Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal

Naoki Ikenaga, Zhen Wei Peng, Kahini A. Vaid, Susan B. Liu, Shuhei Yoshida, Deanna Y. Sverdlov, Amanda Mikels-Vigdal, Victoria Smith, Detlef Schuppan, Yury V. Popov

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

Original languageEnglish
Pages (from-to)1697-1708
Number of pages12
JournalGut
Volume66
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Protein-Lysine 6-Oxidase
Fibrosis
Liver
Hepatocytes
Collagen
Thioacetamide
Stem Cells
Cell Differentiation
Liver Cirrhosis
Antibodies
Blocking Antibodies
Cell Lineage
Therapeutics
Oxidoreductases
Monoclonal Antibodies
Placebos

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. / Ikenaga, Naoki; Peng, Zhen Wei; Vaid, Kahini A.; Liu, Susan B.; Yoshida, Shuhei; Sverdlov, Deanna Y.; Mikels-Vigdal, Amanda; Smith, Victoria; Schuppan, Detlef; Popov, Yury V.

In: Gut, Vol. 66, No. 9, 01.09.2017, p. 1697-1708.

Research output: Contribution to journalArticle

Ikenaga, N, Peng, ZW, Vaid, KA, Liu, SB, Yoshida, S, Sverdlov, DY, Mikels-Vigdal, A, Smith, V, Schuppan, D & Popov, YV 2017, 'Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal', Gut, vol. 66, no. 9, pp. 1697-1708. https://doi.org/10.1136/gutjnl-2016-312473
Ikenaga, Naoki ; Peng, Zhen Wei ; Vaid, Kahini A. ; Liu, Susan B. ; Yoshida, Shuhei ; Sverdlov, Deanna Y. ; Mikels-Vigdal, Amanda ; Smith, Victoria ; Schuppan, Detlef ; Popov, Yury V. / Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. In: Gut. 2017 ; Vol. 66, No. 9. pp. 1697-1708.
@article{24970ceae61a4ccca267709796f7c886,
title = "Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal",
abstract = "Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53{\%} reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45{\%} decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.",
author = "Naoki Ikenaga and Peng, {Zhen Wei} and Vaid, {Kahini A.} and Liu, {Susan B.} and Shuhei Yoshida and Sverdlov, {Deanna Y.} and Amanda Mikels-Vigdal and Victoria Smith and Detlef Schuppan and Popov, {Yury V.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1136/gutjnl-2016-312473",
language = "English",
volume = "66",
pages = "1697--1708",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "9",

}

TY - JOUR

T1 - Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal

AU - Ikenaga, Naoki

AU - Peng, Zhen Wei

AU - Vaid, Kahini A.

AU - Liu, Susan B.

AU - Yoshida, Shuhei

AU - Sverdlov, Deanna Y.

AU - Mikels-Vigdal, Amanda

AU - Smith, Victoria

AU - Schuppan, Detlef

AU - Popov, Yury V.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

AB - Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

UR - http://www.scopus.com/inward/record.url?scp=85010379045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010379045&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2016-312473

DO - 10.1136/gutjnl-2016-312473

M3 - Article

C2 - 28073888

AN - SCOPUS:85010379045

VL - 66

SP - 1697

EP - 1708

JO - Gut

JF - Gut

SN - 0017-5749

IS - 9

ER -