{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T21:33:27Z","timestamp":1793309607308,"version":"4.5.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T00:00:00Z","timestamp":1545004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T00:00:00Z","timestamp":1545004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT088566MA"],"award-info":[{"award-number":["WT088566MA"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/J003352\/1"],"award-info":[{"award-number":["MR\/J003352\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P023541\/1"],"award-info":[{"award-number":["MR\/P023541\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of <jats:italic>Sox9<\/jats:italic>-abrogated myofibroblasts identified &gt;30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. <jats:italic>In vivo<\/jats:italic> all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following <jats:italic>Sox9<\/jats:italic>-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.<\/jats:p>","DOI":"10.1038\/s41598-018-36037-4","type":"journal-article","created":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T17:55:43Z","timestamp":1544550943000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1684-721X","authenticated-orcid":false,"given":"Varinder S.","family":"Athwal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2620-7061","authenticated-orcid":false,"given":"James","family":"Pritchett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Llewellyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abed M.","family":"Zaitoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoibheann F.","family":"Mullan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A. H.","family":"Zeef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1178-6195","authenticated-orcid":false,"given":"Scott L.","family":"Friedman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L.","family":"Irving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A.","family":"Hanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6940-5861","authenticated-orcid":false,"given":"Indra N.","family":"Guha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Piper Hanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,12,17]]},"reference":[{"key":"36037_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-014-0159-5","volume":"12","author":"P Byass","year":"2014","unstructured":"Byass, P. The global burden of liver disease: a challenge for methods and for public health. BMC medicine 12, 159 (2014).","journal-title":"BMC medicine"},{"key":"36037_CR2","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1016\/S0140-6736(17)32866-0","volume":"391","author":"R Williams","year":"2018","unstructured":"Williams, R. et al. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet 391, 1097\u20131107 (2018).","journal-title":"Lancet"},{"key":"36037_CR3","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1016\/S0140-6736(16)32234-6","volume":"389","author":"R Williams","year":"2017","unstructured":"Williams, R. et al. New metrics for the Lancet Standing Commission on Liver Disease in the UK. Lancet 389, 2053\u20132080 (2017).","journal-title":"Lancet"},{"key":"36037_CR4","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","volume":"14","author":"T Tsuchida","year":"2017","unstructured":"Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nature reviews. Gastroenterology & hepatology 14, 397\u2013411 (2017).","journal-title":"Nature reviews. Gastroenterology & hepatology"},{"key":"36037_CR5","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/j.jhep.2011.09.024","volume":"56","author":"EL Ellis","year":"2012","unstructured":"Ellis, E. L. & Mann, D. A. Clinical evidence for the regression of liver fibrosis. Journal of hepatology 56, 1171\u20131180 (2012).","journal-title":"Journal of hepatology"},{"issue":"Suppl 1","key":"36037_CR6","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1016\/j.jhep.2008.01.022","volume":"48","author":"JM Llovet","year":"2008","unstructured":"Llovet, J. M. & Bruix, J. Novel advancements in the management of hepatocellular carcinoma in 2008. Journal of hepatology 48(Suppl 1), S20\u201337 (2008).","journal-title":"Journal of hepatology"},{"key":"36037_CR7","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1016\/S0140-6736(03)14964-1","volume":"362","author":"JM Llovet","year":"2003","unstructured":"Llovet, J. M., Burroughs, A. & Bruix, J. Hepatocellular carcinoma. Lancet 362, 1907\u20131917 (2003).","journal-title":"Lancet"},{"key":"36037_CR8","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1053\/j.gastro.2008.03.001","volume":"134","author":"DS Manning","year":"2008","unstructured":"Manning, D. S. & Afdhal, N. H. Diagnosis and quantitation of fibrosis. Gastroenterology 134, 1670\u20131681 (2008).","journal-title":"Gastroenterology"},{"key":"36037_CR9","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1053\/j.gastro.2004.08.052","volume":"127","author":"WM Rosenberg","year":"2004","unstructured":"Rosenberg, W. M. et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 127, 1704\u20131713 (2004).","journal-title":"Gastroenterology"},{"key":"36037_CR10","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1053\/gast.1996.v110.pm8608892","volume":"110","author":"RC Benyon","year":"1996","unstructured":"Benyon, R. C., Iredale, J. P., Goddard, S., Winwood, P. J. & Arthur, M. J. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 110, 821\u2013831 (1996).","journal-title":"Gastroenterology"},{"key":"36037_CR11","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0009-8981(93)90221-O","volume":"218","author":"Y Murawaki","year":"1993","unstructured":"Murawaki, Y., Yamamoto, H., Kawasaki, H. & Shima, H. Serum tissue inhibitor of metalloproteinases in patients with chronic liver disease and with hepatocellular carcinoma. Clinica chimica acta; international journal of clinical chemistry 218, 47\u201358 (1993).","journal-title":"Clinica chimica acta; international journal of clinical chemistry"},{"key":"36037_CR12","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.15252\/emmm.201707860","volume":"9","author":"VS Athwal","year":"2017","unstructured":"Athwal, V. S. et al. SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. Embo mol med 9, 1696\u20131710 (2017).","journal-title":"Embo mol med"},{"key":"36037_CR13","doi-asserted-by":"publisher","first-page":"14063","DOI":"10.1074\/jbc.M707390200","volume":"283","author":"K Piper Hanley","year":"2008","unstructured":"Piper Hanley, K. et al. Ectopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis. Journal of Biological Chemistry 283, 14063\u201314071 (2008).","journal-title":"Journal of Biological Chemistry"},{"key":"36037_CR14","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.molmed.2010.12.001","volume":"17","author":"J Pritchett","year":"2011","unstructured":"Pritchett, J., Athwal, V., Roberts, N., Hanley, N. A. & Hanley, K. P. Understanding the role of SOX9 in acquired diseases: lessons from development. Trends in molecular medicine 17, 166\u2013174 (2011).","journal-title":"Trends in molecular medicine"},{"key":"36037_CR15","doi-asserted-by":"publisher","first-page":"e100091","DOI":"10.1371\/journal.pone.0100091","volume":"9","author":"J Pritchett","year":"2014","unstructured":"Pritchett, J. et al. Epimorphin alters the inhibitory effects of SOX9 on Mmp13 in activated hepatic stellate cells. PloS one 9, e100091 (2014).","journal-title":"PloS one"},{"key":"36037_CR16","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1002\/hep.25758","volume":"56","author":"J Pritchett","year":"2012","unstructured":"Pritchett, J. et al. Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. Hepatology 56, 1108\u20131116 (2012).","journal-title":"Hepatology"},{"key":"36037_CR17","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3109\/s10165-008-0048-x","volume":"18","author":"H Akiyama","year":"2008","unstructured":"Akiyama, H. Control of chondrogenesis by the transcription factor Sox9. Modern rheumatology 18, 213\u2013219 (2008).","journal-title":"Modern rheumatology"},{"key":"36037_CR18","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1016\/j.biocel.2007.05.019","volume":"39","author":"V Lefebvre","year":"2007","unstructured":"Lefebvre, V., Dumitriu, B., Penzo-Mendez, A., Han, Y. & Pallavi, B. Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. The international journal of biochemistry & cell biology 39, 2195\u20132214 (2007).","journal-title":"The international journal of biochemistry & cell biology"},{"key":"36037_CR19","doi-asserted-by":"publisher","first-page":"3899","DOI":"10.2741\/2359","volume":"12","author":"CJ Liu","year":"2007","unstructured":"Liu, C. J. et al. Transcriptional activation of cartilage oligomeric matrix protein by Sox9, Sox5, and Sox6 transcription factors and CBP\/p300 coactivators. Frontiers in bioscience: a journal and virtual library 12, 3899\u20133910 (2007).","journal-title":"Frontiers in bioscience: a journal and virtual library"},{"key":"36037_CR20","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1111\/j.1349-7006.2010.01524.x","volume":"101","author":"H Huang","year":"2010","unstructured":"Huang, H. et al. Expression and prognostic significance of osteopontin and caspase-3 in hepatocellular carcinoma patients after curative resection. Cancer science 101, 1314\u20131319 (2010).","journal-title":"Cancer science"},{"key":"36037_CR21","doi-asserted-by":"publisher","first-page":"e35612","DOI":"10.1371\/journal.pone.0035612","volume":"7","author":"S Patouraux","year":"2012","unstructured":"Patouraux, S. et al. The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One 7, e35612 (2012).","journal-title":"PLoS One"},{"key":"36037_CR22","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/ncb3160","volume":"17","author":"I Cebola","year":"2015","unstructured":"Cebola, I. et al. TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. Nature cell biology 17, 615\u2013626 (2015).","journal-title":"Nature cell biology"},{"key":"36037_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12502","volume":"7","author":"K Martin","year":"2016","unstructured":"Martin, K. