{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:04:04Z","timestamp":1790859844672,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"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. Pharmacol."],"abstract":"<jats:p>Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of <jats:italic>IL-6<\/jats:italic>, <jats:italic>IL-8<\/jats:italic>, and <jats:italic>RANKL<\/jats:italic> mRNA and TNF-<jats:italic>\u03b1<\/jats:italic>-induced transcription of the <jats:italic>IL-1<\/jats:italic><jats:italic>\u03b2<\/jats:italic>, <jats:italic>IL-8<\/jats:italic>, <jats:italic>MMP-8<\/jats:italic>, and <jats:italic>MMP-9<\/jats:italic> genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-\u03b1-induced phosphorylation of ERK1\/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-\u03b1-induced activation of AKT, p70S6K, 4EBP1, and HIF-1\u03b1 in the AKT\/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT\/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.<\/jats:p>","DOI":"10.3389\/fphar.2021.714566","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T06:25:16Z","timestamp":1631168716000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis"],"prefix":"10.3389","volume":"12","author":[{"given":"Xiaochen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haofeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongnong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","article-title":"Fibroblast-like Synoviocytes: Key Effector Cells in Rheumatoid Arthritis","volume":"233","author":"Bartok","year":"2010","journal-title":"Immunol. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nrrheum.2012.190","article-title":"Duality of Fibroblast-like Synoviocytes in RA: Passive Responders and Imprinted Aggressors","volume":"9","author":"Bottini","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41584-020-00541-7","article-title":"Persistent Inflammatory and Non-inflammatory Mechanisms in Refractory Rheumatoid Arthritis","volume":"17","author":"Buch","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.cytogfr.2007.04.002","article-title":"How TNF Was Recognized as a Key Mechanism of Disease","volume":"18","author":"Clark","year":"2007","journal-title":"Cytokine Growth Factor. Rev."},{"key":"B5","unstructured":"A Study Using Intravenous Paxceed\u2122 to Treat Patients with Rheumatoid Arthritis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"568","DOI":"10.3389\/fphar.2020.00568","article-title":"Tanshinone IIA Suppresses Proliferation and Inflammatory Cytokine Production of Synovial Fibroblasts from Rheumatoid Arthritis Patients Induced by TNF-\u03b1 and Attenuates the Inflammatory Response in AIA Mice","volume":"11","author":"Du","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.3389\/fimmu.2019.01620","article-title":"A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-\u03b1 Induced Inflammatory Cytokine Production of Synovial Fibroblasts from Rheumatoid Arthritis Patients by Targeting MAPK and AKT\/mTOR Signal Pathway","volume":"10","author":"Du","year":"2019","journal-title":"Front. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.jaad.2003.09.018","article-title":"Micellar Paclitaxel Improves Severe Psoriasis in a Prospective Phase II Pilot Study","volume":"50","author":"Ehrlich","year":"2004","journal-title":"J. Am. Acad. Dermatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"R1140","DOI":"10.1186\/ar1797","article-title":"Tumour Necrosis Factor Activates the Mitogen-Activated Protein Kinases P38alpha and ERK in the Synovial Membrane In Vivo","volume":"7","author":"G\u00f6rtz","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"ii84","DOI":"10.1136\/ard.61.suppl_2.ii84","article-title":"Bone Destruction in Arthritis","volume":"61","author":"Gravallese","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/978-1-4939-8997-3_14","article-title":"In Vivo Models of Rheumatoid Arthritis","volume":"1914","author":"Gr\u00f6tsch","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4619","DOI":"10.1242\/jcs.01481","article-title":"MAP Kinases and Cell Migration","volume":"117","author":"Huang","year":"2004","journal-title":"J. Cel Sci."},{"key":"B13","first-page":"1","article-title":"Focal Liver Lesions","volume":"23","author":"Lande","year":"1988","journal-title":"Clin. Diagn. Ultrasound"},{"key":"B14","doi-asserted-by":"publisher","first-page":"352","DOI":"10.2119\/molmed.2010.00049","article-title":"mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis","volume":"16","author":"Laragione","year":"2010","journal-title":"Mol. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.17219\/acem\/127681","article-title":"Paclitaxel Inhibits Proliferation and Invasion and Promotes Apoptosis of Breast Cancer Cells by Blocking Activation of the PI3K\/AKT Signaling Pathway","volume":"29","author":"Li","year":"2020","journal-title":"Adv. Clin. Exp. