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Original article
BMP-9 interferes with liver regeneration and promotes liver fibrosis
  1. Katja Breitkopf-Heinlein1,
  2. Christoph Meyer1,
  3. Courtney König2,
  4. Haristi Gaitantzi1,
  5. Annalisa Addante3,
  6. Maria Thomas4,
  7. Eliza Wiercinska5,
  8. Chen Cai1,
  9. Qi Li1,6,
  10. Fengqi Wan1,
  11. Claus Hellerbrand7,
  12. Nektarios A Valous8,
  13. Maximilian Hahnel9,
  14. Christian Ehlting9,
  15. Johannes G Bode9,
  16. Stephanie Müller-Bohl10,
  17. Ursula Klingmüller10,
  18. Jutta Altenöder1,
  19. Iryna Ilkavets1,
  20. Marie-José Goumans11,
  21. Lukas J A C Hawinkels11,
  22. Se-Jin Lee12,
  23. Matthias Wieland2,
  24. Carolin Mogler13,
  25. Matthias P Ebert1,
  26. Blanca Herrera3,
  27. Hellmut Augustin2,14,15,
  28. Aránzazu Sánchez3,
  29. Steven Dooley1,
  30. Peter ten Dijke11
  1. 1Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  2. 2Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
  3. 3Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain
  4. 4Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
  5. 5German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, Frankfurt, Germany
  6. 6Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
  7. 7Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
  8. 8Applied Tumor Immunity Clinical Cooperation Unit, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany
  9. 9University Hospital of the Heinrich-Heine University, Duesseldorf, Germany
  10. 10Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
  11. 11Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands
  12. 12Johns Hopkins University School of Medicine, Molecular Biology and Genetics, Baltimore, USA
  13. 13Institute of Pathology, Technical University of Munich, München, Germany
  14. 14Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  15. 15German Cancer Consortium, Heidelberg, Germany
  1. Correspondence to Dr Katja Breitkopf-Heinlein, Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim D-68167, Germany; katja.breitkopf{at}medma.uni-heidelberg.de

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-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
  • HEPATOCYTE
  • CYTOKINES
  • GROWTH FACTORS

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Footnotes

  • 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, MH, 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, HA, 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). 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’.

  • 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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