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@ARTICLE{BreitkopfHeinlein:120514,
author = {K. Breitkopf-Heinlein and C. Meyer and C. König$^*$ and H.
Gaitantzi and A. Addante and M. Thomas and E. Wiercinska and
C. Cai and Q. Li and F. Wan and C. Hellerbrand and N.
Valous$^*$ and M. Hahnel and C. Ehlting and J. G. Bode and
S. Müller-Bohl$^*$ and U. Klingmüller$^*$ and J.
Altenöder and I. Ilkavets and M.-J. Goumans and L. J. A. C.
Hawinkels and S.-J. Lee and M. Wieland$^*$ and C. Mogler and
M. P. Ebert and B. Herrera and H. Augustin$^*$ and A.
Sánchez and S. Dooley and P. Ten Dijke},
title = {{BMP}-9 interferes with liver regeneration and promotes
liver fibrosis.},
journal = {Gut},
volume = {66},
number = {5},
issn = {1468-3288},
address = {London},
publisher = {BMJ Publishing Group},
reportid = {DKFZ-2017-00943},
pages = {939 - 954},
year = {2017},
abstract = {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.},
cin = {A190 / B200 / D120 / L101},
ddc = {610},
cid = {I:(DE-He78)A190-20160331 / I:(DE-He78)B200-20160331 /
I:(DE-He78)D120-20160331 / I:(DE-He78)L101-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28336518},
doi = {10.1136/gutjnl-2016-313314},
url = {https://inrepo02.dkfz.de/record/120514},
}