{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:31:48Z","timestamp":1791678708379,"version":"4.3.4"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1308,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>A key feature in the pathogenesis of liver fibrosis is fibrillar Collagen-I deposition; yet, mediators that could be key therapeutic targets remain elusive. We hypothesized that osteopontin (OPN), an extracellular matrix (ECM) cytokine expressed in hepatic stellate cells (HSCs), could drive fibrogenesis by modulating the HSC pro-fibrogenic phenotype and Collagen-I expression. Recombinant OPN (rOPN) up-regulated Collagen-I protein in primary HSCs in a transforming growth factor beta (TGF\u03b2)\u2013independent fashion, whereas it down-regulated matrix metalloprotease-13 (MMP13), thus favoring scarring. rOPN activated primary HSCs, confirmed by increased \u03b1-smooth muscle actin (\u03b1SMA) expression and enhanced their invasive and wound-healing potential. HSCs isolated from wild-type (WT) mice were more profibrogenic than those from OPN knockout (<\/jats:bold>\n                      <jats:bold>Opn<\/jats:bold>\n                      <jats:bold>\u2212\/\u2212) mice and infection of primary HSCs with an Ad-OPN increased Collagen-I, indicating correlation between both proteins. OPN induction of Collagen-I occurred via integrin \u03b1v\u03b23 engagement and activation of the phosphoinositide 3-kinase\/phosphorylated Akt\/nuclear factor kappa B (PI3K\/pAkt\/NF\u03baB)\u2013signaling pathway, whereas cluster of differentiation 44 (CD44) binding and mammalian target of rapamycin\/70-kDa ribosomal protein S6 kinase (mTOR\/p70S6K) were not involved. Neutralization of integrin \u03b1v\u03b23 prevented the OPN-mediated activation of the PI3K\/pAkt\/NF\u03baB\u2013signaling cascade and Collagen-I up-regulation. Likewise, inhibition of PI3K and NF\u03baB blocked the OPN-mediated Collagen-I increase. Hepatitis C Virus (HCV) cirrhotic patients showed coinduction of Collagen-I and cleaved OPN compared to healthy individuals. Acute and chronic liver injury by CCl4 injection or thioacetamide (TAA) treatment elevated OPN expression. Reactive oxygen species up-regulated OPN<\/jats:bold>\n                      <jats:bold>in vitro<\/jats:bold>\n                      <jats:bold>and<\/jats:bold>\n                      <jats:bold>in vivo<\/jats:bold>\n                      <jats:bold>and antioxidants prevented this effect. Transgenic mice overexpressing OPN in hepatocytes (<\/jats:bold>\n                      <jats:bold>Opn<\/jats:bold>\n                      <jats:bold>HEP Tg) mice developed spontaneous liver fibrosis compared to WT mice. Last, chronic CCl4 injection and TAA treatment caused more liver fibrosis to WT than to<\/jats:bold>\n                      <jats:bold>Opn<\/jats:bold>\n                      <jats:bold>\u2212\/\u2212 mice and the reverse occurred in<\/jats:bold>\n                      <jats:bold>Opn<\/jats:bold>\n                      <jats:bold>HEP Tg mice.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion :<\/jats:title>\n                    <jats:p>\n                      <jats:bold>OPN emerges as a key cytokine within the ECM protein network driving the increase in Collagen-I protein contributing to scarring and liver fibrosis. (Hepatology 2012)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.24701","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T22:59:29Z","timestamp":1317164369000},"page":"594-608","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":250,"title":["Osteopontin, an Oxidant Stress Sensitive Cytokine, Up-regulates Collagen-I via Integrin \u03b1V\u03b23 Engagement and PI3K\/pAkt\/NF\u03baB Signaling"],"prefix":"10.1097","volume":"55","author":[{"given":"Raquel","family":"Urtasun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aritz","family":"Lopategi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Ming","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongke","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel","family":"Fiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Nieto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-28-20241201","first-page":"d69d77","article-title":"Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell.","volume":"8","author":"Gabele","year":"2003","journal-title":"Front Biosci"},{"key":"R2-28-20241201","doi-asserted-by":"crossref","first-page":"175184","DOI":"10.1016\/0016-5085(90)91307-R","article-title":"Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis.","volume":"98","author":"Milani","year":"1990","journal-title":"Gastroenterology"},{"key":"R3-28-20241201","doi-asserted-by":"crossref","first-page":"19371946","DOI":"10.1053\/j.gastro.2007.02.033","article-title":"Gene expression profiles during hepatic stellate cell 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