Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone‐Specific Phenotype
Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone‐Specific Phenotype
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DOI：
10.1002/jbmr.4043
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发表时间：
2020-05
影响因子：
6.2
通讯作者：
T. Yorgan;T. Rolvien;J. Stürznickel;Nele Vollersen;Fabiola Lange;Wenbo Zhao;A. Baranowsky;Lana Rosenthal;I. Hermans-Borgmeyer;A. Sharaf;Meliha Karsak;J. David;R. Oheim;M. Amling;T. Schinke
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作者：
T. Yorgan;T. Rolvien;J. Stürznickel;Nele Vollersen;Fabiola Lange;Wenbo Zhao;A. Baranowsky;Lana Rosenthal;I. Hermans-Borgmeyer;A. Sharaf;Meliha Karsak;J. David;R. Oheim;M. Amling;T. Schinke
由于Wnt 1在大脑发育中的关键功能是通过产生非存活的Wnt 1缺陷小鼠早期建立的，因此最初令人惊讶的是，WNT 1突变被发现会导致早发性骨质疏松症（EOOP）或成骨不全XV型（OI-XV）。Wnt 1作为骨合成代谢因子的推断功能已在各种骨特异性失活或过表达的小鼠模型中得到证实，但携带致病Wnt 1突变的小鼠尚未被描述。通过对携带杂合WNT 1突变（p.R235W）的EOOP患者的临床分析，我们将这种突变引入小鼠Wnt 1基因，以解决这是否会导致骨骼表型的问题。我们观察到Wnt 1 +/R235 W和Wnt 1 R235 W/R235 W小鼠以预期的孟德尔比率出生，并且它们没有显示出出生后致死性或明显的非骨骼表型。在12周龄时，Wnt 1突变的纯合子存在与骨小梁和皮质骨量减少相关，这可以通过与野生型同窝仔相比骨形成率较低来解释。在52周龄时，我们还观察到杂合Wnt 1 +/R235 W小鼠的骨量中度减少，从而强调了它们作为WNT 1依赖性EOOP模型的价值。重要的是，当我们通过每天注射甲状旁腺激素（PTH）治疗野生型和Wnt 1 +/R235 W小鼠时，我们在两组中检测到相同的骨合成代谢影响，以及突变小鼠皮质厚度的增加。我们的数据证明了WNT 1-R235 W突变的致病性，证实了控制骨骼完整性是Wnt 1的主要生理功能，并表明特立帕肽的骨合成代谢治疗应适用于WNT 1依赖性EOOP患者。© 2020美国骨与矿物质研究学会。
Since a key function of Wnt1 in brain development was established early on through the generation of non‐viable Wnt1‐deficient mice, it was initially surprising that WNT1 mutations were found to cause either early‐onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI‐XV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mouse models with bone‐specific inactivation or overexpression, but mice carrying disease‐causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced this mutation into the murine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1+/R235W and Wnt1R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild‐type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1+/R235W mice, thereby underscoring their value as a model of WNT1‐dependent EOOP. Importantly, when we treated wild‐type and Wnt1+/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased cortical thickness in the mutant mice. Our data demonstrate the pathogenicity of the WNT1‐R235W mutation, confirm that controlling skeletal integrity is the primary physiological function of Wnt1, and suggest that osteoanabolic treatment with teriparatide should be applicable for individuals with WNT1‐dependent EOOP. © 2020 American Society for Bone and Mineral Research.