{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:19:04Z","timestamp":1788153544948,"version":"build-2803163510"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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:p>Osteoarthritis (OA) is a whole-joint disease involving cartilage, synovium, subchondral bone, and neurovascular structures. Synovitis, damage-associated molecular patterns, and interactions between macrophages and fibroblast-like synoviocytes have been widely studied. However, a tissue-level explanation is still lacking for how low-grade and fluctuating synovial responses become persistent inflammation. We therefore propose a framework of synovial immune control failure. In this framework, the synovium does more than participate in inflammation. By clearing intra-articular damage-related material, limiting the duration of inflammation, maintaining stromal homeostasis, and regulating the entry of peripheral immune cells, it helps determine whether local joint inflammation can return to a low-level state. When damage-related inputs persist and debris clearance, inflammatory resolution, and resetting of cellular states do not occur in parallel, macrophages, fibroblast-like synoviocytes, and the vascular-interstitial interface may form a mutually sustaining pathological cellular network. Disease-associated cellular states and their interactions may then be retained locally in the synovium, forming what this article defines as an inflammatory niche. This niche may form bidirectional feedback with cartilage degeneration and subchondral bone remodeling. However, the synovium is not the common initiating tissue in all patients with OA. This framework may be most relevant to disease subtypes with persistent or recurrent synovitis, myeloid cell activation, and abnormal stromal remodeling. We further discuss the evidence base, boundaries, testable predictions, and potential implications of this model for OA patient stratification and synovium-targeted intervention.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1889424","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:29:49Z","timestamp":1788150589000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Synovial immune control failure in osteoarthritis: from maintenance of tissue homeostasis to inflammatory niche formation"],"prefix":"10.3389","volume":"17","author":[{"given":"Kangyi","family":"Hu","sequence":"first","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjia","family":"Song","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Pan","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiran","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqun","family":"Yan","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongpeng","family":"Xue","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Jia","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luhao","family":"Yu","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Song","sequence":"additional","affiliation":[{"name":"Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Bao","sequence":"additional","affiliation":[{"name":"School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2024.09.006","article-title":"Bone-brain crosstalk in osteoarthritis: pathophysiology and interventions","volume":"31","author":"Tang","year":"2025","journal-title":"Trends Mol Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1016\/s0140-6736(18)31064-x","article-title":"Osteoarthritis","volume":"391","author":"Barnett","year":"2018","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00749-9","article-title":"Synovial inflammation in osteoarthritis progression","volume":"18","author":"Sanchez-Lopez","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2147\/jir.S514002","article-title":"Osteoimmunology in osteoarthritis: unraveling the interplay of immunity, inflammation, and joint degeneration","volume":"18","author":"Hu","year":"2025","journal-title":"J Inflammation Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.joca.2024.01.005","article-title":"Molecular pathogenesis of OA pain: past, present, and future","volume":"32","author":"Vincent","year":"2024","journal-title":"Osteoarthritis Cartilage"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-205894","article-title":"Synovitis in knee osteoarthritis: a precursor of disease","volume":"75","author":"Atukorala","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"12310","DOI":"10.1038\/s41598-020-69328-w","article-title":"Detection of synovitis in early knee osteoarthritis by MRI and serum biomarkers in Japanese general population","volume":"10","author":"Ishibashi","year":"2020","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"10868","DOI":"10.1038\/s41598-020-67730-y","article-title":"Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis","volume":"10","author":"Chou","year":"2020","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1038\/s42003-025-08586-8","article-title":"A multi-tissue human knee single-cell atlas identifies that osteoarthritis reduces regenerative tissue stem cells while increasing inflammatory pain macrophages","volume":"8","author":"Raut","year":"2025","journal-title":"Commun Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1471-1","article-title":"Locally renewing