{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:47:10Z","timestamp":1789987630547,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T00:00:00Z","timestamp":1610236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yuhan corporation","award":["SNUH 0620161280"],"award-info":[{"award-number":["SNUH 0620161280"]}]},{"name":"Ministry of Health Welfare, Republic of Korea","award":["HI14C1277"],"award-info":[{"award-number":["HI14C1277"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were co-incubated with CD14+ mononuclear cells from healthy donors without macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclast differentiation was evaluated via tartrate-resistant acid phosphatase (TRAP) staining and activity and F-actin ring formation. RANKL expression on synovial exosomes was assessed using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Synovial exosomes were the lowest in OA patients; these induced osteoclastogenesis in the absence of M-CSF and RANKL. Osteoclastogenesis was significantly higher with more exosomes in RA (p = 0.030) than in OA patients, but not in AS or gout patients. On treating macrophages with a specified number of synovial exosomes from RA\/AS patients, exosomes induced greater osteoclastogenesis in RA than in AS patients. Synovial exosomal RANKL levels were significantly higher in RA (p = 0.035) than in AS patients. Synovial exosome numbers vary with the type of inflammatory arthritis. Synovial exosomes from RA patients may bear the disease-specific \u201csynovial signature of osteoclastogenesis.\u201d<\/jats:p>","DOI":"10.3390\/cells10010120","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T19:55:56Z","timestamp":1610308556000},"page":"120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Role of Synovial Exosomes in Osteoclast Differentiation in Inflammatory Arthritis"],"prefix":"10.3390","volume":"10","author":[{"given":"Ji Eun","family":"Song","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hye","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03082, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Won","family":"Moon","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Kangwon National University Hospital, Chuncheon 24289, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Kyun","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03082, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea"},{"name":"Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03082, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6975-8627","authenticated-orcid":false,"given":"Eun Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03082, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,10]]},"reference":[{"key":"ref_1","first-page":"CD008951","article-title":"Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity","volume":"1","author":"Radner","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev.immunol.14.1.397","article-title":"Role of cytokines in rheumatoid arthritis","volume":"14","author":"Feldmann","year":"1996","journal-title":"Annu. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/art.1780310404","article-title":"Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction","volume":"31","author":"Miyasaka","year":"1988","journal-title":"Arthritis Rheum."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ii52","DOI":"10.1136\/annrheumdis-2012-202199","article-title":"Bone remodelling in inflammatory arthritis","volume":"72","author":"Goldring","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"iii42","DOI":"10.1136\/ard.2007.078972","article-title":"Joint remodelling in inflammatory disease","volume":"66","author":"Schett","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_6","first-page":"S15","article-title":"Rheumatoid arthritis and ankylosing spondylitis\u2014pathology of acute inflammation","volume":"27","author":"Appel","year":"2009","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/rheumatology\/ket329","article-title":"Bone erosions in patients with chronic gouty arthropathy are associated with tophi but not bone oedema or synovitis: New insights from a 3 T MRI study","volume":"53","author":"McQueen","year":"2014","journal-title":"Rheumatology (Oxford)"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s10875-009-9316-6","article-title":"Osteoimmunology: Crosstalk between the immune and bone systems","volume":"29","author":"Nakashima","year":"2009","journal-title":"J. Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4858","DOI":"10.1074\/jbc.275.7.4858","article-title":"Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts","volume":"275","author":"Azuma","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/jbmr.5650040116","article-title":"Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro","volume":"4","author":"Pfeilschifter","year":"1989","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mabilleau, G., and Sabokbar, A. (2009). Interleukin-32 promotes osteoclast differentiation but not osteoclast activation. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004173"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1007\/s00018-010-0410-y","article-title":"Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes","volume":"67","author":"Mun","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29247","DOI":"10.1074\/jbc.M114.589564","article-title":"First demonstration of transmissible spongiform encephalopathy-associated prion protein (PrPTSE) in extracellular vesicles from plasma of mice infected with mouse-adapted variant Creutzfeldt-Jakob disease by in vitro amplification","volume":"289","author":"Saa","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14240","DOI":"10.3390\/ijms140714240","article-title":"Intercellular communication by exosome-derived microRNAs in cancer","volume":"14","author":"Hannafon","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","first-page":"537","article-title":"Functions and application of exosomes","volume":"71","author":"Qin","year":"2014","journal-title":"Acta Pol. