{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:10:16Z","timestamp":1780402216023,"version":"3.54.1"},"reference-count":63,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Global disability from osteoarthritis (OA) remains a staggering burden, yet disease-modifying pharmacological therapies remain limited. Current evidence supports OA as a whole-joint disease in which subchondral bone remodeling acts as an early and active driver of structural progression and pain. Osteoclasts are key regulators of this process, but clinical trials targeting osteoclast-dependent remodeling have yielded inconsistent results. This translational gap suggests that the traditional view of osteoclasts as a homogeneous, terminally differentiated resorptive population is no longer sufficient. Latest breakthroughs in single-cell and spatial multi-omics have begun to redefine osteoclast biology by revealing heterogeneity across precursor origin, lineage state, functional output, and niche-specific adaptation. In OA, these studies have clarified the osteoclastogenic microenvironment more clearly than the terminal taxonomy of mature osteoclast subsets, thereby shifting the field toward a state-spectrum framework. In this review, we synthesize recent high-resolution evidence to examine how osteoclast-lineage heterogeneity is organized across disease stages and osteochondral microenvironments, and how distinct osteoclast-lineage programs contribute to subchondral remodeling, angiogenic coupling, interface instability, and pain-related pathology. We further discuss how this framework may inform patient stratification, mechanism-matched intervention, and the development of program-specific therapies in OA.<\/jats:p>","DOI":"10.3390\/ijms27114838","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"4838","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Osteoclast Heterogeneity in Osteoarthritis: From Single-Cell Microenvironments to Program-Specific Therapeutic Opportunities"],"prefix":"10.3390","volume":"27","author":[{"given":"Tingxuan","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peidong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Hui","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1776-2750","authenticated-orcid":false,"given":"Deng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e496","DOI":"10.1016\/S2665-9913(23)00207-2","article-title":"The global burden of osteoarthritis: Past and future perspectives","volume":"5","author":"Wong","year":"2023","journal-title":"Lancet Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41584-020-00518-6","article-title":"Emerging pharmaceutical therapies for osteoarthritis","volume":"16","author":"Latourte","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41584-025-01223-y","article-title":"The role of the immune system in osteoarthritis: Mechanisms, challenges and future directions","volume":"21","author":"Moulin","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","first-page":"1461","article-title":"What drives osteoarthritis?-synovial versus subchondral bone pathology","volume":"56","author":"Hugle","year":"2017","journal-title":"Rheumatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/S0140-6736(23)01726-9","article-title":"Inflammation is a relevant treatment target in osteoarthritis","volume":"402","author":"Kloppenburg","year":"2023","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrrheum.2012.130","article-title":"Bone remodelling in osteoarthritis","volume":"8","author":"Burr","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_7","first-page":"499","article-title":"Subchondral osteoclasts and osteoarthritis: New insights and potential therapeutic avenues","volume":"56","author":"Chen","year":"2024","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e14092","DOI":"10.1111\/acel.14092","article-title":"Osteoclasts and osteoarthritis: Novel intervention targets and therapeutic potentials during aging","volume":"23","author":"Wang","year":"2024","journal-title":"Aging Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bone.2013.10.024","article-title":"Bisphosphonate-osteoclasts: Changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients","volume":"59","author":"Jobke","year":"2014","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115352","DOI":"10.1016\/j.bone.2020.115352","article-title":"Bisphosphonates as a treatment modality in osteoarthritis","volume":"143","author":"Eriksen","year":"2021","journal-title":"Bone"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-pathmechdis-031521-040919","article-title":"Osteoclasts, Master Sculptors of Bone","volume":"18","author":"Veis","year":"2023","journal-title":"Annu. Rev. Pathol."},{"key":"ref_12","first-page":"e10631","article-title":"Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets","volume":"6","author":"Omata","year":"2022","journal-title":"J. Bone Miner. Res. Plus"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s41232-022-00213-x","article-title":"Osteoclast biology in the single-cell era","volume":"42","author":"Tsukasaki","year":"2022","journal-title":"Inflamm. Regen."