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.

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis

“…These data indicate that Wnt1 deletion causes osteopenia and fractures primarily due to defects in osteoblast activity. Altogether, the specific deletion of Wnt1 in late osteoblasts and osteocytes caused spontaneous fractures and severe loss of bone, which demonstrates a phenotypic overlap with the swaying mouse model, a global loss-of-function mouse model of WNT1-related OI (30). Together, these data support an essential requirement of WNT1 function in osteocytes as the dominant contributor to the pathogenesis of WNT1-related OI and osteoporosis.…”

“…The semidominant inheritance of this mutation spectrum underscores the strict temporal, spatial, and dosage requirement of this essential Wnt ligand in human bone homeostasis. Moreover, we have established a swaying mouse model (Wnt1 sw/sw mice, which carry a mutation in Wnt1) as a murine model of WNT1-related OI (30). These human and mouse genetic studies strongly suggest that WNT1 is a major Wnt ligand regulating human bone homeostasis; however, the mechanistic basis of WNT1 action in bone homeostasis and its cellular source and targets in bone are unclear.…”

Wnt signaling and cellular metabolism in osteoblasts

“…Activation of Wnt signaling through deletion of Sfrp1, Sost or a single allele of Dkk1 increases osteoblast number and activity [61–63]. In addition, multiple Wnts including Wnt1, Wnt7b, Wnt10b and Wnt16 and the Frizzled receptors Fzd7 and Fzd9 have been shown to regulate bone formation [10, 11, 57, 64–66]. Moreover, targeted deletion of Gpr177 (also known as Wntless – Wls , required for the secretion of all Wnt ligands) inhibits bone formation in mice [67, 68].…”

New Genetic Forms of Childhood-Onset Primary Osteoporosis

“…A murine mouse model, the swaying mouse, was known to exhibit severe cerebellar defects, which in 1991 was shown to be due to a homozygous WNT1 mutation [31]. The swaying mouse was described in 1967, but it was only after the first reports on WNT1 osteoporosis that its skeletal phenotype was characterized and shown to display significant osteoporosis [32]. …”