{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:47:30Z","timestamp":1791859650701,"version":"4.3.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Orthop Surg Res"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>The Cadherin-11 and PI3K\/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K\/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-\u03b1 and to explore the effect of the PI3K\/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>FLS were primarily cultured from synovium of osteoarthritic patients during total knee arthroplasty. Under the simulation of TNF-\u03b1, with or without PI3K\/Akt inhibitor LY294002, Cadherin-11 expression was detected by real-time PCR and Western blot, as well as the migration and invasive capacity changes of OA FLS. Cadherin-11 antibody was injected intraarticularly or LY294002 was injected intraperitoneally in CIOA mice to evaluate the changes of synovitis score, cartilage damage, and Cadherin-11 expression.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>TNF-\u03b1 stimulation increased Cadherin-11 expression at mRNA and protein level in OA FLS and also increased the phosphorylation-dependent activation of Akt. PI3K inhibitor LY294002 attenuated TNF-\u03b1-induced overexpression of Cadherin-11 and decreased the invasive capacity of OA FLS. Intraperitoneal injection of PI3K inhibitor LY294002 could decrease the Cadherin-11 protein expression in synovium of CIOA mice, although it has no significant inhibitory effect on synovitis and cartilage damage. Intraarticular injection of Cadherin-11 antibody attenuated the synovitis and cartilage damage in the CIOA joints and decreased Cadherin-11 expression in the synovial lining.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>PI3K\/Akt pathway was associated with TNF-\u03b1-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. Anti-Cadherin-11 therapy in CIOA mice could attenuate the pathological changes of OA joints.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13018-019-1394-4","type":"journal-article","created":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T15:04:53Z","timestamp":1576076693000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["PI3K\/Akt inhibitor partly decreases TNF-\u03b1-induced activation of fibroblast-like synoviocytes in osteoarthritis"],"prefix":"10.1186","volume":"14","author":[{"given":"Songyang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixia","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqi","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4286-5542","authenticated-orcid":false,"given":"Tiezheng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,11]]},"reference":[{"issue":"1","key":"1394_CR1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1002\/art.1780360105","volume":"36","author":"T Saxne","year":"1993","unstructured":"Saxne T, Glenn\u00e5s A, Kvien T, Melby K, Heineg\u00e5rd D. Release of cartilage macromolecules into the synovial fluid in patients with acute and prolonged phases of reactive arthritis. Arthritis Rheum. 1993;36(1):20\u20135.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"1394_CR2","first-page":"37","volume":"17","author":"DJ Veale","year":"1999","unstructured":"Veale DJ. The role of arthroscopy in early arthritis. Clin Exp Rheumatol. 1999;17(1):37\u20138.","journal-title":"Clin Exp Rheumatol"},{"issue":"5 Pt 1","key":"1394_CR3","doi-asserted-by":"publisher","first-page":"330","DOI":"10.7326\/0003-4819-139-5_Part_1-200309020-00008","volume":"139","author":"DT Felson","year":"2003","unstructured":"Felson DT, McLaughlin S, Goggins J, LaValley MP, Gale ME, Totterman S, et al. Bone marrow edema and its relation to progression of knee osteoarthritis. Ann Intern Med. 2003;139(5 Pt 1):330\u20136.","journal-title":"Ann Intern Med"},{"issue":"11","key":"1394_CR4","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/nrrheum.2010.159","volume":"6","author":"J Sellam","year":"2010","unstructured":"Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6(11):625\u201335.","journal-title":"Nat Rev Rheumatol"},{"issue":"5","key":"1394_CR5","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.joca.2005.01.005","volume":"13","author":"X Ayral","year":"2005","unstructured":"Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthr Cartil. 2005;13(5):361\u20137.","journal-title":"Osteoarthr Cartil"},{"issue":"5","key":"1394_CR6","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1136\/ard.2010.139618","volume":"70","author":"A Guermazi","year":"2011","unstructured":"Guermazi A, Roemer F, Hayashi D, Crema M, Niu J, Zhang Y, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis. 2011;70(5):805\u201311.","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"1394_CR7","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1016\/j.joca.2012.08.027","volume":"20","author":"B de Lange-Brokaar","year":"2012","unstructured":"de Lange-Brokaar B, Ioan-Facsinay A, van Osch G, Zuurmond A, Schoones J, Toes R, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthr Cartil. 2012;20(12):1484\u201399.","journal-title":"Osteoarthr Cartil"},{"issue":"6","key":"1394_CR8","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.joca.2008.09.013","volume":"17","author":"FW Roemer","year":"2009","unstructured":"Roemer FW, Guermazi A, Hunter DJ, Niu J, Zhang Y, Englund M, et al. The association of meniscal damage with joint effusion in persons without radiographic osteoarthritis: the Framingham and MOST osteoarthritis studies. Osteoarthr Cartil. 