Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2 S252W /+ ) mouse model
Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2 S252W /+ ) mouse model
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异常激活的 Wnt/β-连环蛋白通路共受体 LRP5 和 LRP6 调节阿佩尔综合征小鼠模型冠状缝中的成骨细胞分化 (Fgfr2 S252W /+ )
DOI：
10.1002/dvdy.239
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Keiji Moriyama.
中科院分区：
文献类型：
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作者：
Nay Myo Min Swe;Yukiho Kobayashi;Hiroyuki Kamimoto;Keiji Moriyama.
背景Apert 综合征是一种常染色体显性遗传性疾病，其特征是颅缝早闭和并指，由成纤维细胞生长因子受体 2 (FGFR2) 基因功能获得性突变引起。 Wnt/β-连环蛋白信号在调节骨骼发育中发挥着关键作用。在这里，我们分析了该通路在小鼠阿佩尔综合征模型（Fgfr2S252W/+）冠状缝（CS）发育中的作用。结果我们观察到 Fgfr2S252W/+ 小鼠 CS 中 Lrp5 和 Lrp6 mRNA 表达异常增加，而野生型（WT）和 Fgfr2S252W/+ 小鼠显示其他 Wnt/β-catenin 相关基因的相似表达。如原位杂交证明的Wnt3、Wnt3a、Fzd4、Fzd6、Axin2和Dkk1。通过对从Fgfr2S252W/+小鼠的CS分离的培养细胞进行定量PCR分析，观察到Lrp5和Lrp6mRNA表达显着增加。与 WT CS 相比，Fgfr2S252W/+CS 中磷酸-LRP5、磷酸-LRP6 和非磷酸-β-连环蛋白表达上调。靶向Lrp5和Lrp6的短干扰RNA显着降低培养细胞中runt相关转录因子2、1型胶原α1和骨钙素mRNA表达以及碱性磷酸酶活性。结论Fgfr2S252W/+小鼠CS在颅面发育过程中Wnt/β-catenin通路被激活，提示Wnt/β-catenin通路参与CS的发病机制Fgfr2S252W/+小鼠中的骨连接。
BackgroundApert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain‐of‐function mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Wnt/β‐catenin signaling plays critical roles in regulating the skeletal development. Here, we analyzed the role of this pathway in the developing coronal sutures (CS) of a murine Apert syndrome model (Fgfr2S252W/+).ResultsWe observed aberrantly increased mRNA expression ofLrp5andLrp6in CS ofFgfr2S252W/+mice, whereas both wild type (WT) andFgfr2S252W/+mice showed similar expression of other Wnt/β‐catenin‐related genes, such asWnt3,Wnt3a,Fzd4,Fzd6,Axin2, andDkk1as evidenced by in situ hybridization. Significantly increasedLrp5andLrp6mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS ofFgfr2S252W/+mice. Phospho‐LRP5, phospho‐LRP6, and non‐phospho‐β‐catenin were upregulated inFgfr2S252W/+CS compared with that in WT CS. Short‐interfering RNA targetingLrp5andLrp6significantly reduced runt‐related transcription factor 2, collagen type 1 alpha 1, and osteocalcin mRNA expression, and alkaline phosphatase activity in cultured cells.ConclusionsThe Wnt/β‐catenin pathway was activated in the CS ofFgfr2S252W/+mice during craniofacial development, suggesting the involvement of the Wnt/β‐catenin pathway in the pathogenesis of CS synostosis inFgfr2S252W/+mice.