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Hum Mol Genet. 2014 Aug 1;23(15):4035-42. doi: 10.1093/hmg/ddu117. Epub 2014 Mar 14.

The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Howard Hughes Medical Institute, One Baylor Plaza, Houston, TX 77030, USA.
3
Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
4
Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX 77584, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Howard Hughes Medical Institute, One Baylor Plaza, Houston, TX 77030, USA blee@bcm.edu.

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1(sw/sw)) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1(sw/sw) mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations.

PMID:
24634143
PMCID:
PMC4082367
DOI:
10.1093/hmg/ddu117
[Indexed for MEDLINE]
Free PMC Article
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