{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T06:05:37Z","timestamp":1784354737694,"version":"3.55.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2018MH007"],"award-info":[{"award-number":["ZR2018MH007"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972056"],"award-info":[{"award-number":["81972056"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammation"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title><jats:italic>Abstract<\/jats:italic>\n<\/jats:title><jats:p>Osteoarthritis (OA) is considered the most frequent degenerative disease and is characterized by cartilage degradation and synovial inflammation. Fibroblast-like synoviocytes (FLSs) are vital to synovial inflammation in OA. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and hyperinsulinemia (HINS) and has been demonstrated to be an independent risk factor for OA. Autophagy is involved in the processes of various inflammatory diseases, and autophagy inhibition can stimulate OA development. Thus, we aimed to investigate the role of insulin in the inflammatory phenotype and autophagy of FLSs in OA. The data showed that cell viability and proinflammatory cytokine production in FLSs were both increased after insulin stimulation. We also found that high insulin could promote macrophage infiltration and chemokine production but inhibited autophagy in FLSs. To further explore the potential mechanisms, the effects of insulin on PI3K\/Akt\/mTOR and NF-\u0138B signaling activation were evaluated. The results indicated that insulin activated PI3K\/Akt\/mTOR\/NF-\u0138B signaling, and the above-mentioned inflammatory responses, including autophagy inhibition, were notably attenuated by specific signaling inhibitors in the presence of high insulin. Moreover, the data showed that a positive feedback loop existed between proinflammatory cytokines (<jats:italic>e.g.<\/jats:italic>, IL-1\u03b2, IL-6, and TNF-\u03b1) and PI3K\/mTOR\/Akt\/NF-\u0138B signaling in FLSs, and insulin enhanced this feedback loop to accelerate OA progression. Our study suggests that insulin may be a novel therapeutic strategy for OA prevention and treatment in the future.<\/jats:p>","DOI":"10.1007\/s10753-020-01178-0","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T18:02:49Z","timestamp":1579888969000},"page":"916-936","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Insulin Exacerbates Inflammation in Fibroblast-Like Synoviocytes"],"prefix":"10.1007","volume":"43","author":[{"given":"Li","family":"Qiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2456-3014","authenticated-orcid":false,"given":"Shui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,24]]},"reference":[{"issue":"9995","key":"1178_CR1","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S0140-6736(15)60692-4","volume":"386","author":"Global Burden of Disease Study 2013 Collaborators","year":"2015","unstructured":"Global Burden of Disease Study 2013 Collaborators. 2015. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990\u20132013: a systematic analysis for the Global Burden Disease Study 2013. Lancet. 386 (9995): 743\u2013800. https:\/\/doi.org\/10.1016\/S0140-6736(15)60692-4.","journal-title":"Lancet."},{"issue":"1","key":"1178_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","volume":"7","author":"M Kapoor","year":"2011","unstructured":"Kapoor, M., J. Martel-Pelletier, D. Lajeunesse, J.P. Pelletier, and H. Fahmi. 2011. Role of proinflamatory cytokines in the pathophysiology of osteoarthritis. Nature Reviews Rheumatology 7 (1): 33\u201342. https:\/\/doi.org\/10.1038\/nrrheum.2010.196.","journal-title":"Nature Reviews Rheumatology"},{"key":"1178_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.cytogfr.2018.10.002","volume":"44","author":"T Wang","year":"2018","unstructured":"Wang, T., and C. He. 2018. Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine & Growth Factor Reviews 44: 38\u201350. https:\/\/doi.org\/10.1016\/j.cytogfr.2018.10.002.","journal-title":"Cytokine & Growth Factor Reviews"},{"issue":"1","key":"1178_CR4","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/cei.12486","volume":"180","author":"B Moradi","year":"2015","unstructured":"Moradi, B., N. Rosshirt, E. Tripel, J. Kirsch, A. Bari\u00e9, F. Zeifang, T. Gotterbarm, and S. Hagmann. 2015. Unicompartmental and bicompartmental knee osteoarthritis show different patterns of mononuclear cell infiltration and cytokine release in the affected joints. Clinical and Experimental Immunology 180 (1): 143\u2013154. https:\/\/doi.org\/10.1111\/cei.12486.","journal-title":"Clinical and Experimental Immunology"},{"issue":"4","key":"1178_CR5","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3899\/jrheum.151068","volume":"43","author":"IR Klein-Wieringa","year":"2016","unstructured":"Klein-Wieringa, I.R., B.J. de Lange-Brokaar, E. Yusuf, S.N. Andersen, J.C. Kwekkeboom, H.M. Kroon, G.J. van Osch, A.M. Zuurmond, V. Stojanovic-Susulic, R.G. Nelissen, R.E. Toes, M. Kloppenburg, and A. Ioan-Facsinay. 2016. Inflammatory cells in patients with endstage knee osteoarthritis: a comparison between the synovium and the infrapatellar fat pad. Journal of Rheumatology 43 (4): 771\u2013778. https:\/\/doi.org\/10.3899\/jrheum.151068.","journal-title":"Journal of Rheumatology"},{"issue":"2","key":"1178_CR6","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.joca.2017.11.015","volume":"26","author":"X Wang","year":"2018","unstructured":"Wang, X., D.J. Hunter, X. Jin, and C. Ding. 2018. The importance of synovial inflammation in osteoarthritis: current evidence from imaging assessments and clinical trial. Osteoarthritis Cart 26 (2): 165\u2013167. https:\/\/doi.org\/10.1016\/j.joca.2017.11.015.","journal-title":"Osteoarthritis Cart"},{"key":"1178_CR7","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.semcdb.2016.05.009","volume":"62","author":"P Bhattaram","year":"2017","unstructured":"Bhattaram, P., and U. Chandrasekharan. 2017. The joint synovium: a critical determinant of articular cartilage fate in inflammatory joint diseases. Seminars in Cell & Developmental Biology 62: 86\u201393. https:\/\/doi.org\/10.1016\/j.semcdb.2016.05.009.","journal-title":"Seminars in Cell & Developmental Biology"},{"issue":"2","key":"1178_CR8","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","volume":"51","author":"CR Scanzello","year":"2012","unstructured":"Scanzello, C.R., and S.R. Goldring. 2012. The role of synovitis in osteoarthritis pathogenesis. Bone 51 (2): 249\u2013257. https:\/\/doi.org\/10.1016\/j.bone.2012.02.012.","journal-title":"Bone"},{"issue":"5","key":"1178_CR9","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1515\/BC.2010.035","volume":"391","author":"U Pozgan","year":"2010","unstructured":"Pozgan, U., D. Caglic, B. Rozman, H. Nagase, V. Turk, and B. Turk. 2010. Expression and activity profiling of selected cysteine cathepsins and matrix metalloproteinases in synovial fluids from patients with rheumatoid arthritis and osteoarthritis. Biological Chemistry 391 (5): 571\u2013579. https:\/\/doi.org\/10.1515\/BC.2010.035.","journal-title":"Biological Chemistry"},{"issue":"11","key":"1178_CR10","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1016\/j.joca.2015.05.035","volume":"23","author":"S Larsson","year":"2015","unstructured":"Larsson, S., M. Englund, A. Struglics, and L.S. Lohmander. 