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.