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat Commun 7, 12502 (2016).","journal-title":"Nat Commun"},{"key":"36037_CR24","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1016\/j.cell.2014.03.060","volume":"157","author":"D Yimlamai","year":"2014","unstructured":"Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324\u20131338 (2014).","journal-title":"Cell"},{"key":"36037_CR25","doi-asserted-by":"publisher","first-page":"e107577","DOI":"10.1371\/journal.pone.0107577","volume":"9","author":"CD Oh","year":"2014","unstructured":"Oh, C. D. et al. SOX9 regulates multiple genes in chondrocytes, including genes encoding ECM proteins, ECM modification enzymes, receptors, and transporters. PLoS One 9, e107577 (2014).","journal-title":"PLoS One"},{"key":"36037_CR26","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","volume":"22","author":"K Ishak","year":"1995","unstructured":"Ishak, K. et al. Histological grading and staging of chronic hepatitis. Journal of hepatology 22, 696\u2013699 (1995).","journal-title":"Journal of hepatology"},{"key":"36037_CR27","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.celrep.2015.12.071","volume":"14","author":"HM Kang","year":"2016","unstructured":"Kang, H. M. et al. Sox9-Positive Progenitor Cells Play a Key Role in Renal Tubule Epithelial Regeneration in Mice. Cell reports 14, 861\u2013871 (2016).","journal-title":"Cell reports"},{"key":"36037_CR28","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/j.celrep.2015.07.034","volume":"12","author":"S Kumar","year":"2015","unstructured":"Kumar, S. et al. Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney. Cell reports 12, 1325\u20131338 (2015).","journal-title":"Cell reports"},{"key":"36037_CR29","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1161\/CIRCULATIONAHA.117.027832","volume":"136","author":"GPA Lacraz","year":"2017","unstructured":"Lacraz, G. P. A. et al. Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury. Circulation 136, 1396\u20131409 (2017).","journal-title":"Circulation"},{"key":"36037_CR30","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/S0140-6736(00)04258-6","volume":"357","author":"F Imbert-Bismut","year":"2001","unstructured":"Imbert-Bismut, F. et al. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 357, 1069\u20131075 (2001).","journal-title":"Lancet"},{"key":"36037_CR31","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1053\/jhep.2003.50346","volume":"38","author":"CT Wai","year":"2003","unstructured":"Wai, C. T. et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38, 518\u2013526 (2003).","journal-title":"Hepatology"},{"key":"36037_CR32","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/labinvest.2013.104","volume":"93","author":"TM Leung","year":"2013","unstructured":"Leung, T. M., Wang, X., Kitamura, N., Fiel, M. I. & Nieto, N. Osteopontin delays resolution of liver fibrosis. Laboratory investigation; a journal of technical methods and pathology 93, 1082\u20131089 (2013).","journal-title":"Laboratory investigation; a journal of technical methods and pathology"},{"key":"36037_CR33","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1053\/j.gastro.2012.06.036","volume":"143","author":"JS Troeger","year":"2012","unstructured":"Troeger, J. S. et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073\u20131083 e1022 (2012).","journal-title":"Gastroenterology"},{"key":"36037_CR34","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1136\/gutjnl-2011-301857","volume":"61","author":"WK Syn","year":"2012","unstructured":"Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323\u20131329 (2012).","journal-title":"Gut"},{"key":"36037_CR35","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1111\/j.1742-1241.2007.01368.x","volume":"62","author":"L Zhao","year":"2008","unstructured":"Zhao, L. et al. Elevated plasma osteopontin level is predictive of cirrhosis in patients with hepatitis B infection. International journal of clinical practice 62, 1056\u20131062 (2008).","journal-title":"International journal of clinical practice"},{"key":"36037_CR36","doi-asserted-by":"publisher","first-page":"508","DOI":"10.3109\/00365548.2014.907499","volume":"46","author":"MS Abdel-Latif","year":"2014","unstructured":"Abdel-Latif, M. S., Almahal, E. K., Ragab, N. M., Omar, M. F. & Afifi, M. S. Cellular fibronectin expression in chronic hepatitis