resident synovial macrophages provide a protective barrier for the joint","volume":"572","author":"Culemann","year":"2019","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1229-9","article-title":"Synovitis in osteoarthritis: current understanding with therapeutic implications","volume":"19","author":"Mathiessen","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252212082","article-title":"Innate immunity and synovitis: key players in osteoarthritis progression","volume":"25","author":"Panichi","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1093\/rheumatology\/kev330","article-title":"Immunopathology of synovitis: from histology to molecular pathways","volume":"55","author":"van de Sande","year":"2016","journal-title":"Rheumatol (Oxford)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-222021","article-title":"Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go","volume":"81","author":"N\u00e9meth","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0413-5","article-title":"Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes","volume":"16","author":"Nygaard","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1385006","article-title":"Fibrotic pathways and fibroblast-like synoviocyte phenotypes in osteoarthritis","volume":"15","author":"Damerau","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00790-8","article-title":"Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission","volume":"18","author":"Kurowska-Stolarska","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.bioactmat.2025.09.016","article-title":"Remodeling of senescent macrophages in synovium alleviates trauma- and aging-induced osteoarthritis","volume":"55","author":"Liu","year":"2026","journal-title":"Bioact Mater"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.04.022","article-title":"The regulatory landscape of macrophage interferon signaling in inflammation","volume":"152","author":"Siebeler","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adf4590","article-title":"Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology","volume":"16","author":"Tang","year":"2024","journal-title":"Sci Transl Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2019.00192","article-title":"Hyaluronic acid: molecular mechanisms and therapeutic trajectory","volume":"6","author":"Gupta","year":"2019","journal-title":"Front Vet Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12971","article-title":"The inflammatory speech of fibroblasts","volume":"302","author":"Schuster","year":"2021","journal-title":"Immunol Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1263-7","article-title":"Distinct fibroblast subsets drive inflammation and damage in arthritis","volume":"570","author":"Croft","year":"2019","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/s41467-017-02659-x","article-title":"Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation","volume":"9","author":"Stephenson","year":"2018","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/jbmr\/zjad009","article-title":"Synovium and infrapatellar fat pad share common mesenchymal progenitors and undergo coordinated changes in osteoarthritis","volume":"39","author":"Li","year":"2024","journal-title":"J Bone Miner Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1159\/000532008","article-title":"Mild synovitis impairs chondrogenic joint environment","volume":"213","author":"Paudel","year":"2024","journal-title":"Cells Tissues Organs"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0378-1","article-title":"Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry","volume":"20","author":"Zhang","year":"2019","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2017.03.044","article-title":"DKK3 regulates cell proliferation, apoptosis and collagen synthesis in keloid fibroblasts via TGF-\u03b21\/Smad signaling pathway","volume":"91","author":"Li","year":"2017","journal-title":"BioMed Pharmacother"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.07.008","article-title":"Endothelial cells: from innocent bystanders to active participants in immune responses","volume":"16","author":"Al-Soudi","year":"2017","journal-title":"Autoimmun Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19072012","article-title":"Implications of angiogenesis involvement in arthritis","volume":"19","author":"MacDonald","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/art.43089","article-title":"Association of synovial innate immune exhaustion with worse pain in knee osteoarthritis","volume":"77","author":"Philpott","year":"2025","journal-title":"Arthritis Rheumatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.067470","article-title":"Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis","volume":"66","author":"Hill","year":"2007","journal-title":"Ann Rheum Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.12.003","article-title":"Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review","volume":"30","author":"Dainese","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.015","article-title":"Intra-articular depletion of macrophages increases acute synovitis and alters macrophage polarity in the injured mouse knee","volume":"28","author":"Bailey","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13237","article-title":"Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease","volume":"195","author":"van