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BMP9 a possible alternative drug for the recently withdrawn BMP7? New perspectives for (re-)implementation by personalized medicine

  • Molecular Toxicology
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Abstract

Promotion of rhBMP2 and rhBMP7 for the routine use to support fracture healing has been hampered by high costs, safety concerns and reasonable failure rates, imposing restrictions in its clinical use. Since there is little debate regarding its treatment potential, there is rising need for a better understanding of the mode of action of these BMPs to overcome its drawbacks and promote more efficacious treatment strategies for bone regeneration. Recently, BMP9, owing to its improved osteogenic potential, is gaining attention as a promising therapeutic alternative. Our study aimed at identifying specific gene expression patterns which may predict and explain individual responses to rhBMP7 and rhBMP9 treatments. Therefore, we investigated the effect of rhBMP7 and rhBMP9 on primary human osteoblasts from 110 donors and corresponding THP-1-derived osteoclasts. This was further compared with each other and our reported data on rhBMP2 response. Based on the individual donor response, we found three donor groups profiting from rhBMP treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclasts. The response on rhBMP7 treatment correlated with expression levels of the genes BAMBI, SOST, Noggin, Smad4 and RANKL, while the response of rhBMP9 correlated to the expression levels of Alk6, Endoglin, Smurf1, Smurf2, SOST and RANKL in these donors. Noteworthy, rhBMP9 treatment showed significantly increased osteogenic activity (AP activity and Smad nuclear translocation) when compared to the two clinically used rhBMPs. Based on patient’s respective expression profiles, clinical application of rhBMP9 either solely or in combination with rhBMP2 and/or rhBMP7 can become a promising new approach to fit the patient’s needs to promote fracture healing.

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Acknowledgments

We’d like to thank Hanna Scheffler and Rebecca Haupt for their excellent technical assistance. This work was partially supported by the intramural funding of the Eberhard Karls Universität Tübingen (fortüne Junior 2174-0-0) and the BBraun Foundation.

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Authors and Affiliations

  1. Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany

    Vrinda Sreekumar, Romina Haydeé Aspera-Werz, Gauri Tendulkar, Marie Karolina Reumann, Thomas Freude, Stefan Pscherer, Björn Gunnar Ochs, Ingo Flesch, Valeska Hofmann, Andreas Klaus Nussler & Sabrina Ehnert

  2. Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Katja Breitkopf-Heinlein & Steven Dooley

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  1. Vrinda Sreekumar
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Correspondence to Sabrina Ehnert.

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Supplementary Figure 1

BMP and Wnt signaling cascades during osteoblastogenesis and osteoclastogenesis. (A) Classically, BMP dimers bind to a receptor complex consisting of a type 1 and type 2 receptor to initiate intracellular signaling. In the presence of a co-receptor some BMPs might also initiate the intracellular signaling via an alternative receptor complex. The receptor complex is specific for the different BMPs. Upon receptor binding the transcription factors Smad1, -5 and -8 get activated (phosphorylated) and can translocate into the nucleus upon binding to Smad4 in order to initiate target gene expression. Wnt initiates its signaling via the receptors Frizzled and LRP5/6. Activation of this receptor complex inhibits the glycogen synthase kinase-3β (GSK-3β), which then can no longer favor degradation of β-catenin. β-catenin in turn can support nuclear translocation of the Smad1, -5 and -8 complex. BMP7 inhibitors include the extracellular Noggin, the membrane bound BAMBI and the intracellular Smad6 and -7, as well as Smurf1 and -2. Wnt inhibitors include Sclerostin (SOST), Dickkopf 1 and 2 (DKK1 and DKK2). Functional BMP7 and Wnt signaling regulates the expression of receptor activator of NF-kB ligand (RANKL) and its antagonist osteoprotegerin (OPG) which regulate osteoclastogenesis. (B) Overview on the composition of classical (solid line) and alternative (dotted line) receptor complex for BMP2, -7 and -9 (TIFF 9520 kb)

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Sreekumar, V., Aspera-Werz, R.H., Tendulkar, G. et al. BMP9 a possible alternative drug for the recently withdrawn BMP7? New perspectives for (re-)implementation by personalized medicine. Arch Toxicol 91, 1353–1366 (2017). https://doi.org/10.1007/s00204-016-1796-6

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