2015. Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy. Osteoarthritis and Cartilage 23 (11): 1906\u20131914. https:\/\/doi.org\/10.1016\/j.joca.2015.05.035.","journal-title":"Osteoarthritis and Cartilage"},{"issue":"11","key":"1178_CR11","doi-asserted-by":"publisher","first-page":"2580","DOI":"10.1016\/j.biocel.2013.08.018","volume":"45","author":"S Rigoglou","year":"2013","unstructured":"Rigoglou, S., and A.G. Papavassiliou. 2013. The NF-kappaB signalling pathway in osteoarthritis. International Journal of Biochemistry & Cell Biology 45 (11): 2580\u20132584. https:\/\/doi.org\/10.1016\/j.biocel.2013.08.018.","journal-title":"International Journal of Biochemistry & Cell Biology"},{"issue":"59","key":"1178_CR12","doi-asserted-by":"publisher","first-page":"99649","DOI":"10.18632\/oncotarget.20587","volume":"8","author":"W Zheng","year":"2017","unstructured":"Zheng, W., Z. Feng, Y. Lou, C. Chen, and C. Zhang. 2017. Silibinin protects against osteoarthritis through inhibiting the inflammatory response and cartilage matrix degradation in vitro and in vivo. Oncotarget 8 (59): 99649\u201399665. https:\/\/doi.org\/10.18632\/oncotarget.20587.","journal-title":"Oncotarget"},{"issue":"7","key":"1178_CR13","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.3390\/ijms17071178","volume":"17","author":"A Tokito","year":"2016","unstructured":"Tokito, A., and M. Jougasaki. 2016. Matrix metalloproteinases in non-neoplastic disorders. International Journal of Molecular Sciences 17 (7): 1178. https:\/\/doi.org\/10.3390\/ijms17071178.","journal-title":"International Journal of Molecular Sciences"},{"key":"1178_CR14","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/bs.pmbts.2017.03.00","volume":"148","author":"CJ Malemud","year":"2017","unstructured":"Malemud, C.J. 2017. Matrix metalloproteinases and synovial joint pathology. Progress in Molecular Biology and Translational Science 148: 305\u2013325. https:\/\/doi.org\/10.1016\/bs.pmbts.2017.03.00.","journal-title":"Progress in Molecular Biology and Translational Science"},{"issue":"2","key":"1178_CR15","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1097\/BOR.000000000000037310.1038\/nrrheum.2017.50","volume":"29","author":"A Courties","year":"2017","unstructured":"Courties, A., J. Sellam, and F. Berenbaum. 2017. Metabolic syndrome-associated osteoarthritis. Current Opinion in Rheumatology 29 (2): 214\u2013222. https:\/\/doi.org\/10.1097\/BOR.000000000000037310.1038\/nrrheum.2017.50.","journal-title":"Current Opinion in Rheumatology"},{"issue":"1","key":"1178_CR16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.semarthrit.2019.01.005","volume":"49","author":"N Veronese","year":"2019","unstructured":"Veronese, N., C. Cooper, J.Y. Reginster, M. Hochberg, J. Branco, O. Bruere, R. Chapurlat, N. Al-Daghri, E. Dennison, G. Herrero-Beaumont, J.F. Kaux, E. Maheu, R. Rizzoli, R. Roth, L.C. Rovati, D. Uebelhart, M. Vlaskovska, and A. Scheen. 2019. Type 2 diabetes mellitus and osteoarthritis. Seminars in Arthritis and Rheumatism 49 (1): 9\u201319. https:\/\/doi.org\/10.1016\/j.semarthrit.2019.01.005.","journal-title":"Seminars in Arthritis and Rheumatism"},{"issue":"7","key":"1178_CR17","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nrrheum.2015.53","volume":"11","author":"E Lubberts","year":"2015","unstructured":"Lubberts, E. 2015. The IL-23-IL-17 axis in inflammatory arthritis. Nature Reviews Rheumatology 11 (7): 415\u2013429. https:\/\/doi.org\/10.1038\/nrrheum.2015.53.","journal-title":"Nature Reviews Rheumatology"},{"issue":"8","key":"1178_CR18","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1136\/ard.2010.146399","volume":"70","author":"F Berenbaum","year":"2011","unstructured":"Berenbaum, F. 2011. Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype. Annals of the Rheumatic Diseases 70 (8): 1354\u20131356. https:\/\/doi.org\/10.1136\/ard.2010.146399.","journal-title":"Annals of the Rheumatic Diseases"},{"issue":"4","key":"1178_CR19","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.joca.2015.10.017","volume":"24","author":"M Ribeiro","year":"2016","unstructured":"Ribeiro, M., P. Lo\u2019pez de Figueroa, F.J. Blanco, A.F. Mendes, and B. Carame\u2019s. 2016. Insulin decreases autophagy and leads to cartilage degradation. Osteoarthritis and Cartilage 24 (4): 731\u2013739. https:\/\/doi.org\/10.1016\/j.joca.2015.10.017.","journal-title":"Osteoarthritis and Cartilage"},{"issue":"9","key":"1178_CR20","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1590\/s0100-879x2003000900007","volume":"36","author":"E Torres","year":"2003","unstructured":"Torres, E., C. Andrade, E. Fonseca, M. Mello, and M. Duarte M. 2003. Insulin impairs the maturation of chondrocytes in vitro. Brazilian Journal of Medical and Biological Research 36 (9): 1185\u20131192. https:\/\/doi.org\/10.1590\/s0100-879x2003000900007.","journal-title":"Brazilian Journal of Medical and Biological Research"},{"issue":"1","key":"1178_CR21","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/cr.2013.168","volume":"24","author":"Y Feng","year":"2014","unstructured":"Feng, Y., D. He, Z. Yao, and D.J. Klionsky. 2014. The machinery of macroautophagy. Cell Research 24 (1): 24\u201341. https:\/\/doi.org\/10.1038\/cr.2013.168.","journal-title":"Cell Research"},{"issue":"4","key":"1178_CR22","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","volume":"147","author":"N Mizushima","year":"2011","unstructured":"Mizushima, N., and M. Komatsu. 2011. Autophagy: renovation of cells and tissues. Cell 147 (4): 728\u2013741. https:\/\/doi.org\/10.1016\/j.cell.2011.10.026.","journal-title":"Cell"},{"issue":"2","key":"1178_CR23","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.jbspin.2015.06.009","volume":"83","author":"YS Li","year":"2016","unstructured":"Li, Y.S., F.J. Zhang, C. Zeng, W. Luo, W.F. Xiao, S.G. Gao, and G.H. Lei. 2016. Authophagy in osteoarthritis. Joint, Bone, Spine 83 (2): 143\u2013148. https:\/\/doi.org\/10.1016\/j.jbspin.2015.06.009.","journal-title":"Joint, Bone, Spine"},{"issue":"5","key":"1178_CR24","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.3892\/ijmm.2017.2934","volume":"39","author":"NT Cheng","year":"2017","unstructured":"Cheng, N.T., H. Meng, L.F. Ma, L. Zhang, H.M. Yu, Z.Z. Wang, and A. Guo. 2017. Role of autophagy in the progression of osteoarthritis: the autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis. International Journal of Molecular Medicine 39 (5): 1224\u20131232. https:\/\/doi.org\/10.3892\/ijmm.2017.2934.","journal-title":"International Journal of Molecular Medicine"},{"issue":"6","key":"1178_CR25","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1002\/art.39073","volume":"67","author":"B Caram\u00e9s","year":"2015","unstructured":"Caram\u00e9s, B., M. Olmer, W.B. Kiosses, and M.K. Lotz. 2015. The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. Arthritis & Rheumatology 67 (6): 1568\u20131576. https:\/\/doi.org\/10.1002\/art.39073.","journal-title":"Arthritis & Rheumatology"},{"issue":"3","key":"1178_CR26","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","volume":"140","author":"N Mizushima","year":"2010","unstructured":"Mizushima, N., T. Yoshimori, and B. Levine. 