den Bosch","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.48","article-title":"HMGB1-LPS complex promotes transformation of osteoarthritis synovial fibroblasts to a rheumatoid arthritis synovial fibroblast-like phenotype","volume":"5","author":"Qin","year":"2014","journal-title":"Cell Death Dis"},{"key":"B37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/s13075-017-1426-6","article-title":"S100A8\/A9 increases the mobilization of pro-inflammatory Ly6C(high) monocytes to the synovium during experimental osteoarthritis","volume":"19","author":"Cremers","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.515106","article-title":"Low molecular weight hyaluronan activates cytosolic phospholipase A2\u03b1 and eicosanoid production in monocytes and macrophages","volume":"289","author":"Sokolowska","year":"2014","journal-title":"J Biol Chem"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1592751","article-title":"Targeting inflammatory macrophages with hyaluronan tetrasaccharide: effects on fibroblast collagen degradation and synthesis","volume":"16","author":"Uno","year":"2025","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1159\/000530280","article-title":"Low-molecular-weight hyaluronic acid contributes to noise-induced cochlear inflammation","volume":"28","author":"Zhang","year":"2023","journal-title":"Audiol Neurootol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/art.42412","article-title":"Impaired efferocytosis by synovial macrophages in patients with knee osteoarthritis","volume":"75","author":"Del Sordo","year":"2023","journal-title":"Arthritis Rheumatol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.joca.2023.02.050","article-title":"Impaired synovial macrophage-mediated efferocytosis in a rat model of post-traumatic knee osteoarthritis","volume":"31","author":"Del Sordo","year":"2023","journal-title":"Osteoarthritis Cartilage"},{"key":"B43","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41467-025-67473-2","article-title":"Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation","volume":"17","author":"Zhou","year":"2025","journal-title":"Nat Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.83069","article-title":"Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis","volume":"12","author":"Yao","year":"2023","journal-title":"Elife"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-220295","article-title":"Mechanosensitive TRPV4 is required for crystal-induced inflammation","volume":"80","author":"Lan","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.767512","article-title":"The expression of inflammasomes NLRP1 and NLRP3, toll-like receptors, and vitamin D receptor in synovial fibroblasts from patients with different types of knee arthritis","volume":"12","author":"Sakalyte","year":"2021","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1186\/s12967-023-04313-1","article-title":"Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS\/Cl(-) efflux signaling pathway","volume":"21","author":"Zhang","year":"2023","journal-title":"J Transl Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2024.05.033","article-title":"GYY4137-induced p65 sulfhydration protects synovial macrophages against pyroptosis by improving mitochondrial function in osteoarthritis development","volume":"71","author":"Ma","year":"2025","journal-title":"J Adv Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1002\/ptr.8158","article-title":"Quercetin as a promising intervention for rat osteoarthritis by decreasing M1-polarized macrophages via blocking the TRPV1-mediated P2X7\/NLRP3 signaling pathway","volume":"38","author":"Li","year":"2024","journal-title":"Phytother Res"},{"key":"B50","first-page":"694","article-title":"The effect of JAK1\/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib","volume":"37","author":"Choy","year":"2019","journal-title":"Clin Exp Rheumatol"},{"key":"B51","doi-asserted-by":"publisher","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":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1078414","article-title":"Comprehensive bulk and single-cell transcriptome profiling give useful insights into the characteristics of osteoarthritis associated synovial macrophages","volume":"13","author":"Liao","year":"2022","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/art.43299","article-title":"Monocyte-derived macrophages-synovial fibroblasts crosstalk unravels oncostatin signaling network as a driver of synovitis in osteoarthritis","volume":"78","author":"Laouteouet","year":"2026","journal-title":"Arthritis Rheumatol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1344949","article-title":"Songorine modulates macrophage polarization and metabolic reprogramming to alleviate inflammation in osteoarthritis","volume":"15","author":"He","year":"2024","journal-title":"Front Immunol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1186\/s12951-025-03543-3","article-title":"Liposome-encapsulated AICAR hydrogel regulates macrophage metabolic reprogramming via SIK1 activation to alleviate osteoarthritis","volume":"23","author":"Fu","year":"2025","journal-title":"J Nanobiotechnology"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202504768","article-title":"Functionalized