{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:56:10Z","timestamp":1786600570355,"version":"build-2736575974"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Cr\u00e9dit Sectoriel de Recherche en Sciences de la Sant\u00e9"},{"name":"Fond d\u2019Investissement pour la Recherche Scientifique"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously underscored a critical role for CEMIP in fibrosis of OA cartilage. However, its role in OA synovial membrane remains unknown. An in vitro model with fibroblast-like synoviocytes from OA patients and an in vivo model with collagenase-induced OA mice were used to evaluate CEMIP-silencing effects on inflammation, hyperplasia and fibrosis. Our results showed that i. CEMIP expression was increased in human and mouse inflamed synovial membrane; ii. CEMIP regulated the inflammatory response pathway and inflammatory cytokines production in vitro and in vivo; iii. CEMIP induced epithelial to mesenchymal transition pathway and fibrotic markers in vitro and in vivo<jats:italic>;<\/jats:italic> iv. CEMIP increased cell proliferation and synovial hyperplasia; v. CEMIP expression was increased by inflammatory cytokines and by TGF-\u03b2 signaling; vi. anti-fibrotic drugs decreased CEMIP expression. All these findings highlighted the central role of CEMIP in OA synovial membrane development and underscored that targeting CEMIP could be a new therapeutic approach.<\/jats:p>","DOI":"10.1007\/s00018-022-04282-6","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T03:59:56Z","timestamp":1651031996000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["CEMIP (KIAA1199) regulates inflammation, hyperplasia and fibrosis in osteoarthritis synovial membrane"],"prefix":"10.1007","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-0891","authenticated-orcid":false,"given":"C\u00e9line","family":"Deroyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Poulet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Paulissen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Ciregia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Malaise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelda","family":"Plener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebl","family":"Cobraiville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel G.","family":"Malaise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"de Seny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"4282_CR1","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","volume":"393","author":"DJ Hunter","year":"2019","unstructured":"Hunter DJ, Bierma-Zeinstra S (2019) Osteoarthritis. Lancet 393:1745\u20131759","journal-title":"Lancet"},{"key":"4282_CR2","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.joca.2018.11.010","volume":"27","author":"NJ Collins","year":"2019","unstructured":"Collins NJ, Hart HF, Mills KAG (2019) Osteoarthritis year in review 2018: rehabilitation and outcomes. Osteoarthr Cartil 27:378\u2013391","journal-title":"Osteoarthr Cartil"},{"key":"4282_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-017-1229-9","volume":"19","author":"A Mathiessen","year":"2017","unstructured":"Mathiessen A, Conaghan PG (2017) Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis research and therapy. Arthr Res Ther 19:1\u20139","journal-title":"Arthr Res Ther"},{"key":"4282_CR4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.joca.2012.11.012","volume":"21","author":"F Berenbaum","year":"2013","unstructured":"Berenbaum F (2013) Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthr Cartil 21:16\u201321","journal-title":"Osteoarthr Cartil"},{"key":"4282_CR5","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","volume":"51","author":"CR Scanzello","year":"2012","unstructured":"Scanzello CR, Goldring SR (2012) The role of synovitis in osteoarthritis pathogenesis. Bone 51:249\u2013257","journal-title":"Bone"},{"key":"4282_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-56847-4","volume":"10","author":"D de Seny","year":"2020","unstructured":"de Seny D, Bianchi E, Baiwir D, Cobraiville G, Collin C, Deli\u00e8ge M et al (2020) Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score. Sci Rep 10:1\u201314","journal-title":"Sci Rep"},{"key":"4282_CR7","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1093\/rheumatology\/kev228","volume":"54","author":"DFG Remst","year":"2015","unstructured":"Remst DFG, Blaney Davidson EN, van