2009;17(6):748\u201353.","journal-title":"Osteoarthr Cartil"},{"issue":"2","key":"1394_CR9","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/ar1495","volume":"7","author":"HP Kiener","year":"2005","unstructured":"Kiener HP, Brenner MB. Building the synovium: cadherin-11 mediates fibroblast-like synoviocyte cell-to-cell adhesion. Arthritis Res Ther. 2005;7(2):49\u201354.","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"1394_CR10","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.2353\/ajpath.2006.050999","volume":"168","author":"HP Kiener","year":"2006","unstructured":"Kiener HP, Lee DM, Agarwal SK, Brenner MB. Cadherin-11 induces rheumatoid arthritis fibroblast-like synoviocytes to form lining layers in vitro. Am J Pathol. 2006;168(5):1486\u201399.","journal-title":"Am J Pathol"},{"issue":"1","key":"1394_CR11","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1111\/j.0105-2896.2009.00854.x","volume":"233","author":"SK Chang","year":"2010","unstructured":"Chang SK, Gu Z, Brenner MB. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol Rev. 2010;233(1):256\u201366.","journal-title":"Immunol Rev"},{"issue":"8","key":"1394_CR12","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1002\/art.1780290816","volume":"29","author":"R Altman","year":"1986","unstructured":"Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. 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. Arthritis Rheum. 1986;29(8):1039\u201349.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"1394_CR13","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.intimp.2015.03.024","volume":"26","author":"X Ding","year":"2015","unstructured":"Ding X, Zhang Y, Huang Y, Liu S, Lu H, Sun T. Cadherin-11 involves in synovitis and increases the migratory and invasive capacity of fibroblast-like synoviocytes of osteoarthritis. Int Immunopharmacol. 2015;26(1):153\u201361.","journal-title":"Int Immunopharmacol"},{"issue":"20","key":"1394_CR14","doi-asserted-by":"publisher","first-page":"8402","DOI":"10.1073\/pnas.1019437108","volume":"108","author":"SK Chang","year":"2011","unstructured":"Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, et al. Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci U S A. 2011;108(20):8402\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"1394_CR15","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1002\/art.23886","volume":"58","author":"B Vandooren","year":"2008","unstructured":"Vandooren B, Cantaert T, ter Borg M, Noordenbos T, Kuhlman R, Gerlag D, et al. Tumor necrosis factor alpha drives cadherin 11 expression in rheumatoid inflammation. Arthritis Rheum. 2008;58(10):3051\u201362.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"1394_CR16","first-page":"19","volume":"71","author":"PM van der Kraan","year":"1990","unstructured":"van der Kraan PM, Vitters EL, van Beuningen HM, van de Putte LB, van den Berg WB. Degenerative knee joint lesions in mice after a single intra-articular collagenase injection. A new model of osteoarthritis. J Exp Pathol (Oxford). 1990;71(1):19\u201331.","journal-title":"J Exp Pathol (Oxford)"},{"issue":"5","key":"1394_CR17","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/S1063-4584(97)80034-9","volume":"5","author":"MG Chambers","year":"1997","unstructured":"Chambers MG, Bayliss MT, Mason RM. Chondrocyte cytokine and growth factor expression in murine osteoarthritis. Osteoarthr Cartil. 1997;5(5):301\u20138.","journal-title":"Osteoarthr Cartil"},{"key":"1394_CR18","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1186\/1471-2407-14-545","volume":"14","author":"H Cho","year":"2014","unstructured":"Cho H, Chung J, Song K, Noh K, Kim B, Chung E, et al. Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer. BMC Cancer. 2014;14:545.","journal-title":"BMC Cancer"},{"issue":"9","key":"1394_CR19","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/ni0901-771","volume":"2","author":"M Feldmann","year":"2001","unstructured":"Feldmann M. Pathogenesis of arthritis: recent research progress. Nat Immunol. 2001;2(9):771\u20133.","journal-title":"Nat Immunol"},{"issue":"7","key":"1394_CR20","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1002\/1529-0131(200107)44:7<1555::AID-ART279>3.0.CO;2-M","volume":"44","author":"HG Zhang","year":"2001","unstructured":"Zhang HG, Wang Y, Xie JF, Liang X, Liu D, Yang P, et al. Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthritis Rheum. 2001;44(7):1555\u201367.","journal-title":"Arthritis Rheum"},{"issue":"3","key":"1394_CR21","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.ccr.2005.08.008","volume":"8","author":"N Hay","year":"2005","unstructured":"Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8(3):179\u201383.","journal-title":"Cancer Cell"},{"issue":"5","key":"1394_CR22","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.4049\/jimmunol.1300950","volume":"192","author":"B Bartok","year":"2014","unstructured":"Bartok B, Hammaker D, Firestein G. Phosphoinositide 3-kinase \u03b4 regulates migration and invasion of synoviocytes in rheumatoid arthritis. J Immunol. 