biomimetic nanoparticles targeting the IL-10\/IL-10R\u03b1\/glycolytic axis in synovial macrophages alleviate cartilage degeneration in osteoarthritis","volume":"12","author":"Li","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2022.03.006","article-title":"Metabolic reprogramming of synovial fibroblasts in osteoarthritis by inhibition of pathologically overexpressed pyruvate dehydrogenase kinases","volume":"72","author":"Damerau","year":"2022","journal-title":"Metab Eng"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202304617","article-title":"Targeting YAP1-regulated glycolysis in fibroblast-like synoviocytes impairs macrophage infiltration to ameliorate diabetic osteoarthritis progression","volume":"11","author":"Yang","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2021.111616","article-title":"ROS\/TGF-\u03b2 signal mediated accumulation of SOX4 in OA-FLS promotes cell senescence","volume":"156","author":"Ye","year":"2021","journal-title":"Exp Gerontol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202307338","article-title":"Inflammatory fibroblast-like synoviocyte-derived exosomes aggravate osteoarthritis via enhancing macrophage glycolysis","volume":"11","author":"Liu","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B61","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s13075-020-02410-w","article-title":"Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis","volume":"23","author":"Rosshirt","year":"2021","journal-title":"Arthritis Res Ther"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082423","article-title":"T helper cell infiltration in osteoarthritis-related knee pain and disability","volume":"9","author":"Nees","year":"2020","journal-title":"J Clin Med"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10092111","article-title":"Infiltration profile of regulatory T cells in osteoarthritis-related pain and disability","volume":"10","author":"Nees","year":"2022","journal-title":"Biomedicines"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.01.036","article-title":"Downregulation of IL-10 secretion by Treg cells in osteoarthritis is associated with a reduction in Tim-3 expression","volume":"79","author":"Li","year":"2016","journal-title":"BioMed Pharmacother"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.193054","article-title":"Rheumatoid arthritis synovial fibroblasts modulate T cell activation","volume":"10","author":"Romoff","year":"2025","journal-title":"JCI Insight"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1136\/ard.60.8.802","article-title":"Clonal analysis of B cells in the osteoarthritis synovium","volume":"60","author":"Shiokawa","year":"2001","journal-title":"Ann Rheum Dis"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.1.557","article-title":"B cell clonal expansion and somatic hypermutation of Ig variable heavy chain genes in the synovial membrane of patients with osteoarthritis","volume":"178","author":"Da","year":"2007","journal-title":"J Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2023.03.017","article-title":"B-cell capacity for expansion and differentiation into plasma cells are altered in osteoarthritis","volume":"31","author":"Xie","year":"2023","journal-title":"Osteoarthritis Cartilage"},{"key":"B69","doi-asserted-by":"publisher","first-page":"4991","DOI":"10.1038\/s41467-024-49186-0","article-title":"Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium","volume":"15","author":"Dunlap","year":"2024","journal-title":"Nat Commun"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1302\/2046-3758.1112.Bjr-2022-0215.R1","article-title":"Molecular crosstalk between articular cartilage, meniscus, synovium, and subchondral bone in osteoarthritis","volume":"11","author":"Wang","year":"2022","journal-title":"Bone Joint Res"},{"key":"B71","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s13075-017-1318-9","article-title":"Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity","volume":"19","author":"Sw\u00e4rd","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.09.007","article-title":"A tool for evaluating novel osteoarthritis therapies using multivariate analyses of human cartilage-synovium explant co-culture","volume":"30","author":"Chan","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.843056","article-title":"The added value of the \"Co\" in co-culture systems in research on osteoarthritis pathology and treatment development","volume":"10","author":"Muenzebrock","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"R163","DOI":"10.1186\/ar4679","article-title":"Exosomes from IL-1\u03b2 stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes","volume":"16","author":"Kato","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B75","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s13075-024-03398-3","article-title":"Small extracellular vesicles derived from synovial fibroblasts contain distinct miRNA profiles and contribute to chondrocyte damage in osteoarthritis","volume":"26","author":"Asghar","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1080\/08820139.2021.1936010","article-title":"Fibroblast-like synoviocytes-derived exosomal PCGEM1 accelerates IL-1\u03b2-induced apoptosis and cartilage matrix degradation by