der Kraan PM (2015) Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness. Rheumatology (United Kingdom) 54:1954\u20131963","journal-title":"Rheumatology (United Kingdom)"},{"key":"4282_CR8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/ar2073","volume":"8","author":"MMC Steenvoorden","year":"2006","unstructured":"Steenvoorden MMC, Tolboom TCA, van der Pluijm G, L\u00f6wik C, Visser CPJ, DeGroot J et al (2006) Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal\/fibrotic characteristics. Arthritis Res Ther 8:2\u201311","journal-title":"Arthritis Res Ther"},{"key":"4282_CR9","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s12276-021-00558-2","volume":"53","author":"F Ciregia","year":"2021","unstructured":"Ciregia F, Deroyer C, Cobraiville G, Plener Z, Malaise O, Gillet P et al (2021) Modulation of \u03b1V\u03b26 integrin in osteoarthritis-related synovitis and the interaction with VTN(381\u2013397 a.a.) competing for TGF-\u03b21 activation. Exp Mol Med 53:210\u2013222","journal-title":"Exp Mol Med"},{"key":"4282_CR10","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1136\/ard.2004.025270","volume":"64","author":"MJ Benito","year":"2005","unstructured":"Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B (2005) Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis 64:1263\u20131267","journal-title":"Ann Rheum Dis"},{"key":"4282_CR11","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1093\/rheumatology\/kev228","volume":"54","author":"DFG Remst","year":"2015","unstructured":"Remst DFG, Blaney Davidson EN, van der Kraan PM (2015) Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness. Rheumatology (United Kingdom) 54:1954\u20131963","journal-title":"Rheumatology (United Kingdom)"},{"key":"4282_CR12","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.matbio.2017.11.010","volume":"68","author":"M Mack","year":"2018","unstructured":"Mack M (2018) Inflammation and fibrosis. Matrix Biol 68:106\u2013121","journal-title":"Matrix Biol"},{"key":"4282_CR13","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","volume":"51","author":"CR Scanzello","year":"2012","unstructured":"Scanzello CR, Goldring SR (2012) The role of synovitis in osteoarthritis pathogenesis. Bone 51:249\u2013257","journal-title":"Bone"},{"key":"4282_CR14","first-page":"2808","volume":"19","author":"D Li","year":"2019","unstructured":"Li D, Wang H, He JY, Wang CL, Feng WJ, Shen C et al (2019) Inflammatory and fibrosis infiltration in synovium associated with the progression in developmental dysplasia of the hip. Mol Med Rep 19:2808\u20132816","journal-title":"Mol Med Rep"},{"key":"4282_CR15","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.joca.2016.01.001","volume":"24","author":"S Hosseininia","year":"2016","unstructured":"Hosseininia S, Weis MA, Rai J, Kim L, Funk S, Dahlberg LE et al (2016) Evidence for enhanced collagen type III deposition focally in the territorial matrix of osteoarthritic hip articular cartilage. Osteoarthr Cartil 24:1029\u20131035","journal-title":"Osteoarthr Cartil"},{"issue":"2","key":"4282_CR16","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41419-019-1377-8","volume":"10","author":"C Deroyer","year":"2019","unstructured":"Deroyer C, Charlier E, Neuville S, Malaise O, Gillet P, Kurth W et al (2019) CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes. Cell Death Dis 10(2):103. https:\/\/doi.org\/10.1038\/s41419-019-1377-8","journal-title":"Cell Death Dis"},{"key":"4282_CR17","first-page":"1","volume":"11","author":"YA Rim","year":"2021","unstructured":"Rim YA, Ju JH (2021) The role of fibrosis in osteoarthritis progression. Life 11:1\u201313","journal-title":"Life"},{"key":"4282_CR18","doi-asserted-by":"publisher","first-page":"5612","DOI":"10.1073\/pnas.1215432110","volume":"110","author":"H Yoshida","year":"2013","unstructured":"Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T et al (2013) KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Sci USA 110:5612\u20135617","journal-title":"Proc Natl Acad Sci USA"},{"key":"4282_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-014-0514-0","volume":"17","author":"X Yang","year":"2015","unstructured":"Yang X, Qiu P, Chen B, Lin Y, Zhou Z, Ge R et al (2015) KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. Arthr Res Ther 17:1\u201312","journal-title":"Arthr Res Ther"},{"key":"4282_CR20","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1016\/j.ajpath.2018.05.012","volume":"188","author":"H