title: A disintegrin and metalloprotease with thrombospondin type I motif 7: a new protease for connective tissue growth factor in hepatic progenitor/oval cell niche.
abstract: Hepatic progenitor/oval cell (OC) activation occurs when hepatocyte proliferation is inhibited and is tightly associated with the fibrogenic response during severe liver damage. Connective tissue growth factor (CTGF) is important for OC activation and contributes to the pathogenesis of liver fibrosis. By using the Yeast Two-Hybrid approach, we identified a disintegrin and metalloproteinase with thrombospondin repeat 7 (ADAMTS7) as a CTGF binding protein. In vitro characterization demonstrated CTGF binding and processing by ADAMTS7. Moreover, Adamts7 mRNA was induced during OC activation, after the implantation of 2-acetylaminofluorene with partial hepatectomy in rats or on feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet in mice. X-Gal staining showed Adamts7 expression in hepatocyte nuclear factor 4α(+) hepatocytes and desmin(+) myofibroblasts surrounding reactive ducts in DDC-treated Adamts7(-/-) mice carrying a knocked-in LacZ gene. Adamts7 deficiency was associated with higher transcriptional levels of Ctgf and OC markers and enhanced OC proliferation compared to Adamts7(+/+) controls during DDC-induced liver injury. We also observed increased α-smooth muscle actin and procollagen type I mRNAs, large fibrotic areas in α-smooth muscle actin and Sirius red staining, and increased production of hepatic collagen by hydroxyproline measurement. These results suggest that ADAMTS7 is a new protease for CTGF protein and a novel regulator in the OC compartment, where its absence causes CTGF accumulation, leading to increased OC activation and biliary fibrosis.
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida. Electronic address: lpi@peds.ufl.edu.
authors.forename: Liya
authors.initials: L
authors.lastname: Pi
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Marda
authors.initials: M
authors.lastname: Jorgensen
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Yianni
authors.initials: Y
authors.lastname: Protopapadakis
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Altin
authors.initials: A
authors.lastname: Gjymishka
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Alicia
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Paulette
authors.initials: P
authors.lastname: Robinson
authors.affiliation: Departments of Orthopaedic Surgery and Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Schultz
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Bryon E
authors.initials: BE
authors.lastname: Petersen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071118:ADAMTS7 Protein; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000502:physiology*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019483:Disintegrins; D019699:Thrombospondins; D055513:Connective Tissue Growth Factor; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C496264:Adamts7 protein, mouse
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