RT Journal Article
SR Electronic
T1 Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1658
OP 1667
DO 10.1136/gutjnl-2013-305281
VO 63
IS 10
A1 Aura D Urribarri
A1 Patricia Munoz-Garrido
A1 María J Perugorria
A1 Oihane Erice
A1 Maite Merino-Azpitarte
A1 Ander Arbelaiz
A1 Elisa Lozano
A1 Elizabeth Hijona
A1 Raúl Jiménez-Agüero
A1 Maite G Fernandez-Barrena
A1 Juan P Jimeno
A1 Marco Marzioni
A1 Jose J G Marin
A1 Tatyana V Masyuk
A1 Nicholas F LaRusso
A1 Jesús Prieto
A1 Luis Bujanda
A1 Jesús M Banales
YR 2014
UL http://gut.bmj.com/content/63/10/1658.abstract
AB 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.