2010. Methods in mammalian autophagy research. Cell 140 (3): 313\u2013326. https:\/\/doi.org\/10.1016\/j.cell.2010.01.028.","journal-title":"Cell"},{"issue":"4","key":"1178_CR27","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1136\/annrheumdis-2011-200557","volume":"71","author":"B Caram\u00e9s","year":"2012","unstructured":"Caram\u00e9s, B., A. Hasegawa, N. Taniguchi, S. Miyaki, F.J. Blanco, and M. Lotz. 2012. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Annals of the Rheumatic Diseases 71 (4): 575\u2013581. https:\/\/doi.org\/10.1136\/annrheumdis-2011-200557.","journal-title":"Annals of the Rheumatic Diseases"},{"key":"1178_CR28","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.biopha.2017.10.152","volume":"97","author":"W He","year":"2018","unstructured":"He, W., and Y. Cheng. 2018. Inhibition of miR-20 promotes proliferation and autophagy in articular chondrocytes by PI3K\/AKT\/mTOR signaling pathway. Biomedicine & Pharmacotherapy 97: 607\u2013615. https:\/\/doi.org\/10.1016\/j.biopha.2017.10.152.","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"1178_CR29","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1016\/j.biopha.2017.01.130","volume":"89","author":"JF Xue","year":"2017","unstructured":"Xue, J.F., Z.M. Shi, J. Zou, and X.L. Li. 2017. Inhibition of PI3K\/AKT\/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis. Biomedicine & Pharmacotherapy 89: 1252\u20131261. https:\/\/doi.org\/10.1016\/j.biopha.2017.01.130.","journal-title":"Biomedicine & Pharmacotherapy"},{"issue":"3","key":"1178_CR30","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","volume":"124","author":"S Wullschleger","year":"2006","unstructured":"Wullschleger, S., R. Loewith, and M.N. Hall. 2006. TOR signaling in growth and metabolism. Cell 124 (3): 471\u2013484. https:\/\/doi.org\/10.1016\/j.cell.2006.01.016.","journal-title":"Cell"},{"issue":"8","key":"1178_CR31","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/nrc2664","volume":"9","author":"JA Engelman","year":"2009","unstructured":"Engelman, J.A. 2009. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nature Reviews Cancer 9 (8): 550\u2013562. https:\/\/doi.org\/10.1038\/nrc2664.","journal-title":"Nature Reviews Cancer"},{"issue":"9","key":"1178_CR32","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/ni.f.214","volume":"9","author":"F Sallusto","year":"2008","unstructured":"Sallusto, F., and M. Baggiolini. 2008. Chemokines and leukocyte traffic. Nature Immunology 9 (9): 949\u2013952. https:\/\/doi.org\/10.1038\/ni.f.214.","journal-title":"Nature Immunology"},{"issue":"1","key":"1178_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1124\/pr.113.007724","volume":"66","author":"F Bachelerie","year":"2014","unstructured":"Bachelerie, F., A. Ben-Baruch, A.M. Burkhardt, C. Combadiere, J.M. Faeber, G.J. Graham, R. Horuk, A.H. Sparre-Ulrich, M. Locati, A.D. Luster, A. Mantovani, K. Matsushima, P.M. Murphy, R. Nibbs, H. Nomiyama, C.A. Power, A.E. Proudfoot, M.M. Rosenkilde, A. Rot, S. Sozzani, M. Thelen, O. Yoshie, and A. Zlotnik. 2014. International union of basic and clinical pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacological Reviews 66 (1): 1\u201379. https:\/\/doi.org\/10.1124\/pr.113.007724.","journal-title":"Pharmacological Reviews"},{"issue":"1","key":"1178_CR34","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1182\/blood-2009-12-258186","volume":"117","author":"L S\u00e1nchez-Mart\u00edn","year":"2011","unstructured":"S\u00e1nchez-Mart\u00edn, L., A. Estecha, R. Samaniego, S. S\u00e1nchez-Ram\u00f3n, M.\u00c1. Vega, and P. S\u00e1nchez-Mateos. 2011. