ArticleThe Journal of biological chemistry2016
Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.
- High throughput interrogation of human liver stellate cells reveals microenvironmental regulation of phenotype.Acta biomaterialia · 2022Pooled it
- Effects of fluoroquinolone antibiotics on extracellular matrix-related phenotypes in tendon cells.Scientific reports · 2026Article
- The extracellular matrix in inflammation and cancer.Molecular biomedicine · 2026Review
- Extracellular matrix stiffness in hepatocellular carcinoma: mechanisms and targeted therapeutic strategies.Frontiers in immunology · 2026Review
- Review
- Diagnosis and Staging of Metabolic Dysfunction-Associated Steatotic Liver Disease Using Biomarker-Directed Aptamer Panels.Biomolecules · 2025Article
- Unanswered questions regarding the pathogenesis of late onset posterior capsular opacification.Frontiers in ophthalmology · 2025Review
- Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations.Molecular medicine (Cambridge, Mass.) · 2024Article
- TGF-β1 overexpression in severe COVID-19 survivors and its implications for early-phase fibrotic abnormalities and long-term functional impairment.Frontiers in immunology · 2024Article
- The 3Rs in Experimental Liver Disease.Animals : an open access journal from MDPI · 2023Review
- Mesenchymal stem cell-derived exosomal miR-27b-3p alleviates liver fibrosis via downregulating YAP/LOXL2 pathway.Journal of nanobiotechnology · 2023Article
- Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease.Frontiers in physiology · 2023Review
- Weaving the nest: extracellular matrix roles in pre-metastatic niche formation.Frontiers in oncology · 2023Review
- Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy.Journal of hematology & oncology · 2022Review
- lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/Open medicine (Warsaw, Poland) · 2022Article
- The versatility of macrophage heterogeneity in liver fibrosis.Frontiers in immunology · 2022Review
- The dipeptide prolyl-hydroxyproline promotes cellular homeostasis and lamellipodia-driven motility via active β1-integrin in adult tendon cells.The Journal of biological chemistry · 2021Article
- Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity.International journal of molecular sciences · 2021Article
- miR-16 integrates signal pathways in myofibroblasts: determinant of cell fate necessary for fibrosis resolution.Cell death & disease · 2020Article
- Fibronectin has multifunctional roles in posterior capsular opacification (PCO).Matrix biology : journal of the International Society for Matrix Biology · 2020Article
Corrections and comments
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Authors and funding
11 authors at 7 institutions in 3 countries.
Funding
Abstract
Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fn-null livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-β activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-β1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-β1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-β bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.
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