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Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases
  1. Aura D Urribarri1,
  2. Patricia Munoz-Garrido2,
  3. María J Perugorria2,3,4,
  4. Oihane Erice2,
  5. Maite Merino-Azpitarte2,
  6. Ander Arbelaiz2,
  7. Elisa Lozano5,
  8. Elizabeth Hijona2,3,
  9. Raúl Jiménez-Agüero2,
  10. Maite G Fernandez-Barrena1,3,
  11. Juan P Jimeno1,
  12. Marco Marzioni6,
  13. Jose J G Marin3,5,
  14. Tatyana V Masyuk7,
  15. Nicholas F LaRusso7,
  16. Jesús Prieto1,3,
  17. Luis Bujanda2,3,
  18. Jesús M Banales1,2,3,4,7
  1. 1Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain
  2. 2Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
  3. 3National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
  4. 4IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  5. 5Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
  6. 6Department of Gastroenterology, ‘Università Politecnica delle Marche’, Ancona, Italy
  7. 7Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Jesús M Banales, Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, Paseo del Dr Begiristain sn, San Sebastián E-20014, Spain; jesus.banales{at}biodonostia.org

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.

Design 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.

  • HEPATOBILIARY DISEASE
  • BILIARY PHYSIOLOGY
  • CELL MATRIX INTERACTION
  • CHRONIC LIVER DISEASE
  • INTERLEUKINS

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