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117 (1): 88\u201397. https:\/\/doi.org\/10.1182\/blood-2009-12-258186.","journal-title":"Blood"},{"issue":"16","key":"1178_CR35","doi-asserted-by":"publisher","first-page":"3794","DOI":"10.1158\/1078-0432.CCR-15-0204","volume":"21","author":"S Svensson","year":"2015","unstructured":"Svensson, S., A. Abrahamsson, G.V. Rodriguez, A.K. Olsson, L. Jensen, Y. Cao, and C. Dabrosin. 2015. CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clinical Cancer Research 21 (16): 3794\u20133805. https:\/\/doi.org\/10.1158\/1078-0432.CCR-15-0204.","journal-title":"Clinical Cancer Research"},{"issue":"4","key":"1178_CR36","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1002\/jor.23471","volume":"35","author":"CR Scanzello","year":"2017","unstructured":"Scanzello, C.R. 2017. Chemokines and inflammation in osteoarthritis: Insights from patients and animal models. Journal of Orthopaedic Research 35 (4): 735\u2013739. https:\/\/doi.org\/10.1002\/jor.23471.","journal-title":"Journal of Orthopaedic Research"},{"issue":"1","key":"1178_CR37","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/imr.12606","volume":"281","author":"D Boraschi","year":"2018","unstructured":"Boraschi, D., P. Italiani, S. Weil, and M.U. Martin. 2018. The family of the interleukin-1 receptors. Immunological Reviews 281 (1): 197\u2013232. https:\/\/doi.org\/10.1111\/imr.12606.","journal-title":"Immunological Reviews"},{"issue":"18","key":"1178_CR38","doi-asserted-by":"publisher","first-page":"6762","DOI":"10.1074\/jbc.RA117.001163","volume":"293","author":"P Baran","year":"2018","unstructured":"Baran, P., S. Hansen, G.H. Waetzig, M. Akbarzadeh, L. Lamertz, H.J. Huber, M.R. Ahmadian, J.M. Moll, and J. Scheller. 2018. The balance of interleukin (IL)-6, IL-6\u00b7soluble IL-6 receptor (sIL-6R), and IL-6\u00b7sIL-6R\u00b7sgp130 complexes allows simultaneous classic and trans-signaling. Journal of Biological Chemistry 293 (18): 6762\u20136775. https:\/\/doi.org\/10.1074\/jbc.RA117.001163.","journal-title":"Journal of Biological Chemistry"},{"key":"1178_CR39","doi-asserted-by":"publisher","first-page":"12726","DOI":"10.1038\/srep12726","volume":"5","author":"D Becker","year":"2015","unstructured":"Becker, D., T. Deller, and A. Vlachos. 2015. Tumor necrosis factor (TNF)-receptor 1 and 2 mediate homeostatic synaptic plasticity of denervated mouse dentate granule cells. Scientific Reports 5: 12726. https:\/\/doi.org\/10.1038\/srep12726.","journal-title":"Scientific Reports"},{"issue":"6","key":"1178_CR40","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.joca","volume":"19","author":"SC Rosa","year":"2011","unstructured":"Rosa, S.C., A.T. Rufino, F. Judas, C. Tenreiro, M.C. Lopes, and A.F. Mendes. 2011. Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin. Osteoarthritis and Cartilage 19 (6): 719\u2013727. https:\/\/doi.org\/10.1016\/j.joca.","journal-title":"Osteoarthritis and Cartilage"},{"issue":"2","key":"1178_CR41","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.bone.2006.02.067","volume":"39","author":"H Claassen","year":"2006","unstructured":"Claassen, H., M. Schl\u00fcter, M. Sch\u00fcnke, and B. Kurz. 2006. Influence of 17beta-estradiol and insulin on type II collagen and protein synthesis of articular chondrocytes. Bone 39 (2): 310\u2013317. https:\/\/doi.org\/10.1016\/j.bone.2006.02.067.","journal-title":"Bone"},{"issue":"9","key":"1178_CR42","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1053\/joca.2002.0813","volume":"10","author":"L Cai","year":"2002","unstructured":"Cai, L., F.W. Okumu, J.L. Cleland, M. Beresini, D. Hogue, Z. Lin, and E.H. Filvaroff. 