PT  - JOURNAL ARTICLE
AU  - Aura D Urribarri
AU  - Patricia Munoz-Garrido
AU  - María J Perugorria
AU  - Oihane Erice
AU  - Maite Merino-Azpitarte
AU  - Ander Arbelaiz
AU  - Elisa Lozano
AU  - Elizabeth Hijona
AU  - Raúl Jiménez-Agüero
AU  - Maite G Fernandez-Barrena
AU  - Juan P Jimeno
AU  - Marco Marzioni
AU  - Jose J G Marin
AU  - Tatyana V Masyuk
AU  - Nicholas F LaRusso
AU  - Jesús Prieto
AU  - Luis Bujanda
AU  - Jesús M Banales
TI  - Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases
AID  - 10.1136/gutjnl-2013-305281
DP  - 2014 Oct 01
TA  - Gut
PG  - 1658--1667
VI  - 63
IP  - 10
4099  - http://gut.bmj.com/content/63/10/1658.short
4100  - http://gut.bmj.com/content/63/10/1658.full
SO  - Gut2014 Oct 01; 63
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.