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000120514 0247_ $$2doi$$a10.1136/gutjnl-2016-313314
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000120514 1001_ $$aBreitkopf-Heinlein, Katja$$b0
000120514 245__ $$aBMP-9 interferes with liver regeneration and promotes liver fibrosis.
000120514 260__ $$aLondon$$bBMJ Publishing Group$$c2017
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000120514 520__ $$aBone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease.Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice.Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis.Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.
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000120514 7001_ $$aMeyer, Christoph$$b1
000120514 7001_ $$0P:(DE-He78)5ef958977fa3c0658679b496419ce762$$aKönig, Courtney$$b2
000120514 7001_ $$aGaitantzi, Haristi$$b3
000120514 7001_ $$aAddante, Annalisa$$b4
000120514 7001_ $$aThomas, Maria$$b5
000120514 7001_ $$aWiercinska, Eliza$$b6
000120514 7001_ $$aCai, Chen$$b7
000120514 7001_ $$aLi, Qi$$b8
000120514 7001_ $$aWan, Fengqi$$b9
000120514 7001_ $$aHellerbrand, Claus$$b10
000120514 7001_ $$0P:(DE-He78)01ddf9bd69d91bd4b1dbef36f9427f36$$aValous, Nektarios$$b11$$udkfz
000120514 7001_ $$aHahnel, Maximilian$$b12
000120514 7001_ $$aEhlting, Christian$$b13
000120514 7001_ $$aBode, Johannes G$$b14
000120514 7001_ $$0P:(DE-HGF)0$$aMüller-Bohl, Stephanie$$b15
000120514 7001_ $$0P:(DE-He78)860df4ab16c373fb28a815dcd81107a6$$aKlingmüller, Ursula$$b16
000120514 7001_ $$aAltenöder, Jutta$$b17
000120514 7001_ $$aIlkavets, Iryna$$b18
000120514 7001_ $$aGoumans, Marie-José$$b19
000120514 7001_ $$aHawinkels, Lukas J A C$$b20
000120514 7001_ $$aLee, Se-Jin$$b21
000120514 7001_ $$0P:(DE-He78)0792aae05ea250d2937cdfa6c9ca05fc$$aWieland, Matthias$$b22
000120514 7001_ $$aMogler, Carolin$$b23
000120514 7001_ $$aEbert, Matthias P$$b24
000120514 7001_ $$aHerrera, Blanca$$b25
000120514 7001_ $$0P:(DE-He78)2e92d0ae281932fc7347d819fec36b0b$$aAugustin, Hellmut$$b26
000120514 7001_ $$aSánchez, Aránzazu$$b27
000120514 7001_ $$aDooley, Steven$$b28
000120514 7001_ $$aTen Dijke, Peter$$b29
000120514 773__ $$0PERI:(DE-600)1492637-4$$a10.1136/gutjnl-2016-313314$$gVol. 66, no. 5, p. 939 - 954$$n5$$p939 - 954$$tGut$$v66$$x1468-3288$$y2017
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