{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:25:25Z","timestamp":1789140325087,"version":"build-2803163510"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["18K09057"],"award-info":[{"award-number":["18K09057"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["18K09098"],"award-info":[{"award-number":["18K09098"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["17K10960"],"award-info":[{"award-number":["17K10960"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["17K17739"],"award-info":[{"award-number":["17K17739"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Orthop Surg Res"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background and aim<\/jats:title>\n<jats:p>The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-\u03b1\u00a0(TNF-\u03b1), interleukin-1\u03b2\u00a0(IL-1\u03b2), and interleukin-6 (IL-6)\u00a0by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant <jats:italic>N<\/jats:italic>-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We investigated the effect of administering a low dose (1000 \u03bcM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived\u00a02-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Low-dose NAC (1000 \u03bcM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 \u03bcM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 \u03bcM) to RA-FLS suppressed MMP-3.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13018-020-01595-9","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T11:03:08Z","timestamp":1583319788000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3"],"prefix":"10.1186","volume":"15","author":[{"given":"Tomotake","family":"Kanai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8985-3055","authenticated-orcid":false,"given":"Naoki","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayasu","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshige","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Okumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Kijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Ogose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"1595_CR1","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1111\/j.1365-2249.2008.03634.x","volume":"152","author":"LI Filippin","year":"2008","unstructured":"Filippin LI, Vercelino R, Marroni NP, Xavier RM. Redox signaling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol. 2008;152:415\u201322.","journal-title":"Clin Exp Immunol."},{"key":"1595_CR2","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1002\/art.20776","volume":"52","author":"M Kobayashi","year":"2005","unstructured":"Kobayashi M, Squires GR, Mousa A, Tanzer M, Zukour D, Antoniou J, Feige U, Poole R. Role of interleukin-1 and tumor necrosis factor \u03b1 in matrix degradation of human osteoarthritic cartilage. Arthritis Rhum. 2005;52:128\u201335.","journal-title":"Arthritis Rhum."},{"key":"1595_CR3","first-page":"1","volume":"6097417","author":"CM Quinonez-Flores","year":"2016","unstructured":"Quinonez-Flores CM, Gonzalez Chavez SA, Najera DDR, Pacheco-Tena C. Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: a systematic review. Bio Med Res Int. 2016;6097417:1\u201314.","journal-title":"Bio Med Res Int."},{"key":"1595_CR4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s000180300001","volume":"60","author":"M Zafarullah","year":"2003","unstructured":"Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. CMLS. 2003;60:6\u201320.","journal-title":"CMLS."},{"key":"1595_CR5","doi-asserted-by":"publisher","first-page":"315","DOI":"10.2147\/DDDT.S52354","volume":"8","author":"J Li","year":"2014","unstructured":"Li J, Li J, Yue Y, Hu Y, Cheng W, Liu R, Pan X, Zhang P. Genistein suppresses tumor necrosis factor \u03b1-induced inflammation via modulating reactive oxygen species\/Akt\/nuclear factor \u03baB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther. 2014;8:315\u201323.","journal-title":"Drug Des Devel Ther."},{"key":"1595_CR6","doi-asserted-by":"publisher","first-page":"220","DOI":"10.3164\/jcbn.14-129","volume":"56","author":"RC Orihuela-Campos","year":"2015","unstructured":"Orihuela-Campos RC, Tamaki N, Mukai R, Fukui M, Miki K, Terao J, Ito H. Biological impacts of resveratrol, quercetin, and N-acetylcysteine on oxidative stress in human gingival fibroblasts. J Clin Biochem Nutr. 2015;56:220\u20137.","journal-title":"J Clin Biochem Nutr."