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Gut. 2017 May;66(5):939-954. doi: 10.1136/gutjnl-2016-313314. Epub 2017 Mar 23.

BMP-9 interferes with liver regeneration and promotes liver fibrosis.

Author information

1
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
2
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
3
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain.
4
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
5
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, Frankfurt, Germany.
6
Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China.
7
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
8
Applied Tumor Immunity Clinical Cooperation Unit, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
9
University Hospital of the Heinrich-Heine University, Duesseldorf, Germany.
10
Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands.
12
Johns Hopkins University School of Medicine, Molecular Biology and Genetics, Baltimore, USA.
13
Institute of Pathology, Technical University of Munich, München, Germany.
14
Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
15
German Cancer Consortium, Heidelberg, Germany.

Abstract

OBJECTIVE:

Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β 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-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.

KEYWORDS:

CYTOKINES; GROWTH FACTORS; HEPATIC FIBROSIS; HEPATIC STELLATE CELL; HEPATOCYTE

PMID:
28336518
DOI:
10.1136/gutjnl-2016-313314
[Indexed for MEDLINE]

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