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Selective LOXL2 inhibition: potent antifibrotic effects in ongoing fibrosis and fibrosis regression
  1. Fernando Magdaleno1,2,
  2. Jonel Trebicka1,3,4
  1. 1Department of Internal Medicine I, University of Bonn, Bonn, Germany
  2. 2Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
  3. 3Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark
  4. 4European Foundation for the Study of Chronic Liver Failure, Travessera de Gràcia, Barcelona, Spain
  1. Correspondence to Professor Jonel Trebicka, European Foundation for the Study of Chronic Liver Failure, Travessera de Gràcia, 11, 7th floor, Barcelona 08021, Spain; jonel.trebicka{at}

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The study by Ikenaga et al1 represents a significant step forward in the understanding and in the treatment approaches of hepatic fibrosis. Fibrosis is a general repair mechanism of tissue injury resulting from increased extracellular matrix (ECM) synthesis and deposition, followed by contraction of the scar, remodelling and degradation of the ECM when the tissue defect is covered and bridged. In chronic liver injury, this important protective process is altered to a morbid situation with excessive ECM accumulation, which maintains inflammation and contributes to the progression to cirrhosis and which in turn is associated with high morbidity and mortality.

Remodelling of ECM in fibrosis and cirrhosis is important for the regression of fibrosis, but also for its progression. Remodelling might even predict progression of fibrosis.2 ,3 In this context, collagen crosslinking is a key process that increases the persistence of fibrosis, in which lysyl oxidase/lysyl oxidase-like protein (LOX/LOXL) family members are crucial. The LOX/lysyl oxidase-like protein-2 (LOXL2) family is characterised by highly conserved C-terminal lysyl oxidase domain integrated by the copper (Cu) binding, the lysine tyrosylquinone (LTQ) reaction and the cytokine receptor-like domains. These enzymes oxidise and deaminate the side chain of peptidyl lysine to generate an aldehyde residue, and have elastin and collagen as their main substrates. Intriguingly, the current study has elaborated on the intracellular as well as the extracellular localisation of these proteins and their distinctive roles in liver fibrosis.1 It demonstrates that targeting LOXL2 using antibodies (AB0023) mitigates the progression of pre-established fibrosis and favours its resolution. These data render this approach important for the clinical setting. Although the authors attribute these effects to the extracellular LOXL, previous data on its involvement in cell proliferation and inhibition of apoptotic cell death via focal adhesion kinase/protein kinase B/mechanistic target of rapamycin4 suggest that LOXL2 blockage might have direct effects on hepatic stellate cells (HSC), the main source of collagen.5 However, in the present study, the authors focus only on the contraction of these cells, which is possibly due to either the disintegration of their surrounding ECM or direct effect of LOXL2 inhibition on HSC, or both. Importantly, LOXL2 inhibition might also affect the coregulation among the tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9 enzymatic activity, and, in addition to mechanosensing, the HSC profibrogenic intracellular signalling, thus underlining the central role of LOXL2 as a relevant ECM constituent as well as the success of anti-LOXL2 approaches in the therapy of liver fibrosis.

Additionally, the authors elaborated the intracellular effects of LOXL2 in promoting hepatic progenitor cell (HPC) differentiation towards a profibrogenic cholangiocyte phenotype. The current study sets the stage for future groundwork on the molecular mechanisms governed by LOXL2 on ductular reaction and liver regeneration.1 This is of special relevance as LOXL2 possibly act at the epigenetic level on epithelial cell adhesion molecule-positive HPC in fibrosis and since histones are substrates of LOX/LOXL proteins.6 Thus, further research will elucidate whether the LOXL2 profibrogenic signals on HPC differentiation are due to specific nuclear isoform(s) of LOXL2 or receptor-mediated profibrogenic signals, either via scavenger receptors or integrins, such as integrin alphavbeta6.7

Another scientific merit of the current study is that it draws attention to the role of Cu in liver fibrosis independent of the storing disorders. Cu, a cofactor of LOXL enzymes, leads to progressive damage and scarring of the liver. Indeed, Wilson’s disease, as a genetic disorder in which Cu builds up in the body typically affecting the brain and the liver, is characterised by overexpression of LOX and LOXL2 enzymes.8 Moreover, hepatic Cu accumulation is a common feature of primary biliary cirrhosis. Therefore, it is conceivable that LOXL2 activity is a culprit of cholestatic fibrosis and thus of special importance as a therapeutic target.

Likewise, targeting LOXL2 delivered promising results in other diseases such as reduction in stress-induced cardiac fibrosis.9 However, less enthusiastic results were obtained in idiopathic pulmonary fibrosis using a monoclonal antibody.10

In conclusion, while LOXL2 is an important extracellular target to dissolve established liver fibrosis, and a key mediator of intercellular communication in HPC, especially during biliary fibrosis, it might be generalised for other aetiologies (figure 1). Thus, LOXL2 inhibition rightly deserves a prominent position in the new era of antifibrotic therapy for cirrhosis based primarily on the recent findings of Ikenaga et al.1

Figure 1

Schematic diagram of the role of lysyl oxidase-like protein-2 (LOXL2) in liver disease and potential therapeutic use in different aetiologies. LOXL2 participates in collagen crosslinking, extracellular matrix remodelling and in hepatic progenitor cell (HPC) differentiation during the progression of liver fibrosis (black arrows). Hence, anti-LOXL2 treatment might play a relevant role in other liver diseases such alcoholic liver disease (ALD), HCV infection, HBV infection, primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH) by promoting fibrosis resolution and HPC differentiation (green arrow). BEC, biliary epithelial cells; HBV, hepatitis B virus; HCV, hepatitis C virus; HEP, hepatocytes; HSC, hepatic stellate cells.


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  • Contributors FM and JT reviewed the literature and wrote the commentary.

  • Funding JT is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 P18), European Union H2020 and Cellex Foundation.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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