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Chemically modified RNA induces osteogenesis of stem cells and human tissue explants as well as accelerates bone healing in rats

Balmayor, Elizabeth R., Geiger, Johannes P., Aneja, Manish K., Berezhanskyy, Taras, Utzinger, Maximilian, Mykhaylyk, Olga, Rudolph, Carsten, Plank, Christian·2016·Biomaterials
DOI 10.1016/j.biomaterials.2016.02.018
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Abstract

Limitations associated to the use of growth factors represent a major hurdle to musculoskeletal regeneration. On the one hand, they are needed to induce neo-tissue formation for the substitution of a necrotic or missing tissue. On the other hand, these factors are used in supraphysiological concentrations, are short lived and expensive and result in many side effects. Here we develop a gene transfer strategy based on the use of chemically modified mRNA (cmRNA) coding for human bone morphogenetic protein 2 (hBMP-2) that is non-immunogenic and highly stable when compared to unmodified mRNA. Transfected stem cells secrete hBMP-2, show elevated alkaline phosphatase levels and upregulated expression of RunX2, ALP, Osterix, Osteocalcin, Osteopontin and Collagen Type I genes. Mineralization was induced as seen by positive Alizarin red staining. hBMP-2 cmRNA transfected human fat tissue also yielded an osteogenic response in vitro as indicated by expression of hBMP-2, RunX2, ALP and Collagen Type I. Delivering hBMP-2 cmRNA to a femur defect in a rat model results in new bone tissue formation as early as 2 weeks after application of very low doses. Overall, our studies demonstrate the feasibility and therapeutic potential of a new cmRNA-based gene therapy strategy that is safe and efficient. When applied clinically, this approach could overcome BMP-2 growth factor associated limitations in bone regeneration.

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Metadata

Authors
Balmayor, E. R., Geiger, J. P., Aneja, M. K., Berezhanskyy, T., Utzinger, M., Mykhaylyk, O., Rudolph, C., & Plank, C.
ORCID
Balmayor, Elizabeth R.
Venue
Biomaterials
Publisher
Elsevier BV
Published
2016-05
Volume
87
Pages
131-146
ISSN
0142-9612
DOI
10.1016/j.biomaterials.2016.02.018
Cited by
105
References
6
Language
en
Licence
Funders
  • Bundesministerium für Bildung und Forschung
  • Deutsche Forschungsgemeinschaft (PL 281/3-1)

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