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Therapeutic potential of CNP for skeletal dysplasias

Background

We had revealed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth by using transgenic and knockout mice: transgenic mice with targeted overexpression of CNP in cartilage develop prominent skeletal overgrowth [1], whereas mice depleted with CNP exhibit impaired endochondral bone growth [2]. We planned to translate this effect of CNP into the therapy for skeletal dysplasias, of which the effective drug therapy is not established yet. Here we investigated the effect of CNP on the impaired bone growth of mice model of achondroplasia, the most common form of skeletal dysplasias.

Results

First, we investigated the effects of plasma CNP on impaired bone growth in achondroplastic mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter. Increased plasma CNP stimulated the impaired growth of achondroplastic bones, and they grew almost comparable to those of wild type mice at the age of 6 weeks. Then we treated achondroplastic mice with continuous intravenous infusion of CNP at the dose of 1 μg/kg/min, and successfully rescued the shortness of most bones formed endochondral ossification at the end of 3-week experimental period. Figures 1 and 2.

Figure 1
figure1

Soft x-ray picture of wild type mice (Wt), achondroplastic model mice (Ach), and achondroplastic model mice treated with CNP at the dose of 1 μg/kg/min.

Figure 2
figure2

Lengths of bones measured on soft x-ray film.

Conclusion

Our results indicate that treatment with CNP is a potential therapeutic strategy for skeletal dysplasias, including achondroplasia, in humans.

References

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    Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K: Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004, 10: 80-86. 10.1038/nm971.

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  2. 2.

    Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y, Itoh H, Tanaka K, Saito Y, Katsuki M, Nakao K: Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci USA. 2001, 98: 4016-4021. 10.1073/pnas.071389098.

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Acknowledgements

We would like to thank Dr. David Ornitz (Washington University Medical School) for giving us mice model of achondroplasia.

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Correspondence to Akihiro Yasoda.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yasoda, A., Kitamura, H., Fujii, T. et al. Therapeutic potential of CNP for skeletal dysplasias. BMC Pharmacol 9, P74 (2009). https://doi.org/10.1186/1471-2210-9-S1-P74

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Keywords

  • Wild Type Mouse
  • Intravenous Infusion
  • Bone Growth
  • Serum Amyloid
  • Continuous Intravenous Infusion