Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo
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 osteogeni...
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KeAi Communications Co., Ltd.
2023-11-01
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Series: | Bioactive Materials |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X23002153 |
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author | 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 |
author_facet | 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 |
author_sort | Claudia Siverino |
collection | DOAJ |
description | 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. |
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institution | Directory Open Access Journal |
issn | 2452-199X |
language | English |
last_indexed | 2024-03-12T14:13:30Z |
publishDate | 2023-11-01 |
publisher | KeAi Communications Co., Ltd. |
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series | Bioactive Materials |
spelling | doaj.art-45dfb93b0ed2401c8fd6e92803bdb4e32023-08-21T04:20:29ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2023-11-0129241250Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivoClaudia Siverino0Shorouk Fahmy-Garcia1Viktoria Niklaus2Nicole Kops3Laura Dolcini4Massimiliano Maraglino Misciagna5Yanto Ridwan6Eric Farrell7Gerjo J.V.M. van Osch8Joachim Nickel9Department of Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Wuerzburg, GermanyDepartment of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, Rotterdam, the NetherlandsDepartment of Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Wuerzburg, GermanyDepartment of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the NetherlandsFin-Ceramica Faenza SpA, Via Granarolo 177/3, 48018, Faenza, ItalyFin-Ceramica Faenza SpA, Via Granarolo 177/3, 48018, Faenza, ItalyAMIE Core Facility, Erasmus University Medical Center, Rotterdam, the NetherlandsDepartment of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Corresponding author. Dr Molewaterplein 40, 3015GD Rotterdam, the Netherlands.Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Biomechanical Engineering, Faculty of Mechanical, Maritime and Materials Engineering, Delft University of Technology, Delft, the NetherlandsDepartment of Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Wuerzburg, Germany; Fraunhofer ISC, Translational Center RT, Wuerzburg, Germany; Corresponding author. Röntgenring 11, 97070 Würzburg, Germany.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.http://www.sciencedirect.com/science/article/pii/S2452199X23002153Bone morphogenetic protein 9 (BMP9)Heparin binding sitesBone regenerationSubcutaneous animal model |
spellingShingle | 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 Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo Bioactive Materials Bone morphogenetic protein 9 (BMP9) Heparin binding sites Bone regeneration Subcutaneous animal model |
title | Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo |
title_full | Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo |
title_fullStr | Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo |
title_full_unstemmed | Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo |
title_short | Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo |
title_sort | addition of heparin binding sites strongly increases the bone forming capabilities of bmp9 in vivo |
topic | Bone morphogenetic protein 9 (BMP9) Heparin binding sites Bone regeneration Subcutaneous animal model |
url | http://www.sciencedirect.com/science/article/pii/S2452199X23002153 |
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