2002. A slow release formulation of insulin as a treatment for osteoarthritis. Osteoarthritis and Cartilage 10 (9): 692\u2013706. https:\/\/doi.org\/10.1053\/joca.2002.0813.","journal-title":"Osteoarthritis and Cartilage"},{"issue":"1\u20132","key":"1178_CR43","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.mce.2006.02.002","volume":"249","author":"C Phornphutkul","year":"2006","unstructured":"Phornphutkul, C., K.Y. Wu, and P.A. Gruppuso. 2006. The role of insulin in chondrogenesis. Molecular and Cellular Endocrinology 249 (1\u20132): 107\u2013115. https:\/\/doi.org\/10.1016\/j.mce.2006.02.002.","journal-title":"Molecular and Cellular Endocrinology"},{"issue":"4","key":"1178_CR44","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1016\/j.theriogenology.2016.04.003","volume":"86","author":"R Rossetto","year":"2016","unstructured":"Rossetto, R., M.V.A. Saraiva, M.P. Bernuci, G.M. Silva, I.R. Brito, A.M.C.V. Alves, D.M. Magalh\u00e3es-Padilha, S.N. B\u00e1o, C.C. Campello, A.P.R. Rodrigues, and J.R. Figueiredo. 2016. Impact of insulin concentration and mode of FSH addition on the in vitro survival and development of isolated bovine preantral follicles. Theriogenology 86 (4): 1137\u20131145. https:\/\/doi.org\/10.1016\/j.theriogenology.2016.04.003.","journal-title":"Theriogenology"},{"issue":"6","key":"1178_CR45","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.molce","volume":"46","author":"H Kubota","year":"2012","unstructured":"Kubota, H., R. Noguchi, Y. Toyoshima, Y. Ozaki, S. Uda, K. Watanabe, W. Ogawa, and S. Kuroda. 2012. Temporal coding of insulin action through multiplexing of the AKT pathway. Molecular Cell 46 (6): 820\u2013832. https:\/\/doi.org\/10.1016\/j.molce.","journal-title":"Molecular Cell"},{"key":"1178_CR46","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.mce.2015.08.001","volume":"415","author":"Y Mirdamadi","year":"2015","unstructured":"Mirdamadi, Y., A. Thielitz, A. Wiede, A. Goihl, E. Papakonstantinou, R. Hartig, C.C. Zouboulis, D. Reinhold, L. Simeoni, U. Bommhardt, S. Quist, and H. Gollnick. 2015. Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase\/Akt\/FoxO1 pathway in SZ95 sebocytes in vitro. Molecular and Cellular Endocrinology 415: 32\u201344. https:\/\/doi.org\/10.1016\/j.mce.2015.08.001.","journal-title":"Molecular and Cellular Endocrinology"},{"issue":"3","key":"1178_CR47","doi-asserted-by":"publisher","first-page":"513","DOI":"10.3390\/nu11030513","volume":"11","author":"AC Ho-Palma","year":"2019","unstructured":"Ho-Palma, A.C., P. Toro, F. Rotondo, M.D.M. Romero, M. Alemany, X. Remesar, and J.A. Fern\u00e1ndez-L\u00f3pez. 2019. Insulin controls triacylglycerol synthesis through control of glycerol metabolism and despite increased lipogenesis. Nutrients 11 (3): 513. https:\/\/doi.org\/10.3390\/nu11030513.","journal-title":"Nutrients"},{"issue":"1","key":"1178_CR48","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s11033-018-4512-1","volume":"46","author":"ARG de Proen\u00e7a","year":"2019","unstructured":"de Proen\u00e7a, A.R.G., K.D. Pereira, L. Meneguello, L. Tamborlin, and A.D. Luchessi. 2019. Insulin action on protein synthesis and its association with eIF5A expression and hypusination. Molecular Biology Reports 46 (1): 587\u2013596. https:\/\/doi.org\/10.1007\/s11033-018-4512-1.","journal-title":"Molecular Biology Reports"},{"key":"1178_CR49","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.theriogenology.2019.02.023","volume":"130","author":"A Hodonu","year":"2019","unstructured":"Hodonu, A., M. Escobar, L. Beach, J. Hunt, and J. Rose. 2019. Glycogen metabolism in mink uterine epithelial cells and its regulation by estradiol, progesterone and insulin. Theriogenology 130: 62\u201370. https:\/\/doi.org\/10.1016\/j.theriogenology.2019.02.023.","journal-title":"Theriogenology"},{"issue":"50","key":"1178_CR50","doi-asserted-by":"publisher","first-page":"19796","DOI":"10.1073\/pnas.0709805104","volume":"104","author":"CD Chen","year":"2007","unstructured":"Chen, C.D., S. Podvin, E. Gillespie, S.E. Leeman, and C.R. Abraham. 