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



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.



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.



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.
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Katja
K
Breitkopf-Heinlein
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Christoph
C
Meyer
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
Courtney
C
König
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Haristi
H
Gaitantzi
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain.
Annalisa
A
Addante
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
Maria
M
Thomas
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, Frankfurt, Germany.
Eliza
E
Wiercinska
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Chen
C
Cai
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.|Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China.
Qi
Q
Li
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Fengqi
F
Wan
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Claus
C
Hellerbrand
Applied Tumor Immunity Clinical Cooperation Unit, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
Nektarios A
NA
Valous
University Hospital of the Heinrich-Heine University, Duesseldorf, Germany.
Maximilian
M
Hahnel
University Hospital of the Heinrich-Heine University, Duesseldorf, Germany.
Christian
C
Ehlting
University Hospital of the Heinrich-Heine University, Duesseldorf, Germany.
Johannes G
JG
Bode
Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stephanie
S
Müller-Bohl
Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ursula
U
Klingmüller
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Jutta
J
Altenöder
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Iryna
I
Ilkavets
Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands.
Marie-José
MJ
Goumans
Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands.
Lukas J A C
LJ
Hawinkels
Johns Hopkins University School of Medicine, Molecular Biology and Genetics, Baltimore, USA.
Se-Jin
SJ
Lee
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
Matthias
M
Wieland
Institute of Pathology, Technical University of Munich, München, Germany.
Carolin
C
Mogler
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Matthias P
MP
Ebert
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain.
Blanca
B
Herrera
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.|German Cancer Consortium, Heidelberg, Germany.
Hellmut
H
Augustin
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain.
Aránzazu
A
Sánchez
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Steven
S
Dooley
Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands.
Peter
P
Ten Dijke
D055371:Acute Lung Injury / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D055427:Growth Differentiation Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006498:Hepatectomy; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D055427:Growth Differentiation Factor 2; D008070:Lipopolysaccharides
CYTOKINES; GROWTH FACTORS; HEPATIC FIBROSIS; HEPATIC STELLATE CELL; HEPATOCYTE