BMP-9 interferes with liver regeneration and promotes liver fibrosis

Katja Breitkopf-Heinlein, Christoph Meyer, Courtney König, Haristi Gaitantzi, Annalisa Addante, Maria Thomas, Eliza Wiercinska, Chen Cai, Qi Li, Fengqi Wan, Claus Hellerbrand, Nektarios A. Valous, Maximilian J. Hahnel, Christian Ehlting, Johannes G. Bode, Stephanie Mueller-Bohl, Ursula Klingmüller, Jutta Altenöder, Iryna Ilkavets, Marie José GoumansLukas J.A.C. Hawinkels, Se Jin Lee, Matthias Wieland, Carolin Mogler, Matthias P. Ebert, Blanca Herrera, Hellmut G. Augustin, Aránzazu Sánchez, Steven Dooley, Peter Ten Dijke

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)939-954
Number of pages16
JournalGut
Volume66
Issue number5
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Gastroenterology

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    Breitkopf-Heinlein, K., Meyer, C., König, C., Gaitantzi, H., Addante, A., Thomas, M., Wiercinska, E., Cai, C., Li, Q., Wan, F., Hellerbrand, C., Valous, N. A., Hahnel, M. J., Ehlting, C., Bode, J. G., Mueller-Bohl, S., Klingmüller, U., Altenöder, J., Ilkavets, I., ... Ten Dijke, P. (2017). BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut, 66(5), 939-954. https://doi.org/10.1136/gutjnl-2016-313314