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Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway

Nature Medicine volume 10, pages 80–86 (2004)Cite this article

Abstract

Achondroplasia is the most common genetic form of human dwarfism, for which there is presently no effective therapy. C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase. Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. These results demonstrate that activation of the CNP–GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.

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Figure 1: Generation of Nppc mice.
Figure 2: Skeletal rescue of Fgfr3ach mice by overexpression of CNP in cartilage.
Figure 3: Histological analysis of the growth plate of Nppc Fgfr3ach mice.
Figure 4: Effects of CNP on cultured tibiae from Fgfr3ach mice.
Figure 5: Intracellular signaling analysis.
Figure 6: Schematic representation of the mechanism by which CNP compensates for FGFR-3-mediated shortening of bones.

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Acknowledgements

We thank D.M. Ornitz (Department of Molecular Biology and Pharmacology, Washington University School of Medicine) for Fgfr3ach mice and B. DeCrombrugghe (Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center) for the Col2a1 promoter. This work was supported by grants from Research for the Future of the Japan Society for the Promotion of Science (JSPS-RFTF 96100204 and 98L00801); the Japanese Ministry of Education, Sciences, Sports, and Culture (# 12770627); Smoking Research Foundation; Toyobo Biochemical Foundation; and Uehara Memorial Foundation.

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho Sakyo-ku, Kyoto, 606-8507, Japan

    Akihiro Yasoda, Yasato Komatsu, Hideki Chusho, Takashi Miyazawa, Ami Ozasa, Masako Miura, Michio Suda, Naohisa Tamura, Yoshihiro Ogawa & Kazuwa Nakao

  2. Daiichi Suntory Institute for Biomedical Research, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka, 618-8503, Japan

    Tatsuya Kurihara, Tomohiro Rogi & Shoji Tanaka

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Yasoda, A., Komatsu, Y., Chusho, H. et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10, 80–86 (2004). https://doi.org/10.1038/nm971

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