Skeletal Analysis of the Long Bone Abnormality (lbab/lbab) Mouse, A Novel Chondrodysplastic C-Type Natriuretic Peptide Mutant

Abstract

Long bone abnormality (lbab/lbab) is a strain of dwarf mice. Recent studies revealed that the phenotype is caused by a spontaneous mutation in the Nppc gene, which encodes mouse C-type natriuretic peptide (CNP). In this study, we analyzed the chondrodysplastic skeletal phenotype of lbab/lbab mice. At birth, lbab/lbab mice are only slightly shorter than their wild-type littermates. Nevertheless, lbab/lbab mice do not undergo a growth spurt, and their final body and bone lengths are only ~60% of those of wild-type mice. Histological analysis revealed that the growth plate in lbab/lbab mice, especially the hypertrophic chondrocyte layer, was significantly thinner than in wild-type mice. Overexpression of CNP in the cartilage of lbab/lbab mice restored their thinned growth plate, followed by the complete rescue of their impaired endochondral bone growth. Furthermore, the bone volume in lbab/lbab mouse was severely decreased and was recovered by CNP overexpression. On the other hand, the thickness of the growth plate of lbab/+ mice was not different from that of wild-type mice; accordingly, impaired endochondral bone growth was not observed in lbab/+ mice. In organ culture experiments, tibial explants from fetal lbab/lbab mice were significantly shorter than those from lbab/+ mice and elongated by addition of 10(-7) M CNP to the same extent as lbab/+ tibiae treated with the same dose of CNP. These results demonstrate that lbab/lbab is a novel mouse model of chondrodysplasia caused by insufficient CNP action on endochondral ossification.

Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations

“…Similarly, the “long bone abnormality” ( lbab / lbab ) mice, mutants due to a spontaneous autosomal recessive hypomorphic mutation in the Nppc gene, developed severe dwarfism characterized by short tails and extremities, while heterozygous mice did not differ from wild-type mice. These studies confirmed that haploinsufficiency of the NPPC gene does not exist in mice [17]. On the contrary, the effects of haploinsufficiency of this gene are evident in humans which could be due to differences between species or some other unknown mechanism(s).…”

“…On the contrary, the effects of haploinsufficiency of this gene are evident in humans which could be due to differences between species or some other unknown mechanism(s). CNP is especially crucial for skeletal growth spurt that occurs in early life, is expressed in the growth plate cartilage, and works as an autocrine/paracrine regulator [17]. In the study by Moncla et al [12], the NPPC gene was not expressed in normal lymphoblasts under normal conditions while it is expressed 6-fold in chondrocytes of his patient P1.…”

Short Anabolic Peptides for Bone Growth

“…173,174 Another study has shown that inhibition of CNP synthesis reduces both bone volume and trabecular thickness in the humerus of mice, and these values are further restored when these mice are crossed with animals overexpressing CNP in cartilage tissue. 175 CNP also increased collagen synthesis and enhanced chondrocytes proliferation and differentiation in an autocrine/ paracrine manner. 176,177 CNP may represent a valuable avenue to enhance bone growth, however its action on cardiac and vascular functions raise concerns on its use.…”

“…Mice with systemic depletion of CNP are dwarf, whereas overproduction of CNP in cartilage resulted in prominent skeletal overgrowth and deformations . Another study has shown that inhibition of CNP synthesis reduces both bone volume and trabecular thickness in the humerus of mice, and these values are further restored when these mice are crossed with animals overexpressing CNP in cartilage tissue . CNP also increased collagen synthesis and enhanced chondrocytes proliferation and differentiation in an autocrine/paracrine manner …”

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

“…Since profoundly reduced postnatal growth in mice with homozygous mutations in NPPC (long bone abnormal, lbab) is rescued by CNP agonists [66], early detection of this putative genetic disorder in humans will be important, as the condition is likely to be uniquely responsive to exogenous CNP. Dominant activating mutations of FGFR3 , such as those causing achondroplasia, result in profoundly disproportional short stature and are associated with inappropriately raised plasma concentrations of both CNP and NTproCNP [50] in both children and adults.…”