},{"key":"1595_CR7","doi-asserted-by":"publisher","first-page":"e108855","DOI":"10.1371\/journal.pone.0108855","volume":"9","author":"C Wang","year":"2014","unstructured":"Wang C, Chen K, Xia Y, Dai W, Wang F, Shen M, Cheng P, Wang J, Lu J, Zhang Y, Yang J, Zhu R, Zhang H, Li J, Zheng Y, Zhou Y, Guo C. N-acetylcysteine attenuates ischemia-reperfusion induced apoptosis and autophagy in mouse liver via regulation of the ROS \/ JNK \/ Bcl-2 pathway. PLoS One. 2014;9:e108855.","journal-title":"PLoS One."},{"key":"1595_CR8","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1016\/j.yexcr.2013.04.010","volume":"319","author":"M Chambers","year":"2013","unstructured":"Chambers M, Kirkpartrick G, Evans M, Gorshi G, Foater S, Borghaei RC. IL-4 inhibition of IL-1 induced Matrix Metalloproteinase-3 (MMP-3) expression in human fibroblasts involvers decreased AP-1 activation via negative crosstalk involving of Jun N-terminal Kinase (JNK). Exp Cell Res. 2013;319:1398\u2013408.","journal-title":"Exp Cell Res."},{"key":"1595_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/4895050","volume":"4895050","author":"BJ Rose","year":"2016","unstructured":"Rose BJ, Kooyman DL. A tale of two joints: The role of matrix metalloproteases in cartilage biology. Dis Markers. 2016;4895050:1\u20137.","journal-title":"Dis Markers"},{"key":"1595_CR10","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1002\/art.1780390205","volume":"39","author":"K Fujisawa","year":"1996","unstructured":"Fujisawa K, Aono H, Hasunuma T, Yamamoto K, Mita S, Nishioka K. Activation of transcription factor NF-\u03ba B in human synovial cells in response to tumor necrosis factor \u03b1. Arthritis Rheum. 1996;39:197\u2013203.","journal-title":"Arthritis Rheum."},{"key":"1595_CR11","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.pupt.2005.12.007","volume":"20","author":"AM Sadowska","year":"2007","unstructured":"Sadowska AM, Manuel-y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: Discordant in vitro and in vivo dose-effects: A review. Pulm Pharmacol Ther. 2007;20:9\u201322.","journal-title":"Pulm Pharmacol Ther."},{"key":"1595_CR12","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/sj.bjp.0703787","volume":"132","author":"S Hashimoto","year":"2001","unstructured":"Hashimoto S, Gon Y, Mastumoto K, Takeshita I, Horie T. N-acetylcysteine attenuates TNF-\u03b1-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells. Br J Pharmacol. 2001;132:270\u20136.","journal-title":"Br J Pharmacol."},{"key":"1595_CR13","doi-asserted-by":"publisher","first-page":"25310","DOI":"10.18632\/oncotarget.15813","volume":"8","author":"H Yang","year":"2017","unstructured":"Yang H, Xie Y, Yang D, Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget. 2017;8:25310\u201322.","journal-title":"Oncotarget"},{"key":"1595_CR14","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/art.1780310302","volume":"31","author":"FC Arnett","year":"1988","unstructured":"Arnett FC, Edworthy SM, Bloch DA, McSane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315\u201324.","journal-title":"Arthritis Rheum."},{"key":"1595_CR15","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/978-1-59745-401-8_24","volume":"135","author":"S Rosengren","year":"2007","unstructured":"Rosengren S, Boyle DL, Firestein GS. Acquisition, culture, and phenotyping of synovial fibroblasts. Methods Mol Med. 2007;135:365\u201375.","journal-title":"Methods Mol Med."},{"key":"1595_CR16","doi-asserted-by":"publisher","unstructured":"Sano H, Kondo N, Fijisawa J, Netsu T, Kijima Y, Kanai T, Arai K, Endo N. Secretion of vascular endothelial growth factor is inhibited by the antioxidant of N-acetylcysteine in fibroblast-like synoviocytes from rheumatoid arthritis. AJSR. 2016. https:\/\/doi.org\/10.15413\/ajsr.2016.0605.","DOI":"10.15413\/ajsr.2016.0605"},{"key":"1595_CR17","first-page":"432","volume":"23","author":"M Sato","year":"1996","unstructured":"Sato M, Miyazaki T, Nagaya T, Murata Y, Ida N, Maeda K, Seo H. Antioxidants inhibit tumor necrosis factor-\u03b1 mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells. Am J Rheumatol. 1996;23:432\u20138.","journal-title":"Am J Rheumatol."