Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo

Claudia Siverino, Shorouk Fahmy-Garcia, Viktoria Niklaus, Nicole Kops, Laura Dolcini, Massimiliano Maraglino Misciagna, Yanto Ridwan, Eric Farrell*, Gerjo J.V.M. van Osch, Joachim Nickel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Bone Morphogenetic proteins (BMPs) like BMP2 and BMP7 have shown great potential in the treatment of severe bone defects. In recent in vitro studies, BMP9 revealed the highest osteogenic potential compared to other BMPs, possibly due to its unique signaling pathways that differs from other osteogenic BMPs. However, in vivo the bone forming capacity of BMP9-adsorbed scaffolds is not superior to BMP2 or BMP7. In silico analysis of the BMP9 protein sequence revealed that BMP9, in contrast to other osteogenic BMPs such as BMP2, completely lacks so-called heparin binding motifs that enable extracellular matrix (ECM) interactions which in general might be essential for the BMPs' osteogenic function. Therefore, we genetically engineered a new BMP9 variant by adding BMP2-derived heparin binding motifs to the N-terminal segment of BMP9′s mature part. The resulting protein (BMP9 HB) showed higher heparin binding affinity than BMP2, similar osteogenic activity in vitro and comparable binding affinities to BMPR-II and ALK1 compared to BMP9. However, remarkable differences were observed when BMP9 HB was adsorbed to collagen scaffolds and implanted subcutaneously in the dorsum of rats, showing a consistent and significant increase in bone volume and density compared to BMP2 and BMP9. Even at 10-fold lower BMP9 HB doses bone tissue formation was observed. This innovative approach of significantly enhancing the osteogenic properties of BMP9 simply by addition of ECM binding motifs, could constitute a valuable replacement to the commonly used BMPs. The possibility to use lower protein doses demonstrates BMP9 HB's high translational potential.

Original languageEnglish
Pages (from-to)241-250
Number of pages10
JournalBioactive Materials
Volume29
DOIs
Publication statusPublished - Nov 2023

Bibliographical note

Funding Information:
The research leading to these results has received funding from the European Union Seventh Framework Programme FP7-PEOPLE-2013-ITN under grant agreement no. 607051 in project BioInspire , the Netherlands Organisation of Scientific Research – Applied and Engineering Science under the frame of EuroNanoMed III in project Nano-Scores (project nr ENMIII077-2 ) and by the University of Wuerzburg (funding program OpenAccess Publishing).

Publisher Copyright:
© 2023 The Authors

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