Shimizu","year":"2018","unstructured":"Shimizu H, Shimoda M, Mochizuki S, Miyamae Y, Abe H, Chijiiwa M et al (2018) Hyaluronan-binding protein involved in hyaluronan depolymerization is up-regulated and involved in hyaluronan degradation in human osteoarthritic cartilage. Am J Pathol 188:2109\u201319","journal-title":"Am J Pathol"},{"key":"4282_CR21","doi-asserted-by":"publisher","first-page":"3140","DOI":"10.3390\/ijms21093140","volume":"21","author":"T Ohtsuki","year":"2020","unstructured":"Ohtsuki T, Hatipoglu OF, Asano K, Inagaki J, Nishida K, Hirohata S (2020) Induction of cemip in chondrocytes by inflammatory cytokines: underlying mechanisms and potential involvement in osteoarthritis. Int J Mol Sci 21:3140","journal-title":"Int J Mol Sci"},{"key":"4282_CR22","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.ajpath.2020.01.003","volume":"190","author":"J Shiozawa","year":"2020","unstructured":"Shiozawa J, de Vega S, Cilek MZ, Yoshinaga C, Nakamura T, Kasamatsu S et al (2020) Implication of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization) in hyaluronan degradation by synovial fibroblasts in patients with knee osteoarthritis. Am J Pathol 190:1046\u201358","journal-title":"Am J Pathol"},{"key":"4282_CR23","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jcmgh.2015.12.007","volume":"2","author":"A Soroosh","year":"2016","unstructured":"Soroosh A, Albeiroti S, West GA, Willard B, Fiocchi C, de la Motte CA (2016) Crohn\u2019s disease fibroblasts overproduce the novel protein KIAA1199 to create proinflammatory hyaluronan fragments. Cell Mol Gastroenterol Hepatol 2:358\u2013368","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"4282_CR24","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.intimp.2019.05.018","volume":"73","author":"DQ Hai","year":"2019","unstructured":"Hai DQ, Ying QY, Mao LX, Ping CW, Hua WX, Wei JX (2019) Knockdown of KIAA1199 suppresses IL-1\u03b2-induced cartilage degradation and inflammatory responses in human chondrocytes through the Wnt\/\u03b2-catenin signalling pathway. Int Immunopharmacol 73:203\u201311","journal-title":"Int Immunopharmacol"},{"key":"4282_CR25","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S0140-6736(15)60692-4","volume":"386","author":"T Vos","year":"2015","unstructured":"Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I et al (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 of disease study 2013. Lancet 386:743\u2013800","journal-title":"Lancet"},{"key":"4282_CR26","doi-asserted-by":"publisher","first-page":"9518","DOI":"10.1111\/jcmm.15669","volume":"24","author":"D Han","year":"2020","unstructured":"Han D, Fang Y, Tan X, Jiang H, Gong X, Wang X et al (2020) The emerging role of fibroblast-like synoviocytes-mediated synovitis in osteoarthritis: an update. J Cell Mol Med 24:9518\u20139532","journal-title":"J Cell Mol Med"},{"key":"4282_CR27","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/j.joca.2010.07.008","volume":"18","author":"FW Roemer","year":"2010","unstructured":"Roemer FW, Kassim Javaid M, Guermazi A, Thomas M, Kiran A, Keen R et al (2010) Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI. Osteoarthr Cartil 18:1269\u20131274","journal-title":"Osteoarthr Cartil"},{"key":"4282_CR28","first-page":"1","volume":"8","author":"L Zhang","year":"2021","unstructured":"Zhang L, Xing R, Huang Z, Ding L, Zhang L, Li M et al (2021) Synovial fibrosis involvement in osteoarthritis. Front Med 8:1\u201310","journal-title":"Front Med"},{"key":"4282_CR29","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.febslet.2013.11.017","volume":"588","author":"H Yoshida","year":"2014","unstructured":"Yoshida H, Nagaoka A, Nakamura S, Tobiishi M, Sugiyama Y, Inoue S (2014) N-terminal signal sequence is required for cellular trafficking and hyaluronan-depolymerization of KIAA1199. FEBS Lett 588:111\u2013116","journal-title":"FEBS Lett"},{"key":"4282_CR30","doi-asserted-by":"publisher","first-page":"54","DOI":"10.2174\/1389557519666190906115619","volume":"20","author":"A Avenoso","year":"2020","unstructured":"Avenoso A, Bruschetta G, D\u2019Ascola A, Scuruchi M, Mandraffino G, Saitta A et al (2020) Hyaluronan fragmentation during inflammatory pathologies: a signal that empowers tissue damage. Mini-Rev Med Chem 20:54\u201365","journal-title":"Mini-Rev Med Chem"},{"key":"4282_CR31","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s00109-018-1721-y","volume":"97","author":"Z