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1172\/JCI121561","article-title":"Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain","volume":"129","author":"Zhu","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.11005\/jbm.2023.30.2.127","article-title":"Origin of Osteoclasts: Osteoclast Precursor Cells","volume":"30","author":"Tsai","year":"2023","journal-title":"J. Bone Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1007\/s11914-022-00738-7","article-title":"Functional Heterogeneity Within Osteoclast Populations-a Critical Review of Four Key Publications that May Change the Paradigm of Osteoclasts","volume":"20","author":"Sharma","year":"2022","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41586-019-1105-7","article-title":"Developmental origin, functional maintenance and genetic rescue of osteoclasts","volume":"568","author":"Percin","year":"2019","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sun, Y., Li, J., Xie, X., Gu, F., Sui, Z., Zhang, K., and Yu, T. (2021). Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.778078"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1373","DOI":"10.1210\/clinem\/dgad711","article-title":"New Horizons: Translational Aspects of Osteomorphs","volume":"109","author":"Mun","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/j.cell.2021.02.002","article-title":"Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption","volume":"184","author":"McDonald","year":"2021","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1242\/jcs.113.3.377","article-title":"The cell biology of osteoclast function","volume":"113","author":"Vaananen","year":"2000","journal-title":"J. Cell Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Madel, M.B., Ibanez, L., Wakkach, A., de Vries, T.J., Teti, A., Apparailly, F., and Blin-Wakkach, C. (2019). Immune Function and Diversity of Osteoclasts in Normal and Pathological Conditions. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01408"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e002314","DOI":"10.1136\/rmdopen-2022-002314","article-title":"Single-cell RNA-sequencing analysis reveals the molecular mechanism of subchondral bone cell heterogeneity in the development of osteoarthritis","volume":"8","author":"Hu","year":"2022","journal-title":"Rmd Open"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e13517","DOI":"10.1111\/cpr.13517","article-title":"Single-cell RNA sequencing in osteoarthritis","volume":"56","author":"Gu","year":"2023","journal-title":"Cell Prolif."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41584-023-01052-x","article-title":"Profiling joint tissues at single-cell resolution: Advances and insights","volume":"20","author":"Pandey","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.joca.2025.08.016","article-title":"Standardizing single-cell approaches to osteoarthritis: Toward a comprehensive cellular atlas","volume":"34","author":"Duran","year":"2026","journal-title":"Osteoarthr. Cartil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41413-025-00467-4","article-title":"Single-cell sequencing reveals a senescent immune landscape in bone marrow lesions inducing articular cartilage damage in osteoarthritis","volume":"13","author":"Lou","year":"2025","journal-title":"Bone Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.joca.2025.07.007","article-title":"Resolving microenvironment complexity and cellular heterogeneity in osteoarthritis via spatial transcriptomics","volume":"34","author":"Xie","year":"2026","journal-title":"Osteoarthr. Cartil."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41392-025-02136-8","article-title":"Single-cell transcriptomics reveals novel chondrocyte and osteoblast subtypes and their role in knee osteoarthritis pathogenesis","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135446","DOI":"10.1172\/jci.insight.135446","article-title":"Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development","volume":"5","author":"Su","year":"2020","journal-title":"JCI Insight"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95083","DOI":"10.7554\/eLife.95083","article-title":"Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast-osteoblast communication and potential clinical implications","volume":"13","author":"Daponte","year":"2024","journal-title":"Elife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.joca.2023.11.019","article-title":"Three decades of advancements in osteoarthritis research: Insights from transcriptomic, proteomic, and metabolomic studies","volume":"32","author":"Rai","year":"2024","journal-title":"Osteoarthr. Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1146\/annurev-genom-010423-095636","article-title":"The Genetics and Functional Genomics of Osteoarthritis","volume":"25","author":"Arruda","year":"2024","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1182\/blood-2010-02-258558","article-title":"Nomenclature of monocytes and dendritic cells in blood","volume":"116","author":"Ancuta","year":"2010","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1136\/annrheumdis-2016-210426","article-title":"CCL2\/CCR2, but not CCL5\/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis","volume":"76","author":"Raghu","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.4049\/jimmunol.181.2.1232","article-title":"Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo","volume":"181","author":"Chang","year":"2008","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.bone.2008.04.006","article-title":"Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors","volume":"43","author":"Tat","year":"2008","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8792","DOI":"10.1038\/s41467-024-53119-2","article-title":"A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression","volume":"15","author":"Liang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11394","DOI":"10.1038\/s41467-025-66202-z","article-title":"Denosumab attenuates knee osteoarthritis progression by inhibiting synovial inflammation via the