Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems o...

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Published inbioRxiv
Main Authors Horn, Paul, Norlin, Jenny, Kasper Almholt, Viuff, Birgitte M, Galsgaard, Elisabeth D, Hald, Andreas, Zosel, Franziska, Demuth, Helle, Poulsen, Svend, Norby, Peder L, Rasch, Morten G, Vyberg, Mogens, Rink, Marco R, Shepherd, Emma, Northall, Ellie, Lalor, Patricia F, Weston, Chris J, Fog-Tonnesen, Morten, Newsome, Philip
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.01.2024
Subjects
Bone morphogenetic proteins
Fibrosis
Gene expression
Gremlin protein
Heparin
Liver
Liver diseases
Metabolism
Monoclonal antibodies
Stellate cells
Therapeutic targets
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Summary:Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.Competing Interest StatementPH, PFL and CJW report research funding from Novo Nordisk through the University of Birmingham. JN, KA, BMV, EDG, AH, FZ, HD, SP, PLN, MGR, MFT are full-time employees of Novo Nordisk A/S. PNN reports consulting for Boehringer Ingelheim, Novo Nordisk, Intercept, Gilead, Poxel Pharmaceuticals and BMS on behalf of the University of Birmingham and research grants from Novo Nordisk and Boehringer Ingelheim. MV, MRR, ES, and EN report no conflicts of interest related to this manuscript.
DOI:10.1101/2024.01.03.574043