Tang","year":"2019","unstructured":"Tang Z, Ding Y, Shen Q, Zhang C, Li J, Nazar M et al (2019) KIAA1199 promotes invasion and migration in non-small-cell lung cancer (NSCLC) via PI3K-Akt mediated EMT. J Mol Med 97:127\u2013140","journal-title":"J Mol Med"},{"key":"4282_CR32","doi-asserted-by":"publisher","first-page":"8341","DOI":"10.2147\/OTT.S187389","volume":"11","author":"Z Jiang","year":"2018","unstructured":"Jiang Z, Zhai X, Shi B, Luo D, Jin B (2018) KIAA1199 overexpression is associated with abnormal expression of EMT markers and is a novel independent prognostic biomarker for hepatocellular carcinoma. Onco Targets Ther 11:8341\u20138348","journal-title":"Onco Targets Ther"},{"key":"4282_CR33","doi-asserted-by":"publisher","first-page":"1800564","DOI":"10.1183\/13993003.00564-2018","volume":"52","author":"G Kwapiszewska","year":"2018","unstructured":"Kwapiszewska G, Gungl A, Wilhelm J, Marsh LM, Puthenparampil HT, Sinn K et al (2018) Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis. Eur Respir J 52:1800564","journal-title":"Eur Respir J"},{"key":"4282_CR34","doi-asserted-by":"publisher","first-page":"17156","DOI":"10.18632\/oncotarget.15052","volume":"8","author":"S Kohi","year":"2017","unstructured":"Kohi S, Sato N, Koga A, Matayoshi N, Hirata K (2017) KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget 8:17156\u201317163","journal-title":"Oncotarget"},{"key":"4282_CR35","first-page":"1","volume":"19","author":"Q Wei","year":"2021","unstructured":"Wei Q, Kong N, Liu X, Tian R, Jiao M, Li Y et al (2021) Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro. J Translational Med BioMed Cent 19:1\u201312","journal-title":"J Translational Med BioMed Cent"},{"issue":"6","key":"4282_CR36","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.joca.2006.11.005","volume":"15","author":"H-L Ma","year":"2007","unstructured":"Ma H-L, Blanchet TJ, Peluso D, Hopkins B, Morris EA, Glasson SS (2007) Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthr Cartil 15(6):695\u2013700. https:\/\/doi.org\/10.1016\/j.joca.2006.11.005","journal-title":"Osteoarthr Cartil"},{"issue":"1","key":"4282_CR37","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1242\/dmm.016881","volume":"8","author":"S Thysen","year":"2015","unstructured":"Thysen S, Luyten FP, Lories RJU (2015) Targets models and challenges in osteoarthritis research. Dis Models Mech 8(1):17\u201330. https:\/\/doi.org\/10.1242\/dmm.016881","journal-title":"Dis Models Mech"},{"key":"4282_CR38","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fern\u00e1ndez JA, Dombrowski Y, McArt DG, Dunne PD et al (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16878","journal-title":"Sci Rep"},{"key":"4282_CR39","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.joca.2012.11.002","volume":"21","author":"S Kyostio-Moore","year":"2013","unstructured":"Kyostio-Moore S, Bangari DS, Ewing P, Nambiar B, Berthelette P, Sookdeo C et al (2013) Local gene delivery of heme oxygenase-1 by adeno-associated virus into osteoarthritic mouse joints exhibiting synovial oxidative stress. Osteoarthr Cartil 21:358\u2013367","journal-title":"Osteoarthr Cartil"},{"key":"4282_CR40","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/labinvest.2009.41","volume":"89","author":"B Relic","year":"2009","unstructured":"Relic B, Zeddou M, Desoroux A, Beguin Y, de Seny D, Malaise MG (2009) Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts. Lab Investig 89:811\u2013822","journal-title":"Lab Investig"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-022-04282-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-022-04282-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-022-04282-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T02:02:51Z","timestamp":1653616971000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-022-04282-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,27]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["4282"],"URL":"https:\/\/doi.org\/10.1007\/s00018-022-04282-6","relation":{},"ISSN":["1420-682X","1420-9071"],"issn-type":[{"value":"1420-682X","type":"print"},{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,27]]},"assertion":[{"value":"29 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no financial or non-financial interests which are directly or indirectly related to this work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"260"}}