The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations
The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations
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DOI：
10.1093/hmg/ddu117
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发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Lee, Brendan H.
中科院分区：
文献类型：
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作者：
Joeng, Kyu Sang;Lee, Yi-Chien;Lee, Brendan H.
成骨不全症（OI）是一种遗传性结缔组织疾病，以骨脆性和低骨量为特征。最近，我们和其他人报道了WNT1隐性突变导致OI，而WNT1杂合突变导致早发性骨质疏松症。这些发现支持了WNT1是调节骨形成和骨稳态的重要WNT配体的假设。虽然这些研究提供了强有力的人类遗传和体外功能数据，但缺乏研究WNT1在骨中的功能机制的体内动物模型。在这里，我们发现先前报道的携带Wnt1自发突变的摇曳（Wnt1(sw/sw)）小鼠具有成骨不全的主要特征，包括骨折倾向和严重的骨质减少。此外，生物力学和生化分析表明，Wnt1（sw/sw）小鼠表现出骨强度降低，骨基质中矿物质和胶原蛋白水平改变，这也与I型胶原相关的成骨不全不同。进一步的组织形态学分析和基因表达研究表明，骨表型与成骨细胞活性和功能缺陷有关。因此，我们的研究提供了体内证据，证明WNT1突变有助于成骨不全患者的骨脆性，并证明WNT1 （sw/sw）小鼠是由WNT1突变引起的成骨不全的小鼠模型。
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.