{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T09:12:49Z","timestamp":1783761169558,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,12,29]],"date-time":"2018-12-29T00:00:00Z","timestamp":1546041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010600","name":"Tampere University Hospital","doi-asserted-by":"publisher","award":["Competitive Research Funding"],"award-info":[{"award-number":["Competitive Research Funding"]}],"id":[{"id":"10.13039\/501100010600","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007417","name":"Paulo Foundation","doi-asserted-by":"publisher","award":["Competitive Research Funding"],"award-info":[{"award-number":["Competitive Research Funding"]}],"id":[{"id":"10.13039\/501100007417","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Finnish Bioeconomy Cluster Ltd. and The Finnish Funding Agency for Innovation","award":["Fubio-2"],"award-info":[{"award-number":["Fubio-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Interleukin-6 (IL-6) is involved in the pathogenesis of various inflammatory diseases, like rheumatoid arthritis (RA). In the present study, we investigated the role of IL-6 in osteoarthritis (OA) patients and the effects of the stilbenoids monomethyl pinosylvin and pinosylvin on the expression of the cartilage matrix components aggrecan and collagen II and the inflammatory cytokine IL-6 in human OA chondrocytes. Synovial fluid and plasma samples were obtained from 100 patients with severe\u2009OA [BMI 29.7 (8.3) kg\/m2, age 72 (14) years, median (IQR); 62\/38 females\/males] undergoing total knee replacement surgery. IL-6 and matrix metalloproteinase (MMP) concentrations in synovial fluid and plasma were measured by immunoassay. The effects of pinosylvin on the expression of IL-6, aggrecan, and collagen II were studied in primary cultures of human OA chondrocytes. IL-6 levels in synovial fluid from OA patients [119.8\u2009(193.5) pg\/mL, median (IQR)] were significantly increased as compared to the plasma levels [3.1 (2.7) pg\/mL, median (IQR)] and IL-6 levels in synovial fluid were associated with MMPs and radiographic disease severity. Natural stilbenoids monomethyl pinosylvin and pinosylvin increased aggrecan expression and suppressed IL-6 production in OA chondrocytes. The results propose that IL-6 is produced within OA joints and has an important role in the pathogenesis of OA. Stilbenoid compounds monomethyl pinosylvin and pinosylvin appeared to have disease-modifying potential in OA chondrocytes.<\/jats:p>","DOI":"10.3390\/molecules24010109","type":"journal-article","created":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T07:22:30Z","timestamp":1546240950000},"page":"109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["IL-6 in Osteoarthritis: Effects of Pine Stilbenoids"],"prefix":"10.3390","volume":"24","author":[{"given":"Mirka","family":"Laavola","sequence":"first","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina","family":"Lepp\u00e4nen","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"H\u00e4m\u00e4l\u00e4inen","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katriina","family":"Vuolteenaho","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Moilanen","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"},{"name":"Coxa Hospital for Joint Replacement, 33101 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riina","family":"Nieminen","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eeva","family":"Moilanen","sequence":"additional","affiliation":[{"name":"The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in Inflammation, Immunity, and Disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/ni.3153","article-title":"IL-6 as a Keystone Cytokine in Health and Disease","volume":"16","author":"Hunter","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"561459","DOI":"10.1155\/2014\/561459","article-title":"The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis","volume":"2014","author":"Wojdasiewicz","year":"2014","journal-title":"Mediators Inflamm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrrheum.2013.44","article-title":"Biologic Agents in Osteoarthritis: Hopes and Disappointments","volume":"9","author":"Chevalier","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1186\/s13075-014-0429-9","article-title":"Current and Emerging Therapeutic Strategies for Preventing Inflammation and Aggrecanase-Mediated Cartilage Destruction in Arthritis","volume":"16","author":"Dancevic","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0140-6736(14)60802-3","article-title":"Osteoarthritis","volume":"386","author":"Palmer","year":"2015","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/BOR.0000000000000273","article-title":"Current Advances in Therapies for Osteoarthritis","volume":"28","author":"Kalunian","year":"2016","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ejphar.2017.06.032","article-title":"Inhibition of Interleukin-6 Function Attenuates the Central Sensitization and Pain Behavior Induced by Osteoarthritis","volume":"811","author":"Lin","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1021\/jf504606m","article-title":"Pinosylvin and Monomethylpinosylvin, Constituents of an Extract from the Knot of Pinus Sylvestris, Reduce Inflammatory Gene Expression and Inflammatory Responses In Vivo","volume":"63","author":"Laavola","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1159\/000327961","article-title":"Pinosylvin Suppresses LPS-Stimulated Inducible Nitric Oxide Synthase Expression Via the MyD88-Independent, but TRIF-Dependent Downregulation of IRF-3 Signaling Pathway in Mouse Macrophage Cells","volume":"27","author":"Park","year":"2011","journal-title":"Cell Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"734","DOI":"10.3892\/ijmm.2017.2885","article-title":"Resveratrol Inhibits the IL-1beta-Induced Expression of MMP-13 and IL-6 in Human Articular Chondrocytes Via TLR4\/MyD88-Dependent and -Independent Signaling Cascades","volume":"39","author":"Gu","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of Proinflammatory Cytokines in the Pathophysiology of Osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.bbapap.2011.06.020","article-title":"Proteases Involved in Cartilage Matrix Degradation in Osteoarthritis","volume":"1824","author":"Troeberg","year":"2012","journal-title":"Biochim. Biophys Acta."