Dwarfism and early death in mice lacking C-type natriuretic peptide

Hideki Chusho, Naohisa Tamura, Yoshihiro Ogawa, Akihiro Yasoda, Michio Suda, Takashi Miyazawa, Kenji Nakamura, Kazuki Nakao, Tatsuya Kurihara, Yasato Komatsu, Hiroshi Itoh, Kiyoshi Tanaka, Yoshihiko Saito, Motoya Katsuki, Kazuwa Nakao

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Abstract

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc-/- mice). The Nppc-/- mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc-/- mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.

Original languageEnglish
Pages (from-to)4016-4021
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number7
DOIs
Publication statusPublished - 2001 Mar 27

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    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. (2001). Dwarfism and early death in mice lacking C-type natriuretic peptide. Proceedings of the National Academy of Sciences of the United States of America, 98(7), 4016-4021. https://doi.org/10.1073/pnas.071389098