Abstract
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.
Highlights
C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family along with atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [1]
We have determined that CNP/natriuretic peptide receptor (NPR)-B signaling is crucial for endochondral bone growth using knockout (KO) mouse models
Both gain-of-function mutations in the gene encoding NPR-B and increased CNP expression by balanced chromosomal translocations reportedly caused skeletal-overgrowth in humans [20,21,22,23,24,25]. These facts indicate that CNP/NPR-B signaling is a pivotal stimulator of endochondral bone growth in humans as well as in mice
Summary
C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family along with atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [1]. A recent study showed that heterozygous loss-of-function mutations in the CNP gene cause a short stature in humans [19] Both gain-of-function mutations in the gene encoding NPR-B and increased CNP expression by balanced chromosomal translocations reportedly caused skeletal-overgrowth in humans [20,21,22,23,24,25]. These facts indicate that CNP/NPR-B signaling is a pivotal stimulator of endochondral bone growth in humans as well as in mice
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