Bone Regenerative Engineering Using a Protein Kinase A-Specific Cyclic AMP Analogue Administered for Short Term

Abstract

Small molecule-mediated bone regeneration is emerging as a promising strategy for replacing or enhancing the therapeutic protein-based growth factors. However, unknown non-specific toxicity of small molecules on non-target cells or organs due to the long-term exposure has been a concern. We previously demonstrated that the continuous treatment of osteoblast-like MC3T3-E1 cells with small molecule cyclic AMP analogue N6-benzoyladenosine-3′,5′-cyclic monophosphate (6-Bnz-cAMP) was capable of inducing in vitro osteogenesis via the protein kinase A (PKA) signaling pathway. In this study, we investigate the effect of short-term 6-Bnz-cAMP treatment, i.e., 1-day treatment, as compared to continuous treatment, on in vitro osteogenesis in osteoprogenitor cells. It is hypothesized that the proposed short-term 6-Bnz-cAMP treatment scheme would result in osteogenesis as in the case of continuous 6-Bnz-cAMP treatment. Our results showed that both short-term and continuous 6-Bnz-cAMP treatments elicited osteoblastic differentiation and mineralization of osteoblast-like MC3T3-E1 cells. Short-term treatment using small molecule 6-Bnz-cAMP can serve as a highly promising strategy for bone regeneration while mitigating potential non-specific side effect risks associated with small molecules.

Lay Summary

The goal of this work is to develop a simple, inexpensive, effective, and safe method to heal bone defect. We would like to treat the bone defects with a small molecule-based therapeutic agent in a short-term treatment so that undesirable side effects from the therapeutics would be significantly minimized. Our work may also result in novel bone graft materials that can potentially become a viable alternative to existing grafts.

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Acknowledgements

We wish to thank Dr. Cato T. Laurencin, the Director of the Institute for Regenerative Engineering (IRE), for his leadership.

Funding

This work was supported by the Project Fund from the Connecticut Institute for Clinical and Translational Science (CICATS) to Dr. Kevin Lo.

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Correspondence to Kevin W.-H. Lo.

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Ifegwu, O.C., Awale, G., Kan, H.M. et al. Bone Regenerative Engineering Using a Protein Kinase A-Specific Cyclic AMP Analogue Administered for Short Term. Regen. Eng. Transl. Med. 4, 206–215 (2018). https://doi.org/10.1007/s40883-018-0063-1

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Keywords

  • Cyclic AMP
  • Small molecules
  • Regenerative engineering
  • Musculoskeletal tissue
  • Drug discovery
  • Osteogenesis