title: The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Joeng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.affiliation: 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.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Abraham
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX 77584, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX 77584, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Ambrose
authors.affiliation: 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.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D050723:Fractures, Bone / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051155:Wnt1 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse