Molecular Basis for Craniofacial Phenotypes Caused by Sclerostin Deletion
Molecular Basis for Craniofacial Phenotypes Caused by Sclerostin Deletion
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硬化蛋白缺失引起的颅面表型的分子基础
DOI：
10.1177/0022034520963584
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发表时间：
2020-10
影响因子：
7.6
通讯作者：
Helms J. A.
中科院分区：
文献类型：
--
作者：
Chen J.;Yuan X.;Pilawski I.;Liu X.;Delgado-Calle J.;Bellido T.;Turkkahraman H.;Helms J. A.
一些遗传性疾病与独特的面部特征有关，这有助于诊断。虽然在确定致病基因方面取得了相当大的进展，但在理解特定基因型如何导致特征性颅面表型方面取得的进展相对较少。一个例子是硬化症/货车Buchem病，其由Wnt抑制剂硬化素（SOST）的突变引起。受影响的患者有一个高骨量加上一个独特的外观，其中下颌骨扩大和上颌骨缩短。在这里，使用定量微计算机断层扫描（µCT）成像和组织形态学分析来分析携带Sost无效突变的小鼠，以确定颅面骨骼的大小和形状改变的程度。Sost−/−小鼠表现出显著的附着骨生长增加，这增加了下颌骨的高度和宽度，并减少了孔的直径。在体内荧光标记，组织学和免疫组化分析表明，过度的骨沉积在前上颌骨缝间充质削减整体增长，导致面中部发育不全。由Sost−/−细胞产生的骨细胞外基质的量显著增加;因此，整个面部骨骼中的类骨质接缝明显。总的来说，这些分析揭示了人类骨质疏松症/货车Buchem病特征与Sost−/−表型之间的显著保真度，并为sclerostin信号转导在调节颅面形态中的保守作用提供了线索。
Some genetic disorders are associated with distinctive facial features, which can aid in diagnosis. While considerable advances have been made in identifying causal genes, relatively little progress has been made toward understanding how a particular genotype results in a characteristic craniofacial phenotype. An example is sclerosteosis/van Buchem disease, which is caused by mutations in the Wnt inhibitor sclerostin (SOST). Affected patients have a high bone mass coupled with a distinctive appearance where the mandible is enlarged and the maxilla is foreshortened. Here, mice carrying a null mutation in Sost were analyzed using quantitative micro–computed tomographic (µCT) imaging and histomorphometric analyses to determine the extent to which the size and shape of craniofacial skeleton were altered. Sost−/− mice exhibited a significant increase in appositional bone growth, which increased the height and width of the mandible and reduced the diameters of foramina. In vivo fluorochrome labeling, histology, and immunohistochemical analyses indicated that excessive bone deposition in the premaxillary suture mesenchyme curtailed overall growth, leading to midfacial hypoplasia. The amount of bone extracellular matrix produced by Sost−/− cells was significantly increased; as a consequence, osteoid seams were evident throughout the facial skeleton. Collectively, these analyses revealed a remarkable fidelity between human characteristics of sclerosteosis/van Buchem disease and the Sost−/− phenotype and provide clues into the conserved role for sclerostin signaling in modulating craniofacial morphology.
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作者：
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通讯作者：
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