miR-142-5p\/RUNX2 in chondrocytes","volume":"51","author":"Zeng","year":"2022","journal-title":"Immunol Invest"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3390\/cells14070519","article-title":"Synovial fibroblast extracellular vesicles induce inflammation via delivering miR-21-5p in osteoarthritis","volume":"14","author":"Konteles","year":"2025","journal-title":"Cells"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25158547","article-title":"Connexin 43 modulation in human chondrocytes, osteoblasts and cartilage explants: Implications for inflammatory joint disorders","volume":"25","author":"Della Morte","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B79","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1186\/s13075-015-0833-9","article-title":"Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes","volume":"17","author":"Hwang","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"B80","doi-asserted-by":"publisher","first-page":"18043","DOI":"10.1038\/s41598-024-68404-9","article-title":"Catabolic mediators from TLR2-mediated proteoglycan aggrecan peptide-stimulated chondrocytes are reduced by Lactobacillus-conditioned media","volume":"14","author":"Sengprasert","year":"2024","journal-title":"Sci Rep"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/s41368-025-00424-1","article-title":"Single-cell transcriptional atlas reveals distinct immune-chondrocyte crosstalk mechanisms in temporomandibular joint osteoarthritis induced by different types of occlusal disorder","volume":"18","author":"Wang","year":"2026","journal-title":"Int J Oral Sci"},{"key":"B82","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.joca.2022.10.002","article-title":"Changes of the subchondral bone microchannel network in early osteoarthritis","volume":"31","author":"Taheri","year":"2023","journal-title":"Osteoarthritis Cartilage"},{"key":"B83","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s13018-025-05578-6","article-title":"RANKL-mediated osteoclastic subchondral bone loss at a very early stage precedes subsequent cartilage degeneration and uncoupled bone remodeling in a mouse knee osteoarthritis model","volume":"20","author":"Hashimoto","year":"2025","journal-title":"J Orthop Surg Res"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202302391RR","article-title":"Mechanisms of vascular invasion after cartilage injury and potential engineering cartilage treatment strategies","volume":"38","author":"Zhao","year":"2024","journal-title":"FASEB J"},{"key":"B85","doi-asserted-by":"publisher","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":"B86","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s00418-025-02365-6","article-title":"Increased vascularization of the subchondral region in human osteoarthritic femoral head in the elderly","volume":"163","author":"He","year":"2025","journal-title":"Histochem Cell Biol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.joca.2023.10.010","article-title":"Is RANKL a potential molecular target in osteoarthritis","volume":"32","author":"Muratovic","year":"2024","journal-title":"Osteoarthritis Cartilage"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-019-0111-3","article-title":"RANKL biology: Bone metabolism, the immune system, and beyond","volume":"40","author":"Ono","year":"2020","journal-title":"Inflammation Regener"},{"key":"B89","doi-asserted-by":"publisher","first-page":"499","DOI":"10.3724\/abbs.2024017","article-title":"Subchondral osteoclasts and osteoarthritis: New insights and potential therapeutic avenues","volume":"56","author":"Chen","year":"2024","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-\u03b2 signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat Med"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo7868","article-title":"Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression","volume":"9","author":"Zhang","year":"2023","journal-title":"Sci Adv"},{"key":"B92","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41413-022-00229-6","article-title":"Endothelial PDGF-BB\/PDGFR-\u03b2 signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation","volume":"10","author":"Cui","year":"2022","journal-title":"Bone Res"},{"key":"B93","doi-asserted-by":"publisher","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":"B94","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41413-022-00201-4","article-title":"PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis","volume":"10","author":"Jiang","year":"2022","journal-title":"Bone Res"},{"key":"B95","doi-asserted-by":"publisher","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":"B96","doi-asserted-by":"publisher","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 Invest"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-025-01257-2","article-title":"Targeting osteoarthritis where it hurts: The osteochondral junction","volume":"21","author":"Malfait","year":"2025","journal-title":"Nat Rev Rheumatol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.161596","article-title":"Associations between knee effusion-synovitis and joint structural changes in patients with knee osteoarthritis","volume":"44","author":"Wang","year":"2017","journal-title":"J Rheumatol"},{"key":"B99","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/art.40660","article-title":"Association