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Materials today. Bio2024; 25; 100983; doi: 10.1016/j.mtbio.2024.100983

Cell-permeable bone morphogenetic protein 2 facilitates bone regeneration by promoting osteogenesis.

Abstract: The use of the FDA-approved osteoinductive growth factor BMP2 is widespread for bone regeneration. However, its clinical application has been hindered by limitations in cell permeability and a short half-life in circulation. To address this issue, we have developed a modified version of BMP2, referred to as Cell Permeable (CP)-BMP2, which possesses improved cell permeability. CP-BMP2 incorporates an advanced macromolecular transduction domain (aMTD) to facilitate transfer across the plasma membrane, a solubilization domain, and recombinant human BMP2. Compared to traditional rhBMP2, CP-BMP2 exhibits enhanced cell permeability, solubility, and bioavailability, and activates Smad phosphorylation through binding to BMP receptor 2. The effectiveness of CP-BMP2 was evaluated in three animal studies focusing on bone regeneration. In the initial study, mice and rabbits with critical-size calvarial defects received subcutaneous (SC) injections of CP-BMP2 and rhBMP2 (7.5 mg/kg, 3 injections per week for 8 weeks).Following 8 weeks of administration, CP-BMP2 demonstrated a remarkable 65 % increase in bone formation in mice when compared to both the vehicle and rhBMP2. Moreover, rabbits exhibited faster bone formation, characterized by a filling pattern originating from the center. In a subsequent study involving injured horses, hind limb bones treated with CP-BMP2 exhibited an 85 % higher bone regeneration rate, as evidenced by Micro-CT results, in contrast to horses treated with the vehicle or rhBMP2 (administered at 150 μg/defect, subcutaneously, once a week for 8 weeks, without a scaffold). These results underscore the potential of CP-BMP2 to facilitate rapid and effective healing. No noticeable adverse effects, such as ectopic bone formation, were observed in any of the studies. Overall, our findings demonstrate that CP-BMP2 holds therapeutic potential as a novel and effective osteogenic agent.
© 2024 The Authors.
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Publication Date: 2024-02-01 PubMed ID: 38327977PubMed Central: PMC10848039DOI: 10.1016/j.mtbio.2024.100983Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This research developed a modified version of bone morphogenetic protein 2 (BMP2), named Cell Permeable BMP2 (CP-BMP2), designed to improve bone regeneration by enhancing cell permeability and bioavailability.
  • Animal studies showed CP-BMP2 significantly accelerated and increased bone formation compared to traditional BMP2 treatments without notable side effects.

Background

  • BMP2 is an FDA-approved growth factor widely used to promote bone regeneration due to its osteoinductive properties.
  • Despite its therapeutic potential, clinical use of BMP2 is limited by two major challenges:
    • Poor permeability across cell membranes, limiting cellular uptake.
    • Short half-life in systemic circulation, reducing its effectiveness.

Development of CP-BMP2

  • The researchers engineered CP-BMP2 by fusing several components:
    • An advanced macromolecular transduction domain (aMTD) that enhances transfer of the protein across plasma membranes to improve cell permeability.
    • A solubilization domain to increase protein solubility, addressing aggregation and stability issues.
    • Recombinant human BMP2 as the osteoinductive core component.
  • This design aimed to increase the intracellular availability of BMP2, thereby augmenting its biological activity.
  • Functional testing demonstrated CP-BMP2’s enhanced ability to activate Smad phosphorylation signaling pathways by binding to BMP receptor 2, validating its osteogenic activity.

Animal Studies for Bone Regeneration

  • Three different animal models were employed to evaluate CP-BMP2’s efficacy:
    • Mice and rabbits with critical-size calvarial defects:
      • Received subcutaneous injections of CP-BMP2 or traditional rhBMP2 (7.5 mg/kg, 3x/week for 8 weeks).
      • Results showed a 65% increase in bone formation in mice treated with CP-BMP2 versus both vehicle and rhBMP2.
      • Rabbits exhibited faster bone regeneration, with a distinctive central filling pattern.
    • Horses with hind limb bone injuries:
      • CP-BMP2 or vehicle/rhBMP2 administered subcutaneously once weekly (150 μg/defect for 8 weeks, scaffold-free).
      • CP-BMP2 treated limbs showed an 85% higher rate of bone regeneration measured by Micro-CT scans compared to controls.
      • The treatment was effective without surgical scaffolds, highlighting its translational potential.

Safety and Side Effects

  • No significant adverse events were observed in any animal model.
  • No ectopic (abnormal) bone formation occurred, a common concern with BMP2 therapies.
  • This suggests CP-BMP2 is a safer alternative than conventional BMP2 treatments.

Conclusions and Implications

  • CP-BMP2 exhibits superior characteristics compared to traditional BMP2:
    • Enhanced cell permeability facilitates better intracellular delivery.
    • Improved solubility and stability increase bioavailability.
    • Stronger activation of osteogenic signaling pathways supports bone growth.
  • The significant improvements in bone regeneration across multiple animal species demonstrate CP-BMP2’s broad therapeutic potential.
  • Its ability to work without scaffolds provides a practical advantage for clinical use.
  • Overall, CP-BMP2 represents a promising novel osteogenic agent to address limitations of current BMP2-based bone regeneration therapies.

Cite This Article

APA
Kang M, Lee S, Seo JP, Lee EB, Ahn D, Shin J, Paik YK, Jo D. (2024). Cell-permeable bone morphogenetic protein 2 facilitates bone regeneration by promoting osteogenesis. Mater Today Bio, 25, 100983. https://doi.org/10.1016/j.mtbio.2024.100983

Publication

Materials today. Bio
ISSN: 2590-0064
NlmUniqueID: 101757228
Country: England
Language: English
Volume: 25
Pages: 100983
PII: 100983

Researcher Affiliations

Kang, Mingu
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.
Lee, Seokwon
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.
Seo, Jong-Pil
  • College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, 63243, South Korea.
Lee, Eun-Bee
  • College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, 63243, South Korea.
Ahn, Daye
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.
Shin, Jisoo
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.
Paik, Young-Ki
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.
Jo, Daewoong
  • Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul, 03929, South Korea.

Conflict of Interest Statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Citations

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