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1002\/art.21350","article-title":"Microparticles as regulators of inflammation: Novel players of cellular crosstalk in the rheumatic diseases","volume":"52","author":"Distler","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10238-013-0271-4","article-title":"PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis","volume":"15","author":"Song","year":"2015","journal-title":"Clin. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gy\u00f6rgy, B., Szabo, T.G., Turiak, L., Wright, M., Herczeg, P., Ledeczi, Z., Kittel, A., Polgar, A., Toth, K., and Derfalvi, B. (2012). Im-proved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049726"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13772","DOI":"10.18632\/oncotarget.3830","article-title":"Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation","volume":"6","author":"Raimondi","year":"2015","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1038\/s41598-017-03460-y","article-title":"Am-phiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway","volume":"7","author":"Taverna","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s00428-006-0200-y","article-title":"Stimulation of osteoclast formation by inflammatory synovial fluid","volume":"449","author":"Adamopoulos","year":"2006","journal-title":"Virchows Arch."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.4049\/jimmunol.147.7.2187","article-title":"Synovial tissue macrophage as a source of the chemotactic cytokine IL-8","volume":"147","author":"Koch","year":"1991","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1046\/j.1365-3083.1998.00399.x","article-title":"Synovial fluid cytokines in patients with rheumatoid arthritis or other arthritic lesions","volume":"48","author":"Nordstrom","year":"1998","journal-title":"Scand. J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1073\/pnas.1010030108","article-title":"TNF activates calcium-nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages","volume":"108","author":"Yarilina","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1210\/endo.143.3.8701","article-title":"TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL","volume":"143","author":"Fuller","year":"2002","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1172\/JCI200523394","article-title":"IL-1 mediates TNF-induced osteoclastogenesis","volume":"115","author":"Wei","year":"2005","journal-title":"J. Clin. Invest"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.lfs.2004.10.079","article-title":"IL-1 alpha stimulates the formation of osteoclast-like cells by increasing M-CSF and PGE2 production and decreasing OPG production by osteoblasts","volume":"77","author":"Tanabe","year":"2005","journal-title":"Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0083-6729(06)74014-6","article-title":"The role of the interleukin-6\/gp130 signaling pathway in bone metabolism","volume":"74","author":"Liu","year":"2006","journal-title":"Vitam. Horm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/art.1780310302","article-title":"The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis","volume":"31","author":"Arnett","year":"1988","journal-title":"Arthritis Rheum."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1242\/jcs.115.12.2505","article-title":"The exosome pathway in K562 cells is regulated by Rab11","volume":"115","author":"Savina","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"52347","DOI":"10.1074\/jbc.M309009200","article-title":"Evidence that HIV budding in primary macrophages occurs through the exosome release pathway","volume":"278","author":"Nguyen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/BF02411252","article-title":"Bone acid phosphatase: Tartrate-resistant acid phosphatase as a marker of osteoclast function","volume":"34","author":"Minkin","year":"1982","journal-title":"Calcif. Tissue Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.4049\/jimmunol.0804206","article-title":"SLP-76 couples Syk to the osteoclast cytoskeleton","volume":"183","author":"Reeve","year":"2009","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3389\/fimmu.2014.00442","article-title":"Tetraspanins in extracellular vesicle formation and function","volume":"5","author":"Andreu","year":"2014","journal-title":"Front Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R536","DOI":"10.1186\/ar1706","article-title":"Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes","volume":"7","author":"Berckmans","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R40","DOI":"10.1186\/ar2648","article-title":"Microparticle-induced release of B-lymphocyte regulators by rheumatoid synoviocytes","volume":"11","author":"Messer","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1002\/art.10312","article-title":"Elevated levels of platelet micro-particles are associated with disease activity in rheumatoid arthritis","volume":"46","author":"Koerts","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1074\/jbc.M805777200","article-title":"Impaired micro-RNA pathways diminish osteoclast differentiation and function","volume":"284","author":"Sugatani","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3648","DOI":"10.1182\/blood-2010-10-311415","article-title":"A microRNA expression signature of osteoclastogenesis","volume":"117","author":"Sugatani","year":"2011","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R102","DOI":"10.1186\/ar4282","article-title":"miR-31 controls osteoclast formation and bone resorption by targeting RhoA","volume":"15","author":"Mizoguchi","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/jbmr.1845","article-title":"miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B","volume":"28","author":"Cheng","year":"2013","journal-title":"J. Bone Miner. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:09:27Z","timestamp":1760159367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,10]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["cells10010120"],"URL":"https:\/\/doi.org\/10.3390\/cells10010120","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,10]]}}}