{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:43:50Z","timestamp":1786977830759,"version":"build-2736575974"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2191,"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":[[2009,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Connective tissue growth factor (CCN2) is a matricellular protein that is up-regulated in many fibrotic disorders and coexpressed with transforming growth factor \u03b2. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up-regulated levels of CCN2 that are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of human CCN2 (hCCN2) messenger RNA and elevated CCN2 protein levels was demonstrated in transgenic livers, whereas levels of endogenous mouse CCN2 were comparable between transgenic and wild-type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of CCl\n                      <jats:sub>4<\/jats:sub>\n                      , \u03b1-smooth muscle actin (\u03b1-SMA)\u2013expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (\n                      <jats:italic toggle=\"yes\">hccn2<\/jats:italic>\n                      <jats:sup>+\/+<\/jats:sup>\n                      &gt;\n                      <jats:italic toggle=\"yes\">hccn2<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      &gt;\n                      <jats:italic toggle=\"yes\">hccn<\/jats:italic>\n                      2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ). Moreover, CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced serum hyaluronic acid, hepatic tissue levels of \u03b1-SMA or acid-soluble collagen, and messenger RNA expression of \u03b1-SMA, collagen \u03b11 (I), matrix metalloprotease-2, or tissue inhibitor of metalloprotease-1 were greater in transgenic mice than in wild-type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen 2 weeks after bile duct ligation.\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                      Production of elevated CCN2 levels in hepatocytes of transgenic mice\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      does not cause hepatic injury or fibrosis\n                      <jats:italic toggle=\"yes\">per se<\/jats:italic>\n                      but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support a central role of CCN2 in hepatic fibrosis and demonstrate a role of the microenvironment in regulating the profibrotic action of CCN2. (Hepatology 2009.)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23102","type":"journal-article","created":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T15:52:47Z","timestamp":1243525967000},"page":"939-947","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":67,"title":["Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes # \u2020"],"prefix":"10.1097","volume":"50","author":[{"given":"ZhenYue","family":"Tong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruju","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Alt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri","family":"Kemper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Perbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Brigstock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-34-20241201","first-page":"189","article-title":"The connective tissue growth factorcysteinerich 61nephroblastoma overexpressed (CCN) family.","volume":"20","author":"Brigstock","year":"1999","journal-title":"Endocr Rev"},{"key":"R2-34-20241201","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.biocel.2008.07.025","article-title":"Functions and mechanisms of action of CCN matricellular proteins.","volume":"41","author":"Chen","year":"2009","journal-title":"Int J Biochem Cell Biol"},{"key":"R3-34-20241201","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1386-6346(03)00115-3","article-title":"Connective tissue growth factor (CTGFCCN2) in hepatic fibrosis.","volume":"26","author":"Rachfal","year":"2003","journal-title":"Hepatol Res"},{"key":"R4-34-20241201","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/S0168-8278(00)80244-5","article-title":"Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells.","volume":"32","author":"Williams","year":"2000","journal-title":"J Hepatol"},{"key":"R5-34-20241201","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S0002-9440(10)64074-6","article-title":"Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.","volume":"158","author":"Sedlaczek","year":"2001","journal-title":"Am J Pathol"},{"key":"R6-34-20241201","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/sj.gt.3302929","article-title":"siRNAmediated knockdown of connective tissue growth factor prevents Nnitrosodimethylamineinduced hepatic fibrosis in rats.","volume":"14","author":"George","year":"2007","journal-title":"Gene Ther"},{"key":"R7-34-20241201","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1006\/bbrc.1998.9543","article-title":"Establishment of the enzymelinked immunosorbent assay for connective tissue growth factor (CTGF) and its detection in the sera of biliary atresia.","volume":"251","author":"Tamatani","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"R8-34-20241201","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1373\/clinchem.2006.070466","article-title":"Connective tissue growth factor in serum as a new candidate test for assessment of hepatic fibrosis.","volume":"52","author":"Gressner","year":"2006","journal-title":"Clin Chem"},{"key":"R9-34-20241201","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1111\/j.1478-3231.2008.01826.x","article-title":"Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases.","volume":"28","author":"Gressner","year":"2008","journal-title":"Liver Int"},{"key":"R10-34-20241201","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1006\/bbrc.2000.3693","article-title":"Kinetics of expression of connective tissue growth factor gene during liver regeneration after partial hepatectomy and Dgalactosamine induced liver injury in rats.","volume":"277","author":"Ujike","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"R11-34-20241201","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S1386-6346(00)00101-7","article-title":"Expression of Nov, CYR61 and CTGF genes in human hepatocellular carcinoma.","volume":"19","author":"Hirasaki","year":"2001","journal-title":"Hepatol Res"},{"key":"R12-34-20241201","first-page":"248A","article-title":"Expression of connective tissue growth factor (CTGF) in alcoholic liver fibrosis and in HEPG2 cell line stably expressiong cytochrome P4502E1. 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