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PLoS One. 2018 Mar 22;13(3):e0194812. doi: 10.1371/journal.pone.0194812. eCollection 2018.

Rats deficient C-type natriuretic peptide suffer from impaired skeletal growth without early death.

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Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Asubio Pharma Co., Ltd., Kobe, Japan.
Department of Maxillofacial Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Genome Editing Research and Development (R&D) Center and Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan.
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.


We have previously investigated the physiological role of C-type natriuretic peptide (CNP) on endochondral bone growth, mainly with mutant mouse models deficient in CNP, and reported that CNP is indispensable for physiological endochondral bone growth in mice. However, the survival rate of CNP knockout (KO) mice fell to as low as about 70% until 10 weeks after birth, and we could not sufficiently analyze the phenotype at the adult stage. Herein, we generated CNP KO rats by using zinc-finger nuclease-mediated genome editing technology. We established two lines of mutant rats completely deficient in CNP (CNP KO rats) that exhibited a phenotype identical to that observed in mice deficient in CNP, namely, a short stature with severely impaired endochondral bone growth. Histological analysis revealed that the width of the growth plate, especially that of the hypertrophic chondrocyte layer, was markedly lower and the proliferation of growth plate chondrocytes tended to be reduced in CNP KO rats. Notably, CNP KO rats did not have malocclusions and survived for over one year after birth. At 33 weeks of age, CNP KO rats persisted significantly shorter than wild-type rats, with closed growth plates of the femur in all samples, which were not observed in wild-type rats. Histologically, CNP deficiency affected only bones among all body tissues studied. Thus, CNP KO rats survive over one year, and exhibit a deficit in endochondral bone growth and growth retardation throughout life.

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