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 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 Interests: PH Research funding from Novo Nordisk through the University of Birmingham. Research grant from MSD for research not related to this manuscript. Payment from Orphalan for lecture presentation and travel support and conference attendance fee from IPSEN, JN, BV, EG, AH, FZ, HD, SP, PN, MR, JF Employee of Novo Nordisk A/S. Holding stocks of Novo Nordisk A/S, KA, MF Employee of Novo Nordisk A/S. Holding stocks of Novo Nordisk A/S, Genmab A/S and ALK Abello A/S. Involved in a planned patent indirectly related to MASH, but with no direct relation to this manuscript, MV, MW, MR, ES, EN No competing interests declared, LG Consulting fees and payment or honoraria for lectures, presentations or manuscript writing from: Novo Nordisk, Pfizer, Gilead, AstraZeneca, Norgine, Sobi, Becton Dickinson, Alexion and Vingmed, PL, CW Funding from Novo Nordisk through the University of Birmingham, PN Consulting and honoraria for Boehringer Ingelheim, Novo Nordisk, Intercept, Gilead, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal, Eli, Lilly and GSK on behalf of the University of Birmingham. Research grants from Novo Nordisk and Boehringer Ingelheim
(© 2024, Horn et al.)