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1186\/s13075-014-0441-0","article-title":"Cytokine Profiles in the Joint Depend on Pathology, but are Different between Synovial Fluid, Cartilage Tissue and Cultured Chondrocytes","volume":"16","author":"Tsuchida","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.joca.2013.04.002","article-title":"An Explorative Study Comparing Levels of Soluble Mediators in Control and Osteoarthritic Synovial Fluid","volume":"21","author":"Beekhuizen","year":"2013","journal-title":"Osteoarthritis Cartilage"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1002\/art.24598","article-title":"Interleukin-6 is a Significant Predictor of Radiographic Knee Osteoarthritis: The Chingford Study","volume":"60","author":"Livshits","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1002\/jor.22859","article-title":"Intra-Articular Resveratrol Injection Prevents Osteoarthritis Progression in a Mouse Model by Activating SIRT1 and Thereby Silencing HIF-2alpha","volume":"33","author":"Li","year":"2015","journal-title":"J. Orthop. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1007\/s00296-010-1720-y","article-title":"Effect of Resveratrol on Cartilage Protection and Apoptosis Inhibition in Experimental Osteoarthritis of Rabbit","volume":"32","author":"Wang","year":"2012","journal-title":"Rheumatol. Int."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zou, T., Yang, Y., Xia, F., Huang, A., Gao, X., Fang, D., Xiong, S., and Zhang, J. (2013). Resveratrol Inhibits CD4+ T Cell Activation by Enhancing the Expression and Activity of Sirt1. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075139"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"535189","DOI":"10.1155\/2015\/535189","article-title":"Omega-3 PUFAs and Resveratrol Differently Modulate Acute and Chronic Inflammatory Processes","volume":"2015","author":"Schwager","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.gene.2013.05.069","article-title":"A Current Review of Molecular Mechanisms regarding Osteoarthritis and Pain","volume":"527","author":"Lee","year":"2013","journal-title":"Gene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s10561-012-9354-9","article-title":"The Role of IL-6 in Bone Marrow (BM)-Derived Mesenchymal Stem Cells (MSCs) Proliferation and Chondrogenesis","volume":"14","author":"Wei","year":"2013","journal-title":"Cell Tissue Bank."},{"key":"ref_23","first-page":"756","article-title":"Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: A possible explanation for oxidative stress generation","volume":"7","author":"Hogge","year":"2008","journal-title":"Osteoarthritis Cartilage"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/(SICI)1097-4644(19980401)69:1<19::AID-JCB3>3.0.CO;2-Y","article-title":"Interleukin-1 beta induction of c-fos and collagenase expression in articular chondrocytes: Involvement of reactive oxygen species","volume":"1","author":"Lo","year":"1998","journal-title":"J. Cell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S1063-4584(03)00150-X","article-title":"The role of reactive oxygen species in homeostasis and degradation of cartilage","volume":"10","author":"Henrotin","year":"2003","journal-title":"Osteoarthritis Cartilage"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.bbadis.2016.01.003","article-title":"ROS\/oxidative stress signaling in osteoarthritis","volume":"4","author":"Lepetsos","year":"2016","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1744-8069-9-3","article-title":"Modulation of TRP Channels by Resveratrol and Other Stilbenoids","volume":"9","author":"Yu","year":"2013","journal-title":"Mol. Pain."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/bcpt.12485","article-title":"Pinosylvin Inhibits TRPA1-Induced Calcium Influx in Vitro and TRPA1-Mediated Acute Paw Inflammation in vivo","volume":"118","author":"Moilanen","year":"2016","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/art.1780290816","article-title":"Development of Criteria for the Classification and Reporting of Osteoarthritis. Classification of Osteoarthritis of the Knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association","volume":"29","author":"Altman","year":"1986","journal-title":"Arthritis. Rheum."},{"key":"ref_30","first-page":"57","article-title":"Leptin Enhances MMP-1, MMP-3 and MMP-13 Production in Human Osteoarthritic Cartilage and Correlates with MMP-1 and MMP-3 in Synovial Fluid from OA Patients","volume":"29","author":"Koskinen","year":"2011","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1172\/JCI117595","article-title":"Interleukin-1 \u03b2-Modulated Gene Expression in Immortalized Human Chondrocytes","volume":"94","author":"Goldring","year":"1994","journal-title":"J. Clin. Investig."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/1\/109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:36:36Z","timestamp":1760196996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/1\/109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,29]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["molecules24010109"],"URL":"https:\/\/doi.org\/10.3390\/molecules24010109","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,29]]}}}