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Smad7 dependent expression signature highlights BMP2 and HK2 signaling in HSC transdifferentiation
Bernd Denecke, Lucia Wickert, Yan Liu, Loredana Ciuclan, Steven Dooley, Nadja M Meindl-Beinker
Bernd Denecke, Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, 52074 Aachen, Germany
Lucia Wickert, Institute of Clinical Chemistry and Pathobiochemistry of RWTH-University Hospital, 52074 Aachen, Germany
Yan Liu, Steven Dooley, Nadja M Meindl-Beinker, Molecular Hepatology, Alcohol Induced Diseases, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
Loredana Ciuclan, Department of Biology, Babes-Bolyai University, 400084 Cluj-Napoca, Romania
Author contributions: Denecke B, Wickert L and Liu Y performed the majority of the experiments and were involved in editing the manuscript and preparing the figures; Ciuclan L was directly involved in discussing the results and editing the manuscript; Dooley S was involved in designing the study and providing financial support for this work; Meindl-Beinker NM was involved in designing and coordinating the study and writing the manuscript.
Supported by Deutsche Forschungsgemeinschaft DO373/6-1 and SFB TRR77, BMBF (HepatoSys), European Research Advisory Board and the Schlieben-Lange-Programm of the Ministerium für Wissenschaft, Forschung und Kunst of Baden-Württemberg and the Europäische Sozialfond
Correspondence to: Dr. Nadja M Meindl-Beinker, Molecular Hepatology, Alcohol Induced Diseases, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. nadja.meindl-beinker@medma.uni-heidelberg.de
Telephone: +49-621-3834983 Fax: +49-621-3831467
Received: April 14, 2010
Revised: May 11, 2010
Accepted: May 18, 2010
Published online: November 7, 2010
AIM: To analyse the influence of Smad7, antagonist of transforming growth factor (TGF)-β canonical signaling pathways on hepatic stellate cell (HSC) transdifferentiation in detail.
METHODS: We systematically analysed genes regulated by TGF-β/Smad7 in activated HSCs by microarray analysis and validated the results using real time polymerase chain reaction and Western blotting analysis.
RESULTS: We identified 100 known and unknown targets underlying the regulation of Smad7 expression and delineated 8 gene ontology groups. Hk2, involved in glycolysis, was one of the most downregulated proteins, while BMP2, activator of the Smad1/5/8 pathway, was extremely upregulated by Smad7. However, BMP2 dependent Smad1 activation could be inhibited in vitro by Smad7 overexpression in HSCs.
CONCLUSION: We conclude (1) the existence of a tight crosstalk of TGF-β and BMP2 pathways in HSCs and (2) a Smad7 dependently decreased sugar metabolism ameliorates HSC activation probably by energy withdrawal.