RANK\/TRAF6\/FSTL1 signalling","volume":"16","author":"Hu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/ar4405","article-title":"Subchondral bone in osteoarthritis: Insight into risk factors and microstructural changes","volume":"15","author":"Li","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s00167-010-1054-z","article-title":"The basic science of the subchondral bone","volume":"18","author":"Madry","year":"2010","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e002617","DOI":"10.1136\/rmdopen-2022-002617","article-title":"Insights into osteoarthritis development from single-cell RNA sequencing of subchondral bone","volume":"8","author":"Shen","year":"2022","journal-title":"RMD Open"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00428-012-1274-3","article-title":"Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption","volume":"461","author":"Knowles","year":"2012","journal-title":"Virchows Arch."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1111\/joa.13728","article-title":"Structural clues to articular calcified cartilage function: A descriptive review of this crucial interface tissue","volume":"241","author":"Evans","year":"2022","journal-title":"J. Anat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1302\/2046-3758.127.BJR-2022-0310.R1","article-title":"Multiple roles of ALK3 in osteoarthritis","volume":"12","author":"Ruan","year":"2023","journal-title":"Bone Jt. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1002\/jbmr.4642","article-title":"Mineral Crystal Thickness in Calcified Cartilage and Subchondral Bone in Healthy and Osteoarthritic Human Knees","volume":"37","author":"Finnila","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Prieto-Potin, I., Largo, R., Roman-Blas, J.A., Herrero-Beaumont, G., and Walsh, D.A. (2015). Characterization of multinucleated giant cells in synovium and subchondral bone in knee osteoarthritis and rheumatoid arthritis. BMC Musculoskelet. Disord., 16.","DOI":"10.1186\/s12891-015-0664-5"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"93283","DOI":"10.7554\/eLife.93283","article-title":"Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis","volume":"12","author":"Knights","year":"2025","journal-title":"Elife"},{"key":"ref_49","first-page":"108","article-title":"Osteoclast-derived apoptotic bodies accelerate the pathological progression of osteoarthritis via disturbing subchondral bone remodeling","volume":"51","author":"Ai","year":"2025","journal-title":"J. Orthop. Transl."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nrrheum.2016.148","article-title":"Changes in the osteochondral unit during osteoarthritis: Structure, function and cartilage-bone crosstalk","volume":"12","author":"Goldring","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/nm.3668","article-title":"PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis","volume":"20","author":"Xie","year":"2014","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e2235060","DOI":"10.1001\/jamanetworkopen.2022.35060","article-title":"Placebo Response to Oral Administration in Osteoarthritis Clinical Trials and Its Associated Factors: A Model-Based Meta-analysis","volume":"5","author":"Wen","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1136\/annrheumdis-2011-200970","article-title":"Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: A randomised controlled trial","volume":"71","author":"Laslett","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/nm.2489","article-title":"Suppression of bone formation by osteoclastic expression of semaphorin 4D","volume":"17","author":"Shinohara","year":"2011","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1001\/jama.2018.19319","article-title":"Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis","volume":"320","author":"Gregori","year":"2018","journal-title":"JAMA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41413-021-00147-z","article-title":"Subchondral bone microenvironment in osteoarthritis and pain","volume":"9","author":"Hu","year":"2021","journal-title":"Bone Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nrrheum.2010.159","article-title":"The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis","volume":"6","author":"Sellam","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41413-022-00219-8","article-title":"Bone remodeling: An operational process ensuring survival and bone mechanical competence","volume":"10","author":"Bolamperti","year":"2022","journal-title":"Bone Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"86","DOI":"10.7326\/M19-0675","article-title":"Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial","volume":"172","author":"Conaghan","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41577-019-0178-8","article-title":"Osteoimmunology: Evolving concepts in bone-immune interactions in health and disease","volume":"19","author":"Tsukasaki","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41584-025-01323-9","article-title":"Mechanisms of osteoclast activation in inflammatory bone loss in rheumatoid arthritis","volume":"22","author":"Rauner","year":"2026","journal-title":"Nat. Rev. Rheumatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4838\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:30:33Z","timestamp":1780399833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4838"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":63,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114838"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114838","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}