Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.

Aura D. Urribarri, Patricia Munoz-Garrido, María J. Perugorria, Oihane Erice, Maite Merino-Azpitarte, Ander Arbelaiz, Elisa Lozano, Elizabeth Hijona, Raúl Jiménez-Agüero, Maite G. Fernandez-Barrena, Juan P. Jimeno, Marco Marzioni, Jose J G Marin, Tatyana V. Masyuk, Nicholas F La Russo, Jesús Prieto, Luis Bujanda, Jesús M. Banales

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Original languageEnglish (US)
Pages (from-to)1658-1667
Number of pages10
JournalGut
Volume63
Issue number10
StatePublished - 2014

Fingerprint

Metalloproteases
Polycystic Kidney Diseases
Interleukin-6
Liver
Licensure
Interleukin-8
Polycystic liver disease
Interleukin-8 Receptors
Choledochal Cyst
Inborn Genetic Diseases
Interleukin-17
MicroRNAs
Human Activities
Real-Time Polymerase Chain Reaction
Dilatation
Estradiol
Intercellular Signaling Peptides and Proteins
Estrogens
Fibrosis
Animal Models

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Urribarri, A. D., Munoz-Garrido, P., Perugorria, M. J., Erice, O., Merino-Azpitarte, M., Arbelaiz, A., ... Banales, J. M. (2014). Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. Gut, 63(10), 1658-1667.

Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. / Urribarri, Aura D.; Munoz-Garrido, Patricia; Perugorria, María J.; Erice, Oihane; Merino-Azpitarte, Maite; Arbelaiz, Ander; Lozano, Elisa; Hijona, Elizabeth; Jiménez-Agüero, Raúl; Fernandez-Barrena, Maite G.; Jimeno, Juan P.; Marzioni, Marco; Marin, Jose J G; Masyuk, Tatyana V.; La Russo, Nicholas F; Prieto, Jesús; Bujanda, Luis; Banales, Jesús M.

In: Gut, Vol. 63, No. 10, 2014, p. 1658-1667.

Research output: Contribution to journalArticle

Urribarri, AD, Munoz-Garrido, P, Perugorria, MJ, Erice, O, Merino-Azpitarte, M, Arbelaiz, A, Lozano, E, Hijona, E, Jiménez-Agüero, R, Fernandez-Barrena, MG, Jimeno, JP, Marzioni, M, Marin, JJG, Masyuk, TV, La Russo, NF, Prieto, J, Bujanda, L & Banales, JM 2014, 'Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.', Gut, vol. 63, no. 10, pp. 1658-1667.
Urribarri AD, Munoz-Garrido P, Perugorria MJ, Erice O, Merino-Azpitarte M, Arbelaiz A et al. Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. Gut. 2014;63(10):1658-1667.
Urribarri, Aura D. ; Munoz-Garrido, Patricia ; Perugorria, María J. ; Erice, Oihane ; Merino-Azpitarte, Maite ; Arbelaiz, Ander ; Lozano, Elisa ; Hijona, Elizabeth ; Jiménez-Agüero, Raúl ; Fernandez-Barrena, Maite G. ; Jimeno, Juan P. ; Marzioni, Marco ; Marin, Jose J G ; Masyuk, Tatyana V. ; La Russo, Nicholas F ; Prieto, Jesús ; Bujanda, Luis ; Banales, Jesús M. / Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. In: Gut. 2014 ; Vol. 63, No. 10. pp. 1658-1667.
@article{5f0caf132fe54e98a572bf46fb46216d,
title = "Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.",
abstract = "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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",
author = "Urribarri, {Aura D.} and Patricia Munoz-Garrido and Perugorria, {Mar{\'i}a J.} and Oihane Erice and Maite Merino-Azpitarte and Ander Arbelaiz and Elisa Lozano and Elizabeth Hijona and Ra{\'u}l Jim{\'e}nez-Ag{\"u}ero and Fernandez-Barrena, {Maite G.} and Jimeno, {Juan P.} and Marco Marzioni and Marin, {Jose J G} and Masyuk, {Tatyana V.} and {La Russo}, {Nicholas F} and Jes{\'u}s Prieto and Luis Bujanda and Banales, {Jes{\'u}s M.}",
year = "2014",
language = "English (US)",
volume = "63",
pages = "1658--1667",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "10",

}

TY - JOUR

T1 - Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.

AU - Urribarri, Aura D.

AU - Munoz-Garrido, Patricia

AU - Perugorria, María J.

AU - Erice, Oihane

AU - Merino-Azpitarte, Maite

AU - Arbelaiz, Ander

AU - Lozano, Elisa

AU - Hijona, Elizabeth

AU - Jiménez-Agüero, Raúl

AU - Fernandez-Barrena, Maite G.

AU - Jimeno, Juan P.

AU - Marzioni, Marco

AU - Marin, Jose J G

AU - Masyuk, Tatyana V.

AU - La Russo, Nicholas F

AU - Prieto, Jesús

AU - Bujanda, Luis

AU - Banales, Jesús M.

PY - 2014

Y1 - 2014

N2 - 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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

AB - 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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

UR - http://www.scopus.com/inward/record.url?scp=84908544836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908544836&partnerID=8YFLogxK

M3 - Article

C2 - 24436140

AN - SCOPUS:84908544836

VL - 63

SP - 1658

EP - 1667

JO - Gut

JF - Gut

SN - 0017-5749

IS - 10

ER -