of changes in effusion-synovitis with progression of cartilage damage over eighteen months in patients with osteoarthritis and meniscal tear","volume":"71","author":"MacFarlane","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.28223","article-title":"Impact of sustained synovitis on knee joint structural degeneration: 4-year MRI data from the osteoarthritis initiative","volume":"57","author":"Ramezanpour","year":"2023","journal-title":"J Magn Reson Imaging"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.3109\/1354750x.2015.1105497","article-title":"Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis","volume":"20","author":"Kjelgaard-Petersen","year":"2015","journal-title":"Biomarkers"},{"key":"B102","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s13075-022-02881-z","article-title":"Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system","volume":"24","author":"Dwivedi","year":"2022","journal-title":"Arthritis Res Ther"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26146665","article-title":"Patient-derived explants of osteoarthritic synovium as ex vivo model for preclinical research","volume":"26","author":"D'Oria","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B104","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41598-018-36909-9","article-title":"Pro-resolving lipid mediator ameliorates obesity induced osteoarthritis by regulating synovial macrophage polarisation","volume":"9","author":"Sun","year":"2019","journal-title":"Sci Rep"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3390\/ph16050703","article-title":"Gas6\/Axl axis activation dampens the inflammatory response in osteoarthritic fibroblast-like synoviocytes and synovial explants","volume":"16","author":"Vago","year":"2023","journal-title":"Pharm (Basel)"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1054938","article-title":"Engineered M2a macrophages for the treatment of osteoarthritis","volume":"13","author":"Liang","year":"2022","journal-title":"Front Immunol"},{"key":"B107","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s13075-019-1923-x","article-title":"Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation","volume":"21","author":"Haraden","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.125325","article-title":"Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients","volume":"4","author":"Wood","year":"2019","journal-title":"JCI Insight"},{"key":"B109","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1080\/14737159.2024.2315282","article-title":"From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers","volume":"24","author":"Hannani","year":"2024","journal-title":"Expert Rev Mol Diagn"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2024.11.002","article-title":"Longitudinal stability of molecular endotypes of knee osteoarthritis patients","volume":"33","author":"Hannani","year":"2025","journal-title":"Osteoarthritis Cartilage"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kead135","article-title":"Metabolic and inflammatory profiles define phenotypes with clinical relevance in female knee osteoarthritis patients with joint effusion","volume":"62","author":"Calvet","year":"2023","journal-title":"Rheumatol (Oxford)"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2022.105444","article-title":"Effect of disease-modifying anti-rheumatic drugs in osteoarthritis: a meta-analysis","volume":"89","author":"Mathieu","year":"2022","journal-title":"Joint Bone Spine"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(23)01572-6","article-title":"Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial","volume":"402","author":"Wang","year":"2023","journal-title":"Lancet"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02822-0","article-title":"RANKL blockade for erosive hand osteoarthritis: a randomized placebo-controlled phase 2a trial","volume":"30","author":"Wittoek","year":"2024","journal-title":"Nat Med"},{"key":"B115","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13075-024-03309-6","article-title":"Targeting STAT6-mediated synovial macrophage activation improves pain in experimental knee osteoarthritis","volume":"26","author":"Blackler","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10281","article-title":"Resolvin D1-loaded nanoliposomes promote M2 macrophage polarization and are effective in the treatment of osteoarthritis","volume":"7","author":"Dravid","year":"2022","journal-title":"Bioeng Transl Med"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70162","article-title":"Targeted blockage of pathological extracellular vesicles and particles from fibroblast-like synoviocytes for osteoarthritis relief: proteomic analysis and cellular effect","volume":"14","author":"Liu","year":"2025","journal-title":"J Extracell Vesicles"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1889424\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:29:50Z","timestamp":1788150590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1889424\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":117,"alternative-id":["10.3389\/fimmu.2026.1889424"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1889424","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"article-number":"1889424"}}