":"20","author":"Dimitrov","year":"2014","journal-title":"J Mol Model"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1471-2105-8-4","article-title":"VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines","volume":"8","author":"Doytchinova","year":"2007","journal-title":"BMC Bioinf"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp386","article-title":"SOLpro: accurate sequence-based prediction of protein solubility","volume":"25","author":"Magnan","year":"2009","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA118.000799","article-title":"Glycomics@ExPASy: bridging the gap","volume":"17","author":"Mariethoz","year":"2018","journal-title":"Mol Cell Proteomics"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/7.2.157","article-title":"SOPM: a self-optimized method for protein secondary structure prediction","volume":"7","author":"Geourjon","year":"1994","journal-title":"Protein Eng"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/16.4.404","article-title":"The PSIPRED protein structure prediction server","volume":"16","author":"McGuffin","year":"2000","journal-title":"Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx345","article-title":"Protein-Sol: a web tool for predicting protein solubility from sequence","volume":"33","author":"Hebditch","year":"2017","journal-title":"Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt458","article-title":"GalaxyRefine: Protein structure refinement driven by side-chain repacking","volume":"41","author":"Heo","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560020916","article-title":"Verification of protein structures: patterns of nonbonded atomic interactions","volume":"2","author":"Colovos","year":"1993","journal-title":"Protein Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/BF00228148","article-title":"AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR","volume":"8","author":"Laskowski","year":"1996","journal-title":"J Biomol NMR"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz437","article-title":"PRODIGY-crystal: a web-tool for classification of biological interfaces in protein complexes","volume":"35","author":"Jim\u00e9nez-Garc\u00eda","year":"2019","journal-title":"Bioinformatics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.05.022","article-title":"Inference of macromolecular assemblies from crystalline state","volume":"372","author":"Krissinel","year":"2007","journal-title":"J Mol Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku339","article-title":"iMODS: internal coordinates normal mode analysis server","volume":"42","author":"L\u00f3pez-Blanco","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki376","article-title":"JCat: a novel tool to adapt codon usage of a target gene to its potential expression host","volume":"33","author":"Grote","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607948","article-title":"Romosozumab treatment in postmenopausal women with osteoporosis","volume":"375","author":"Cosman","year":"2016","journal-title":"N Engl J Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1759720x231197094","DOI":"10.1177\/1759720X231197094","article-title":"Anti-sclerostin antibodies: a new frontier in fragility fractures treatment","volume":"15","author":"Iolascon","year":"2023","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2022-002851","article-title":"Peptide-based vaccine targeting IL17A attenuates experimental spondyloarthritis in HLA-B27 transgenic rats","volume":"9","author":"Hayashi","year":"2023","journal-title":"RMD Open"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4161\/hv.27520","article-title":"Hypertension Vaccine may be a boon to millions in developing world","volume":"10","author":"Bairwa","year":"2014","journal-title":"Hum Vaccin Immunother"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1177\/01939459211005710","article-title":"Assessing vaccine protection for older adults with diabetes: A systematic review","volume":"44","author":"Almasri","year":"2022","journal-title":"West J Nurs Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/17460441.2019.1667329","article-title":"How plausible is an Alzheimer's disease vaccine","volume":"15","author":"Cacabelos","year":"2020","journal-title":"Expert Opin Drug Discov"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M807994200","article-title":"Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation","volume":"284","author":"Veverka","year":"2009","journal-title":"J Biol Chem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.350108","article-title":"Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors","volume":"287","author":"Holdsworth","year":"2012","journal-title":"J Biol Chem"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.7150\/thno.63177","article-title":"Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice","volume":"12","author":"Wang","year":"2022","journal-title":"Theranostics"},{"key":"B46","doi-asserted-by":"publisher","first-page":"4241","DOI":"10.1038\/s41467-022-31997-8","article-title":"Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation","volume":"13","author":"Yu","year":"2022","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","first-page":"116414","DOI":"10.1016\/j.ejmech.2024.116414","article-title":"Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design","volume":"271","author":"Yu","year":"2024","journal-title":"Eur J Med Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/biom15020239","article-title":"Reduced bone quality of sacrum and lumbal vertebrae spongiosa in toll-like receptor 2- and toll-like receptor 4-knockout mice: A blinded micro-computerized analysis","volume":"15","author":"Roth","year":"2025","journal-title":"Biomolecules"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1383113","article-title":"Toll-like receptor-2 induced inflammation causes local bone formation and activates canonical Wnt signaling","volume":"15","author":"Henning","year":"2024","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.011","article-title":"Role of TLR2 and TLR4 in regulation of articular chondrocyte homeostasis","volume":"28","author":"Wang","year":"2020","journal-title":"Osteoarthritis Cartilage"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1644437\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T05:16:13Z","timestamp":1764566173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1644437\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2025.1644437"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1644437","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"article-number":"1644437"}}