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.4155\/fmc.15.55","article-title":"The PI3K\/Akt\/PTEN\/mTOR Pathway: a Fruitful Target for Inducing Cell Death in Rheumatoid Arthritis?","volume":"7","author":"Malemud","year":"2015","journal-title":"Future Med. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"107064","DOI":"10.1016\/j.intimp.2020.107064","article-title":"Role of Glucose Metabolism in Aggressive Phenotype of Fibroblast-like Synoviocytes: Latest Evidence and Therapeutic Approaches in Rheumatoid Arthritis","volume":"89","author":"Masoumi","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1626","DOI":"10.21769\/bioprotoc.1626","article-title":"Collagen-Induced Arthritis: A Model for Murine Autoimmune Arthritis","volume":"5","author":"Pietrosimone","year":"2015","journal-title":"Bio Protoc."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8289","DOI":"10.3892\/mmr.2018.8868","article-title":"Paclitaxel Suppresses Proliferation and Induces Apoptosis through Regulation of ROS and the AKT\/MAPK Signaling Pathway in Canine Mammary Gland Tumor Cells","volume":"17","author":"Ren","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/S0140-6736(10)60826-4","article-title":"Rheumatoid Arthritis","volume":"376","author":"Scott","year":"2010","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"892","DOI":"10.3390\/cells8080892","article-title":"Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling","volume":"8","author":"Shetti","year":"2019","journal-title":"Cells"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.3892\/ol.2015.3425","article-title":"Paclitaxel Combined with Harmine Inhibits the Migration and Invasion of Gastric Cancer Cells through Downregulation of Cyclooxygenase-2 Expression","volume":"10","author":"Sun","year":"","journal-title":"Oncol. Lett."},{"key":"B24","doi-asserted-by":"publisher","first-page":"600","DOI":"10.3109\/10799893.2015.1030412","article-title":"Signaling Pathway of MAPK\/ERK in Cell Proliferation, Differentiation, Migration, Senescence and Apoptosis","volume":"35","author":"Sun","year":"","journal-title":"J. Recept Signal. Transduct Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e70725","DOI":"10.1371\/journal.pone.0070725","article-title":"Low-dose Paclitaxel Ameliorates Pulmonary Fibrosis by Suppressing TGF-\u03b21\/Smad3 Pathway via miR-140 Upregulation","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1111\/os.12414","article-title":"Paclitaxel Induce Apoptosis of Giant Cells Tumor of Bone via TP53INP1 Signaling","volume":"11","author":"Xiao","year":"2019","journal-title":"Orthop. Surg."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e8885","DOI":"10.1590\/1414-431x20208885","article-title":"Treatment with \u03b2-elemene Combined with Paclitaxel Inhibits Growth, Migration, and Invasion and Induces Apoptosis of Ovarian Cancer Cells by Activation of STAT-NF-\u039ab Pathway","volume":"53","author":"Xiaomeng","year":"2020","journal-title":"Braz. J. Med. Biol. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s10067-017-3646-1","article-title":"Taxol Alleviates Collagen-Induced Arthritis in Mice by Inhibiting the Formation of Microvessels","volume":"38","author":"Xu","year":"2019","journal-title":"Clin. Rheumatol."},{"key":"B29","first-page":"1572","article-title":"Remission of Rheumatoid Arthritis with Taxol in a Patient with Breast Carcinoma","volume":"27","author":"Yoo","year":"2000","journal-title":"J. Rheumatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/labinvest.2009.149","article-title":"Low-dose Paclitaxel Ameliorates Renal Fibrosis in Rat UUO Model by Inhibition of TGF-beta\/Smad Activity","volume":"90","author":"Zhang","year":"2010","journal-title":"Lab. Invest."},{"key":"B31","doi-asserted-by":"publisher","first-page":"279","DOI":"10.2147\/DDDT.S56801","article-title":"Paclitaxel: New Uses for an Old Drug","volume":"8","author":"Zhang","year":"2014","journal-title":"Drug Des. Devel Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1097\/CAD.0000000000000935","article-title":"Chidamide Combined with Paclitaxel Effectively Reverses the Expression of Histone Deacetylase in Lung Cancer","volume":"31","author":"Zhang","year":"2020","journal-title":"Anticancer Drugs"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.2147\/IJN.S188049","article-title":"Chronic Chemotherapy with Paclitaxel Nanoparticles Induced Apoptosis in Lung Cancer In Vitro and In Vivo","volume":"14","author":"Zhao","year":"2019","journal-title":"Int. J. Nanomedicine."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.714566\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T06:25:24Z","timestamp":1631168724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.714566\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":33,"alternative-id":["10.3389\/fphar.2021.714566"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.714566","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"article-number":"714566"}}