{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:38:39Z","timestamp":1793306319516,"version":"4.5.0"},"reference-count":26,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2015,12,28]]},"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and results<\/jats:title>\n                    <jats:p>\n                      Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl\n                      <jats:sub>4<\/jats:sub>\n                      -injected\n                      <jats:italic>Opn<\/jats:italic>\n                      <jats:sup>Hep<\/jats:sup>\n                      transgenic yet it was less in wild type and almost absent in\n                      <jats:italic>\n                        Opn\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      mice.\n                      <jats:italic>Hmgb1<\/jats:italic>\n                      ablation in hepatocytes (\n                      <jats:italic>Hmgb1<\/jats:italic>\n                      <jats:sup>\u0394Hep<\/jats:sup>\n                      ) protected mice from CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by\n                      <jats:italic>Opn<\/jats:italic>\n                      or\n                      <jats:italic>Hmgb1<\/jats:italic>\n                      ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1\/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K\u2013pAkt1\/2\/3 pathway to upregulate collagen-I.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2015-310752","type":"journal-article","created":{"date-parts":[[2016,2,14]],"date-time":"2016-02-14T20:09:19Z","timestamp":1455480559000},"page":"1123-1137","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":135,"title":["Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury"],"prefix":"10.1136","volume":"66","author":[{"given":"Elena","family":"Arriazu","sequence":"first","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Ge","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"},{"name":"Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Ming","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Magdaleno","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"},{"name":"Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aritz","family":"Lopategi","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongke","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Kitamura","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Urtasun","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Theise","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases, Mount Sinai Beth Israel Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Antoine","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Nieto","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA"},{"name":"Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2016,1,27]]},"reference":[{"key":"2025090715261996000_66.6.1123.1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-306373"},{"key":"2025090715261996000_66.6.1123.2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2013.104"},{"key":"2025090715261996000_66.6.1123.3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24701"},{"key":"2025090715261996000_66.6.1123.4","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2009.47"},{"key":"2025090715261996000_66.6.1123.5","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvt056"},{"key":"2025090715261996000_66.6.1123.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2007.00574.x"},{"key":"2025090715261996000_66.6.1123.7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.552141"},{"key":"2025090715261996000_66.6.1123.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature00858"},{"key":"2025090715261996000_66.6.1123.9","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2010.0080"},{"key":"2025090715261996000_66.6.1123.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.02.180"},{"key":"2025090715261996000_66.6.1123.11","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26976"},{"key":"2025090715261996000_66.6.1123.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119021"},{"key":"2025090715261996000_66.6.1123.13","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg516"},{"key":"2025090715261996000_66.6.1123.14","doi-asserted-by":"publisher","DOI":"10.1021\/bi035615y"},{"key":"2025090715261996000_66.6.1123.15","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12040"},{"key":"2025090715261996000_66.6.1123.16","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12042"},{"key":"2025090715261996000_66.6.1123.17","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26081"},{"key":"2025090715261996000_66.6.1123.18","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12531"},{"key":"2025090715261996000_66.6.1123.19","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.03.052"},{"key":"2025090715261996000_66.6.1123.20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070247"},{"key":"2025090715261996000_66.6.1123.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2009.11.016"},{"key":"2025090715261996000_66.6.1123.22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms140611224"},{"key":"2025090715261996000_66.6.1123.23","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12197"},{"key":"2025090715261996000_66.6.1123.24","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12132"},{"key":"2025090715261996000_66.6.1123.25","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2119\/molmed.2010.00126","article-title":"Diet 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