},{"key":"1595_CR18","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1186\/s12906-018-2308-4","volume":"18","author":"YH Huang","year":"2018","unstructured":"Huang YH, Wu PY, Wen KC, Lin CY, Chiang HM. Protective effects and mechanisms of Terminalia catappa L. methenolic extract on hydrogen-peroxide-induced oxidative stress in human skin fibroblasts. BMC Complement Altern Med. 2018;18:266.","journal-title":"BMC Complement Altern Med"},{"key":"1595_CR19","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1172\/JCI12466","volume":"108","author":"Z Han","year":"2001","unstructured":"Han Z, Bolye DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is requited for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108:73\u201381.","journal-title":"J Clin Invest"},{"key":"1595_CR20","doi-asserted-by":"publisher","first-page":"11957","DOI":"10.1074\/jbc.M304935200","volume":"279","author":"L Du","year":"2004","unstructured":"Du L, Lyle CS, Obey TB, Gaarde WA, Muir JA, Bennett BL, Chambers TC. Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity. J Biol Chem. 2004;279:11957\u201366.","journal-title":"J Biol Chem."},{"key":"1595_CR21","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/ncb2021","volume":"12","author":"M Komatsu","year":"2010","unstructured":"Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichmura Y. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213\u201323.","journal-title":"Nat Cell Biol."},{"key":"1595_CR22","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.molcel.2011.07.039","volume":"44","author":"G Matsumoto","year":"2011","unstructured":"Matsumoto G, Koji W, Okuno M, Kurosawa M, Nukina N. Serine 403 phosphorylation of p62\/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell. 2011;44:279\u201389.","journal-title":"Mol Cell."},{"key":"1595_CR23","doi-asserted-by":"publisher","first-page":"10074","DOI":"10.3390\/molecules190710074","volume":"19","author":"YS Keum","year":"2014","unstructured":"Keum YS, Choi BY. Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway. Molecules. 2014;19:10074\u201389.","journal-title":"Molecules."},{"issue":"s","key":"1595_CR24","doi-asserted-by":"publisher","first-page":"396","DOI":"10.3109\/10799893.2014.908916","volume":"34","author":"L Zhang","year":"2014","unstructured":"Zhang L, Zhu Z, Liu J, Zhu Z, Hu Z. Protective effect of N-acetlcysteine (NAC) on renal ischemia\/reperfusion injury through Nrf2 signaling pathway. J Recept Signal Transduct Res. 2014;34(s):396\u2013400.","journal-title":"J Recept Signal Transduct Res."},{"key":"1595_CR25","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3164\/jcbn.14-134","volume":"56","author":"K Itoh","year":"2015","unstructured":"Itoh K, Ye P, Matsumia T, Tanji K, Ozaki T. Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria. J Clin Biochem Nutr. 2015;56:91\u20137.","journal-title":"J Clin Biochem Nutr."},{"key":"1595_CR26","doi-asserted-by":"publisher","first-page":"2772","DOI":"10.3390\/ijms18122772","volume":"18","author":"S Vomund","year":"2017","unstructured":"Vomund S, Sch\u00e4ffer A, Parnham MJ, Br\u00fcne B, Knethen AV. Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci. 2017;18:2772.","journal-title":"Int J Mol Sci."},{"key":"1595_CR27","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1007\/s10753-017-0575-8","volume":"40","author":"H Shen","year":"2017","unstructured":"Shen H, Wu N, Wang Y, Han X, Zheng Q, Cai X, Zhang H, Zhao M. JNK inhibitor SP600125 attenuates paraquat-induced acute lung injury: an in vivo and in vitro study. Inflammation. 2017;40:1319\u201330.","journal-title":"Inflammation."}],"container-title":["Journal of Orthopaedic Surgery and Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-020-01595-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13018-020-01595-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13018-020-01595-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T00:06:15Z","timestamp":1626480375000},"score":1,"resource":{"primary":{"URL":"https:\/\/josr-online.biomedcentral.com\/articles\/10.1186\/s13018-020-01595-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,17]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1595"],"URL":"https:\/\/doi.org\/10.1186\/s13018-020-01595-9","relation":{},"ISSN":["1749-799X"],"issn-type":[{"value":"1749-799X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,17]]},"assertion":[{"value":"6 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Written informed consent was obtained from each patient for publication.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"87"}}