title: Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.
abstract: OBJECTIVE
  Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs.
  
  
  METHODS
  Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats.
  
  
  RESULTS
  Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis.
  
  
  CONCLUSIONS
  PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Aura D
authors.initials: AD
authors.lastname: Urribarri
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Munoz-Garrido
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Perugorria
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Oihane
authors.initials: O
authors.lastname: Erice
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Merino-Azpitarte
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Arbelaiz
authors.affiliation: Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lozano
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hijona
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Jiménez-Agüero
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Jimeno
authors.affiliation: Department of Gastroenterology, 'Università Politecnica delle Marche', Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.affiliation: National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Masyuk
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D003560:Cysts / Q000201:enzymology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D003592:Cytophotometry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C100342:marimastat; D008666:Metalloendopeptidases
keywords: BILIARY PHYSIOLOGY; CELL MATRIX INTERACTION; CHRONIC LIVER DISEASE; HEPATOBILIARY DISEASE; INTERLEUKINS