The Lrp4 R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans
The Lrp4 R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans
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DOI：
10.1002/jbmr.3160
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发表时间：
2017-08-01
影响因子：
6.2
通讯作者：
Van Hul, Wim
中科院分区：
文献类型：
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作者：
Boudin, Eveline;Yorgan, Timur;Van Hul, Wim
硬化症是一种罕见的常染色体隐性遗传性骨病，以颅骨和管状骨的骨质增生为特征。最初，我们和其他人报道了骨质疏松症是由编码硬化素的SOST的功能缺失突变引起的。最近，我们在三名骨质疏松症患者中发现了LRP 4（硬化素的结合伴侣）的致病突变。在与硬化蛋白结合后，LRP 4可以抑制典型的WNT信号传导，该信号传导已知是骨形成调节中的重要途径。为了进一步研究LRP 4在骨形成过程中的作用，我们通过在小鼠基因组中引入p.Arg1170Gln突变来产生LRP 4突变的骨质疏松症小鼠模型。对Lrp 4 R1170 Q/R1170 Q基因敲入（KI）小鼠的骨表型的广泛分析显示，由于成骨细胞增加的骨形成，存在增加的小梁和皮质骨质量。此外，三点弯曲分析还表明，骨量增加导致骨强度增加。与人硬化性骨病表型相反，我们在Lrp 4 KI动物的前肢或后肢中未观察到并指畸形。最后，我们在突变小鼠的血清中未检测到骨形成和骨吸收标志物的任何显著变化。然而，在Lrp 4 R1170 Q/R1170 Q小鼠中，血清sclerostin水平强烈增加，胫骨中sclerostin水平降低，证实了LRP 4作为骨中sclerostin的锚的作用。总之，Lrp 4 R1170 Q/R1170 Q小鼠是由LRP 4突变引起的人类骨质疏松症表型的良好模型，并且可以在将来用于进一步研究LRP 4调节骨形成的机制。c 2017年美国骨与矿物质研究学会。
Sclerosteosis is a rare autosomal recessive bone disorder marked by hyperostosis of the skull and tubular bones. Initially, we and others reported that sclerosteosis was caused by loss-of-function mutations in SOST, encoding sclerostin. More recently, we identified disease-causing mutations in LRP4, a binding partner of sclerostin, in three sclerosteosis patients. Upon binding to sclerostin, LRP4 can inhibit the canonical WNT signaling that is known to be an important pathway in the regulation of bone formation. To further investigate the role of LRP4 in the bone formation process, we generated an Lrp4 mutated sclerosteosis mouse model by introducing the p. Arg1170Gln mutation in the mouse genome. Extensive analysis of the bone phenotype of the Lrp4R1170Q/R1170Q knock-in (KI) mouse showed the presence of increased trabecular and cortical bone mass as a consequence of increased bone formation by the osteoblasts. In addition, three-point bending analysis also showed that the increased bone mass results in increased bone strength. In contrast to the human sclerosteosis phenotype, we could not observe syndactyly in the forelimbs or hindlimbs of the Lrp4 KI animals. Finally, we could not detect any significant changes in the bone formation and resorption markers in the serum of the mutant mice. However, the serum sclerostin levels were strongly increased and the level of sclerostin in the tibia was decreased in Lrp4R1170Q/R1170Q mice, confirming the role of LRP4 as an anchor for sclerostin in bone. In conclusion, the Lrp4R1170Q/R1170Q mouse is a good model for the human sclerosteosis phenotype caused by mutations in LRP4 and can be used in the future for further investigation of the mechanism whereby LRP4 regulates bone formation. c 2017 American Society for Bone and Mineral Research.