Kyu Sang Joeng, Yi-Chien Lee, Ming-Ming Jiang, Terry K. Bertin, Yuqing Chen, Annie Mary Abraham, Hao Ding, Xiaohong Bi, Catherine Ambrose and Brendan H. Lee
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 while 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 (Wnt1sw/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 Wnt1sw/sw mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from 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 the in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1sw/sw mouse is a murine model of OI caused by WNT1 mutations.