{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:08:58Z","timestamp":1776276538016,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T00:00:00Z","timestamp":1527206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["Grant #SAF2015\u201069145\u2010R"],"award-info":[{"award-number":["Grant #SAF2015\u201069145\u2010R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["Grant #PI10\/00274"],"award-info":[{"award-number":["Grant #PI10\/00274"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2018,9]]},"abstract":"Abstract<\/jats:title>Background & Aims<\/jats:title>Bone morphogenetic protein 9 (BMP<\/jats:styled-content>9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride\u2010induced chronic injury. We have now addressed the role of BMP<\/jats:styled-content>9 in 3,5 diethoxicarbonyl\u20101,4 dihydrocollidine (DDC<\/jats:styled-content>)\u2010induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion.<\/jats:p><\/jats:sec>Methods<\/jats:title>WT<\/jats:styled-content> and BMP<\/jats:styled-content>9KO<\/jats:styled-content> mice were submitted to DDC<\/jats:styled-content> diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT<\/jats:styled-content>\u2010qPCR<\/jats:styled-content> and western blot. BMP<\/jats:styled-content>9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA<\/jats:styled-content> synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA<\/jats:styled-content> approaches were used to identify the receptors mediating BMP<\/jats:styled-content>9 effects.<\/jats:p><\/jats:sec>Results<\/jats:title>Deletion of BMP<\/jats:styled-content>9 reduces liver damage and fibrosis, but enhances inflammation upon DDC<\/jats:styled-content> feeding. Molecularly, absence of BMP<\/jats:styled-content>9 results in overactivation of PI<\/jats:styled-content>3K\/AKT<\/jats:styled-content>, ERK<\/jats:styled-content>\u2010MAPK<\/jats:styled-content>s and c\u2010Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC<\/jats:styled-content> feeding. Importantly, BMP<\/jats:styled-content>9 directly targets oval cells, it activates SMAD<\/jats:styled-content>1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor\u2010Like Kinase 2 (ALK<\/jats:styled-content>2) type I receptor.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>We identify BMP<\/jats:styled-content>9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP<\/jats:styled-content>9 as an attractive therapeutic target for chronic liver diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.13879","type":"journal-article","created":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T23:30:00Z","timestamp":1526081400000},"page":"1664-1675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC<\/scp>\u2010induced cholestatic liver injury"],"prefix":"10.1111","volume":"38","author":[{"given":"Annalisa","family":"Addante","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Department Biochemistry and Molecular Biology Complutense University of Madrid Health Research Institute of the Hospital Cl\u00ednico San Carlos Madrid 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