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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.

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