Laboratory investigation, 2018-08, Vol.98 (8), p.999-1013
2018
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- Autor(en) / Beteiligte
- Titel
- BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling
- Ist Teil von
- Laboratory investigation, 2018-08, Vol.98 (8), p.999-1013
- Ort / Verlag
- New York: Elsevier Inc
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Transforming growth factor-β (TGF-β) plays a central role in hepatic fibrogenesis. This study investigated the function and mechanism of bone morphogenetic protein-2 (BMP-2) in regulation of hepatic fibrogenesis. BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation surgery or carbon tetrachloride administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC), HSC-T6 and clone-9 cell lines were used to study the interplay between BMP-2 and TGF-β1. Hepatic BMP-2 was localized in parenchymal hepatocytes and activated HSCs and significantly decreased in human and mouse fibrotic livers, showing an opposite pattern of hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, cholangiocyte marker CK19, HSC activation markers, and liver fibrosis in both models. Mechanistically, exogenous TGF-β1 dose dependently reduced BMP-2 expression, whereas BMP-2 significantly suppressed expression of TGF-β and its cognate type I and II receptor peptides, as well as the induced Smad3 phosphorylation levels in primary mouse HSCs. Aside from its suppressive effects on cell proliferation and migration, BMP-2 treatment prominently attenuated the TGF-β1-stimulated α-SMA and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. The mutual regulation between BMP-2 and TGF-β1 signaling axes may constitute the anti-fibrogenic mechanism of BMP-2 in the pathogenesis of liver fibrosis. BMP-2 may potentially serve as a novel therapeutic target for treatment of liver fibrosis. The authors identified BMP-2 downregulation in human and experimental fibrotic livers, and found that adenovirus-mediated BMP-2 gene delivery ameliorates liver fibrosis and biliary injury in mice. Mechanistically, BMP-2 suppresses proliferation and migration of hepatic stellate cells by antagonizing TGF-β signaling and epithelial-to-mesenchymal transition. BMP-2 may therefore constitute a therapeutic target for liver fibrosis treatment.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0023-6837eISSN: 1530-0307DOI: 10.1038/s41374-018-0069-9Titel-ID: cdi_proquest_journals_2097567735
- Format
- –
- Schlagworte
- 13, 13/51, 13/95, 14, 14/105, 14/34, 631/80/304, 64/60, 692/308/1426, 82/80, 96/95, Animal models, Animals, Bile, Bile ducts, Bone morphogenetic protein 2, Bone Morphogenetic Protein 2 - genetics, Bone Morphogenetic Protein 2 - metabolism, Bone Morphogenetic Protein 2 - pharmacology, Carbon tetrachloride, Cell Line, Cell lines, Cell migration, Cell Movement - drug effects, Cell Movement - genetics, Cell proliferation, Cell Proliferation - drug effects, Cell Proliferation - genetics, Cells, Cultured, DNA microarrays, Fibronectin, Fibrosis, Gene Expression - drug effects, Gene transfer, Growth factors, Hepatic Stellate Cells - metabolism, Hepatocytes, Hepatocytes - metabolism, Humans, Laboratory Medicine, Liver, Liver - metabolism, Liver - pathology, Liver Cirrhosis - genetics, Liver Cirrhosis - metabolism, Medicine, Medicine & Public Health, Mesenchyme, Mice, Pathogenesis, Pathology, Peptides, Phosphorylation, Proteins, Rats, Restoration, Signal Transduction, Signaling, Smad3 protein, Stellate cells, Surgery, Therapeutic applications, Transforming Growth Factor beta1 - genetics, Transforming Growth Factor beta1 - metabolism, Transforming Growth Factor beta1 - pharmacology, Transforming growth factor-b, Transforming growth factor-b1