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.
- HEPATIC STELLATE CELL
- HEPATIC FIBROSIS
- GROWTH FACTORS
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CM, CK, HG and AA shared second authorship. AS, SD, PtD shared senior authorship.
Contributors KB-H, AS, SD and PtD did the planning for the study and are responsible for the overall content. Experiments were conducted by KB-H, CMe, CK, HG, AA, MT, EW, QL, FW, CH, MJH, SM-B, JA, MG, LJACH, SL, MW, CMo, CC, CE and BH. Reporting of the data and writing of the manuscript was performed by KB-H, CMe, HG, EW, CH, NAV, JGB, SM-B, UK, JA, LJACH, CM, MPE, BH, HGA, AS, SD and PtD.
Funding This study was supported by Cancer Genomics Centre Netherlands and FP7-PEOPLE-2012-ITN IT-LIVER (SD, AA, PtD, BH, AS: grant no 316549). The study was further supported by the Robert Bosch Foundation, Stuttgart, Germany, and the German Research Foundation; Contract grant numbers: ‘He2458/18-1’ and ‘Do373/8-1’ as well as the Federal Ministry of Education and Research grants ‘The Virtual Liver’ and ‘LiSyM’ (SD). QL was a fellow supported by the China Scholarship Council and CC by a scholarship from Wu Jin Ren Min Hospital, China. CM is supported by the Deutsche Forschungsgemeinschaft (Me4532/1-1). AA is an ESR (early-stage researcher) within the ITN. KB-H was further supported by the ‘Förderprogramm ZIM des BMWi’ (KF3431901AJ4) and the programme ‘Entwicklung von Alternativmethoden zur Vermeidung von Tierversuchen’ granted by the ‘Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg’. S-JL was supported by the NIH grant no. R01AR060636.
Competing interests None declared.
Ethics approval The tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the ethics committee of Heidelberg University (Ethikvotes # 206/207, year: 2005).
Provenance and peer review Not commissioned; externally peer reviewed.
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