2014;192(5):2063\u201370.","journal-title":"J Immunol"},{"issue":"11","key":"1394_CR23","first-page":"833","volume":"12","author":"S Lin","year":"2014","unstructured":"Lin S, Fan W, Sun L, Li F, Zhao R, Zhang L, et al. The saponin DT-13 inhibits gastric cancer cell migration through down-regulation of CCR5-CCL5 axis. Chin J Nat Med. 2014;12(11):833\u201340.","journal-title":"Chin J Nat Med"},{"issue":"3","key":"1394_CR24","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1002\/eji.201040504","volume":"41","author":"L Berod","year":"2011","unstructured":"Berod L, Heinemann C, Heink S, Escher A, Stadelmann C, Drube S, et al. PI3Kgamma deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome. Eur J Immunol. 2011;41(3):833\u201344.","journal-title":"Eur J Immunol"},{"issue":"21","key":"1394_CR25","doi-asserted-by":"publisher","first-page":"4361","DOI":"10.1093\/nar\/29.21.4361","volume":"29","author":"J. A. Mengshol","year":"2001","unstructured":"Mengshol JA, Vincenti MP, Brinckerhoff CE. IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways. Nucleic Acids Res. 2001;29(21):4361\u201372. PMID:11691923.","journal-title":"Nucleic Acids Research"},{"issue":"12","key":"1394_CR26","doi-asserted-by":"publisher","first-page":"e28663","DOI":"10.1371\/journal.pone.0028663","volume":"6","author":"Azadeh Montaseri","year":"2011","unstructured":"Montaseri A, Busch F, Mobasheri A, Buhrmann C, Aldinger C, Rad JS, Shakibaei M. IGF-1 and PDGF-bb suppress IL-1\u03b2-induced cartilage degradation through down-regulation of NF-\u03baB signaling: involvement of Src\/PI-3K\/AKT pathway. PLoS One. 2011;6(12):e28663. https:\/\/doi.org\/10.1371\/journal.pone.0028663. Epub 2011 Dec 14. PMID: 22194879.","journal-title":"PLoS ONE"},{"issue":"24","key":"1394_CR27","doi-asserted-by":"publisher","first-page":"7578","DOI":"10.1016\/j.bmc.2013.10.042","volume":"21","author":"Y Oka","year":"2013","unstructured":"Oka Y, Yabuuchi T, Oi T, Kuroda S, Fujii Y, Ohtake H, et al. Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl }acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase gamma inhibitor for the treatment of inflammatory diseases. Bioorg Med Chem. 2013;21(24):7578\u201383.","journal-title":"Bioorg Med Chem"},{"issue":"6","key":"1394_CR28","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s00011-012-0444-8","volume":"61","author":"K Haruta","year":"2012","unstructured":"Haruta K, Mori S, Tamura N, Sasaki A, Nagamine M, Yaguchi S, et al. Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats. Inflamm Res. 2012;61(6):551\u201362.","journal-title":"Inflamm Res"},{"issue":"5814","key":"1394_CR29","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1137306","volume":"315","author":"DM Lee","year":"2007","unstructured":"Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007;315(5814):1006\u201310.","journal-title":"Science."},{"issue":"1\u20132","key":"1394_CR30","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s11010-012-1463-z","volume":"372","author":"GQ Li","year":"2013","unstructured":"Li GQ, Zhang Y, Liu D, Qian YY, Zhang H, Guo SY, et al. PI3 kinase\/Akt\/HIF-1alpha pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol Cell Biochem. 2013;372(1\u20132):221\u201331.","journal-title":"Mol Cell Biochem"},{"issue":"3","key":"1394_CR31","first-page":"880","volume":"6","author":"L Hu","year":"2000","unstructured":"Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res. 2000;6(3):880\u20136.","journal-title":"Clin Cancer Res"},{"issue":"12","key":"1394_CR32","doi-asserted-by":"publisher","first-page":"2254","DOI":"10.1136\/annrheumdis-2014-206517","volume":"74","author":"RF Schelbergen","year":"2015","unstructured":"Schelbergen RF, Geven EJ, van den Bosch MH, Eriksson H, Leanderson T, Vogl T, et al. Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Ann Rheum Dis. 2015;74(12):2254\u20138.","journal-title":"Ann Rheum Dis"},{"key":"1394_CR33","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.jsbmb.2014.07.002","volume":"143","author":"XX Kou","year":"2014","unstructured":"Kou XX, Wang XD, Li CS, Bi RY, Meng Z, Li B, et al. Estradiol-potentiated cadherin-11 in synovial membrane involves in temporomandibular joint inflammation in rats. J Steroid Biochem Mol Biol. 2014;143:444\u201350.","journal-title":"J Steroid Biochem Mol Biol"}],"container-title":["Journal of Orthopaedic Surgery and Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-019-1394-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13018-019-1394-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-019-1394-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T01:02:45Z","timestamp":1607562165000},"score":1,"resource":{"primary":{"URL":"https:\/\/josr-online.biomedcentral.com\/articles\/10.1186\/s13018-019-1394-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1394"],"URL":"https:\/\/doi.org\/10.1186\/s13018-019-1394-4","relation":{},"ISSN":["1749-799X"],"issn-type":[{"value":"1749-799X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"3 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Written informed consent was obtained from all patients, and the research protocol was approved by the Institutional Review Board of the People\u2019s Hospital, Peking University (Beijing, China). Animal experimental protocols were approved by Peking University Institutional Animal Care and Use Committee.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent was obtained from all individual participants included in the study. All patients provided written informed consent for the use of chondrocytes.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"425"}}