BMP-9 interferes with liver regeneration and promotes liver fibrosis

被引：171

作者：

Breitkopf-Heinlein, Katja ^{[1
]}

Meyer, Christoph ^{[1
]}

Koenig, Courtney ^{[2
]}

Gaitantzi, Haristi ^{[1
]}

Addante, Annalisa ^{[3
]}

Thomas, Maria ^{[4
,5
]}

Wiercinska, Eliza ^{[6
,7
]}

Cai, Chen ^{[1
]}

Li, Qi ^{[8
]}

Wan, Fengqi ^{[1
]}

Hellerbrand, Claus ^{[9
]}

Valous, Nektarios A. ^{[10
]}

Hahnel, Maximilian J. ^{[11
]}

Ehlting, Christian ^{[11
]}

Bode, Johannes G. ^{[11
]}

Mueller-Bohl, Stephanie ^{[12
]}

Klingmueller, Ursula ^{[12
]}

Altenoeder, Jutta

Ilkavets, Iryna

Goumans, Marie-Jose ^{[13
,14
]}

Hawinkels, Lukas J. A. C. ^{[13
,14
]}

Lee, Se-Jin ^{[15
]}

Wieland, Matthias ^{[1
]}

Mogler, Carolin ^{[16
]}

Ebert, Matthias P.

Herrera, Blanca

Augustin, Hellmut G. ^{[17
,18
]}

Sanchez, Aranzazu

Dooley, Steven ^{[1
]}

ten Dijke, Peter ^{[1
]}

机构：

[1] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany

[2] German Canc Res Ctr Heidelberg DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, Heidelberg, Germany

[3] Univ Complutense Madrid, Dept Biochem & Mol Biol 2, San Carlos Clin Hosp Hlth Res Inst IdISSC, Fac Pharm, Madrid, Spain

[4] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[5] Univ Tubingen, Stuttgart, Germany

[6] Goethe Univ, German Red Cross Blood Serv Baden Wurttemberg Hes, Frankfurt, Germany

[7] Goethe Univ, Inst Transfus Med & Immunohaematol, Frankfurt, Germany

[8] Capital Med Univ, Beijing Youan Hosp, Dept Gastroenterol & Hepatol, Beijing, Peoples R China

[9] Univ Hosp Regensburg, Dept Internal Med 1, Regensburg, Germany

[10] German Canc Res Ctr, Natl Ctr Tumor Dis, Appl Tumor Immun Clin Cooperat Unit, Heidelberg, Germany

[11] Univ Hosp Heinrich Heine Univ, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany

[12] German Canc Res Ctr, Div Syst Biol Signal Transduct, DKFZ ZMBH Alliance, Heidelberg, Germany

[13] Leiden Univ, Dept Mol Cell Biol, Med Ctr, Leiden, Netherlands

[14] Leiden Univ, Ctr Canc Genom, Med Ctr, Leiden, Netherlands

[15] Johns Hopkins Univ, Sch Med Mol Biol & Genet, Baltimore, MD USA

[16] Tech Univ Munich, Inst Pathol, Munich, Germany

[17] Heidelberg Univ, Dept Vasc Biol & Tumor Angiogenesis CBTM, Med Fac Mannheim, Mannheim, Germany

[18] German Canc Consortium, Heidelberg, Germany

来源：

GUT | 2017年 / 66卷 / 05期

关键词：

BONE MORPHOGENETIC PROTEIN-9; TGF-BETA SUPERFAMILY; HEPATIC STELLATE CELLS; HEPATOCELLULAR-CARCINOMA CELLS; SINUSOIDAL ENDOTHELIAL-CELLS; SIGNALING PATHWAYS; PROLIFERATION; EXPRESSION; ANGIOGENESIS; FIBROGENESIS;

D O I：

10.1136/gutjnl-2016-313314

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：939 / 954

页数：16

共 56 条

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