The role of LRP-1 in fibrotic signalling pathways across human fibrotic diseases

Abstract

Human fibrotic diseases are characterised by the progressive accumulation of extracellular matrix components, driven by dysregulated cellular signalling pathways, which ultimately result in organ dysfunction and constrained therapeutic options. Although significant profibrotic signalling cascades, including transforming growth factor-β (TGF-β)/SMAD and Cellular Communication Network factor 2 (CCN2), have been extensively investigated, the regulatory mechanisms that modulate these pathways remain incompletely understood. Low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed cellsurface receptor involved in various physiological processes. LRP1 mediates clathrin-dependent endocytosis of a broad range of molecules (LRP1 ligands) and regulates cellular signalling pathways. Genome-wide association studies (GWAS) have identified the LRP1 gene as significantly associated with tissue homeostasis and disease-related phenotypes. Although LRP1 has been implicated in diverse physiological processes, its role in the regulation of fibrotic signalling pathways remains incompletely understood. We hypothesised that LRP1 regulates key fibrotic signalling pathways, particularly those mediated by TGF-β/SMAD and CCN2, and that disruption of LRP1 alters cellular responses that contribute to fibrotic tissue remodelling. A combination of in vitro cellular models, in vivo experimental systems, and proteomic analyses of human samples was employed to elucidate the LRP1-dependent regulation of fibrotic signalling. To explain the in vivo necessity of LRP1-mediated signalling, an inducible global deletion of LRP1 was conducted in adult murine models revealing a critical role for LRP1 in maintaining adult tissue homeostasis. 5 Subsequently, the effect of CCN2 deletion on matrix factors, including Col1a1, MMP14, and LRP1, was studied using established experimental models of fibrosis. The results showed significant changes in protein expression associated with fibrosis, further supporting a regulatory role for LRP1 in fibrotic signalling pathways. Finally, proteomic analysis of human samples obtained under severe disease conditions identified differential protein expression patterns associated with fibrotic disease states, providing further insight into dysregulated fibrotic signalling pathways. In conclusion, this study identifies LRP1 as an important regulator of fibrotic signalling pathways, particularly those involving TGF-β/SMAD and CCN2. Experimental models were used to investigate conserved fibrotic signalling mechanisms. These findings provide mechanistic insight into how LRP1 modulates cellular responses that contribute to fibrotic tissue remodelling. Collectively, this work advances understanding of fibrotic signalling regulation with relevance across human fibrotic diseases.