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

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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.

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Acknowledgments

We thank B. de Crombrugghe (Department of Genetics, University of Texas M.D. Anderson Cancer Center) for the Col2a1 promoter. This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan and the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan (21591176, 21119013).

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan

    Eri Kondo, Akihiro Yasoda, Toshihito Fujii, Masako Miura, Naotestu Kanamoto, Naohisa Tamura, Hiroshi Arai & Kazuwa Nakao

  2. Department of Animal Science, Okayama University Graduate School of Natural Science and Technology, Okayama, 700-8530, Japan

    Takehito Tsuji & Tetsuo Kunieda

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  1. Eri Kondo
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  2. Akihiro Yasoda
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  3. Takehito Tsuji
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  4. Toshihito Fujii
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Correspondence to Akihiro Yasoda.

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Kondo, E., Yasoda, A., Tsuji, T. et al. Skeletal Analysis of the Long Bone Abnormality (lbab/lbab) Mouse, A Novel Chondrodysplastic C-Type Natriuretic Peptide Mutant. Calcif Tissue Int 90, 307–318 (2012). https://doi.org/10.1007/s00223-011-9567-0

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