[Frontiers in Bioscience 14, 4992-5012, June 1, 2009]

BMP-7 as antagonist of organ fibrosis

Ralf Weiskirchen, Steffen K. Meurer, Olav A. Gressner, Jens Herrmann, Erawan Borkham-Kamphorst, Axel M. Gressner

Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Individual sections
3.1. Structural insights of BMPs
3.2. BMP signaling: Modes of signal transmission and their regulation
3.2.1. The BMP subgroups
3.2.2. BMP receptors
3.2.3. Secreted BMP signaling modulators
3.2.4. BMP intracellular signaling pathways
3.2.5. BMP-mediated transcriptional control
3.2.6. BMP target genes
3.2.7. Regulation of intracellular BMP signaling
3.3. Physiological functions of BMP-7 in normal and fibrotic organs
3.4. Efficacy of BMP-7 as physiological and therapeutic antifibrotic agent
3.5. The complex regulatory network of BMP-7 and TGF-beta in epithelial-to-mesenchymal transition 3.6. Functional interplay between BMP-7 and connective tissue growth factor (CTGF/CCN2) and other crucial modifiers and regulators in organ fibrosis 3.7. BMP-7 as a novel diagnostic marker?
4. Summary and perspectives
5. Acknowledgements
6. References

1. ABSTRACT

Fibrosis is a scarring process that is a common feature of chronic organ injury. It is characterized by elevated activity of transforming growth factor-beta resulting in increased and altered deposition of extracellular matrix and other fibrosis-associated proteins. Recent work has demonstrated that bone morphogenetic protein-7 blocks transforming growth factor-beta signaling. Moreover, member of the CCN family, Endoglin, Sclerostin, Sclerostin domain-containing proteins, Gremlin, Noggin, Chordin, and Kielin/Chordin-like protein influence the biological activity of both cytokines. As a consequence, they modulate cellular proliferation, migration, adhesion and extracellular matrix production. This tight protein network consisting of transforming growth factor-betas, bone morphogenetic proteins and various binding partners includes potential novel molecular targets and biomarkers useful for prognostication, disease monitoring and therapy. We here summarize recent advances in understanding bone morphogenetic protein-7 function and signaling and the current attempts to use this critical modulator as a pharmacological device to reverse transforming growth factor-beta-induced fibrogenesis.