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

Akihiro Yasoda, Yasato Komatsu, Hideki Chusho, Takashi Miyazawa, Ami Ozasa, Masako Miura, Tatsuya Kurihara, Tomohiro Rogi, Shoji Tanaka, Michio Suda, Naohisa Tamura, Yoshihiro Ogawa, Kazuwa Nakao

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267 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)80-86
Number of pages7
JournalNature medicine
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 1 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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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. (2004). Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nature medicine, 10(1), 80-86. https://doi.org/10.1038/nm971