C virus patients. Scandinavian journal of infectious diseases 46, 508\u2013514 (2014).","journal-title":"Scandinavian journal of infectious diseases"},{"issue":"5","key":"36037_CR37","doi-asserted-by":"publisher","first-page":"jcs201293","DOI":"10.1242\/jcs.201293","volume":"131","author":"Franco Klingberg","year":"2018","unstructured":"Klingberg, F., et al. The fibronectin ED-A domain enhances recruitment of latent TGF-beta-binding protein-1 to the fibroblast matrix. Journal of cell science 131 (2018).","journal-title":"Journal of Cell Science"},{"key":"36037_CR38","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1083\/jcb.142.3.873","volume":"142","author":"G Serini","year":"1998","unstructured":"Serini, G. et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. The Journal of cell biology 142, 873\u2013881 (1998).","journal-title":"The Journal of cell biology"},{"key":"36037_CR39","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1136\/gutjnl-2016-311526","volume":"66","author":"T Hardy","year":"2017","unstructured":"Hardy, T. et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 66, 1321\u20131328 (2017).","journal-title":"Gut"},{"key":"36037_CR40","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/hep.21695","volume":"46","author":"H Huang","year":"2007","unstructured":"Huang, H. et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 46, 297\u2013306 (2007).","journal-title":"Hepatology"},{"key":"36037_CR41","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1002\/hep.23111","volume":"50","author":"M Marcolongo","year":"2009","unstructured":"Marcolongo, M. et al. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 50, 1038\u20131044 (2009).","journal-title":"Hepatology"},{"key":"36037_CR42","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.jhep.2010.10.018","volume":"55","author":"E Trepo","year":"2011","unstructured":"Trepo, E. et al. Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease. Journal of hepatology 55, 38\u201344 (2011).","journal-title":"Journal of hepatology"},{"key":"36037_CR43","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1136\/gut.48.5.707","volume":"48","author":"AH Mohsen","year":"2001","unstructured":"Mohsen, A. H. The epidemiology of hepatitis C in a UK health regional population of 5.12 million. Gut 48, 707\u2013713 (2001).","journal-title":"Gut"},{"key":"36037_CR44","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1136\/gut.2003.021691","volume":"53","author":"SD Ryder","year":"2004","unstructured":"Ryder, S. D., Irving, W. L., Jones, D. A., Neal, K. R. & Underwood, J. C. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut 53, 451\u2013455 (2004).","journal-title":"Gut"},{"key":"36037_CR45","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1111\/j.1365-2893.2008.01035.x","volume":"16","author":"MJ Williams","year":"2009","unstructured":"Williams, M. J., Lawson, A., Neal, K. R., Ryder, S. D. & Irving, W. L. Autoantibodies in chronic hepatitis C virus infection and their association with disease profile. Journal of viral hepatitis 16, 325\u2013331 (2009).","journal-title":"Journal of viral hepatitis"},{"key":"36037_CR46","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1093\/nar\/gng012","volume":"31","author":"J Seibler","year":"2003","unstructured":"Seibler, J. et al. Rapid generation of inducible mouse mutants. Nucleic acids research 31, e12 (2003).","journal-title":"Nucleic acids research"},{"key":"36037_CR47","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/gene.10050","volume":"32","author":"R Kist","year":"2002","unstructured":"Kist, R., Schrewe, H., Balling, R. & Scherer, G. Conditional inactivation of Sox9: a mouse model for campomelic dysplasia. Genesis 32, 121\u2013123 (2002).","journal-title":"Genesis"}],"updated-by":[{"DOI":"10.1038\/s41598-019-47715-2","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T00:00:00Z","timestamp":1565049600000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36037-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36037-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36037-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T12:21:24Z","timestamp":1671625284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36037-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,17]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["36037"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-36037-4","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-019-47715-2","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,17]]},"assertion":[{"value":"9 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2019","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"An amendment to this paper has been published and can be accessed via a link at the top of the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"17905"}}