2007. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proceedings of the National Academy of Sciences of the United States of America 104 (50): 19796\u201319801. https:\/\/doi.org\/10.1073\/pnas.0709805104.","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"8","key":"1178_CR51","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1210\/me.2002-0074","volume":"16","author":"M Montagnani","year":"2002","unstructured":"Montagnani, M., L.V. Ravichandran, H. Chen, D.L. Esposito, and M.J. Quon. 2002. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Molecular Endocrinology 16 (8): 1931\u20131942. https:\/\/doi.org\/10.1210\/me.2002-0074.","journal-title":"Molecular Endocrinology"},{"issue":"13","key":"1178_CR52","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1161\/01.cir.101.13.1539","volume":"101","author":"G Zeng","year":"2000","unstructured":"Zeng, G., F.H. Nystrom, L.V. Ravichandran, L.N. Cong, M. Kriby, H. Mostowski, and M.J. Quon. 2000. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101 (13): 1539\u20131545. https:\/\/doi.org\/10.1161\/01.cir.101.13.1539.","journal-title":"Circulation"},{"issue":"4","key":"1178_CR53","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.bbrc","volume":"509","author":"K Wu","year":"2019","unstructured":"Wu, K., W. Wang, H. Chen, W. Gao, and C. Yu. 2019. Insulin promotes proliferation of pancreatic ductal epithelial cells by increasing expression of PLK1 through PI3K\/AKT and NF-kB pathway. Biochemical and Biophysical Research Communications 509 (4): 925\u2013930. https:\/\/doi.org\/10.1016\/j.bbrc.","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"2","key":"1178_CR54","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/sj.onc.1204064","volume":"20","author":"C Desbois-Mouthon","year":"2001","unstructured":"Desbois-Mouthon, C., A. Cadoret, M.J. Blivet-Van Eggelpo\u00ebl, F. Bertrand, G. Cherqui, C. Perret, and J. Capeau. 2001. Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene 20 (2): 252\u2013259. https:\/\/doi.org\/10.1038\/sj.onc.1204064.","journal-title":"Oncogene"}],"container-title":["Inflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-020-01178-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10753-020-01178-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-020-01178-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T01:06:25Z","timestamp":1611363985000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10753-020-01178-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,24]]},"references-count":54,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["1178"],"URL":"https:\/\/doi.org\/10.1007\/s10753-020-01178-0","relation":{},"ISSN":["0360-3997","1573-2576"],"issn-type":[{"value":"0360-3997","type":"print"},{"value":"1573-2576","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,24]]},"assertion":[{"value":"24 January 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"This study was permitted by the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong University (Jinan, China) on March 3, 2017 (approval number 2017-53).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval and Consent to Participate"}},{"value":"The authors declare that they have no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}