Breitkopf-Heinlein, Katja and Meyer, Christoph and Koenig, Courtney and Gaitantzi, Haristi and Addante, Annalisa and Thomas, Maria and Wiercinska, Eliza and Cai, Chen and Li, Qi and Wan, Fengqi and Hellerbrand, Claus and Valous, Nektarios A. and Hahnel, Maximilian J. and Ehlting, Christian and Bode, Johannes G. and Mueller-Bohl, Stephanie and Klingmueller, Ursula and Altenoeder, Jutta and Ilkavets, Iryna and Goumans, Marie-Jose and Hawinkels, Lukas J. A. C. and Lee, Se-Jin and Wieland, Matthias and Mogler, Carolin and Ebert, Matthias P. and Herrera, Blanca and Augustin, Hellmut G. and Sanchez, Aranzazu and Dooley, Steven and ten Dijke, Peter (2017) BMP-9 interferes with liver regeneration and promotes liver fibrosis. GUT, 66 (5). pp. 939-954. ISSN 0017-5749, 1468-3288
Full text not available from this repository. (Request a copy)Abstract
Objective Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-beta family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease. Design Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. Results Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin receptor-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. Conclusions Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BONE MORPHOGENETIC PROTEIN-9; TGF-BETA SUPERFAMILY; HEPATIC STELLATE CELLS; HEPATOCELLULAR-CARCINOMA CELLS; SINUSOIDAL ENDOTHELIAL-CELLS; SIGNALING PATHWAYS; PROLIFERATION; EXPRESSION; ANGIOGENESIS; FIBROGENESIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:10 |
| Last Modified: | 19 Feb 2019 15:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1007 |
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