title: Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ikenaga
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Peng
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kahini A
authors.initials: KA
authors.lastname: Vaid
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Deanna Y
authors.initials: DY
authors.lastname: Sverdlov
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mikels-Vigdal
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Mainz, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yury V
authors.identifier: 0000-0001-7973-942X
authors.initials: YV
authors.lastname: Popov
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D022781:Hepatocytes / Q000502:physiology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy / Q000379:methods; D020127:Recovery of Function / Q000187:drug effects; D013234:Stem Cells / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C485601:Loxl2 protein, mouse
keywords: CIRRHOSIS; HEPATIC FIBROSIS; HEPATITIS; PRIMARY BILIARY CIRRHOSIS; PRIMARY SCLEROSING CHOLANGITIS