Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects
Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects
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DOI：
10.1016/j.bone.2011.07.023
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发表时间：
2011-10-01
期刊：
影响因子：
4.1
通讯作者：
Komori, Toshihisa
中科院分区：
文献类型：
--
作者：
Maeno, Takafumi;Moriishi, Takeshi;Komori, Toshihisa
RUNX2是成骨细胞分化的重要转录因子，因为在Runx2缺陷的小鼠中，成骨细胞分化被完全阻断。然而，RUNX2是否足以在胚胎发生过程中促进成骨细胞分化仍有待澄清。为了解决这个问题，在 Prrx1 启动子的控制下产生了 Runx2 转基因小鼠，该启动子在骨发育开始之前将转基因表达引导至间充质细胞。在颅骨、肢芽以及从下颌骨到前胸壁的区域中检测到转基因表达。根据转基因表达的水平，头骨变小，四肢缩短。颅骨间充质中 Runx2 表达的早期开始在 E13.0 上诱导矿化，而在野生型小鼠中未观察到矿化，并导致颅缝早闭，如 E18.5 上缝线和囟门的闭合所示。在 E12.5-13.5 的矿化区域检测到 Col1a1 和 Spp1 表达。四肢骨发育不全、融合，手足形成异位骨。 E12.5 肢芽中 Col2a1 表达受到抑制，但 Col1a1 表达被诱导。在前胸壁，通过膜内骨化过程形成异位骨，中断胸骨柄软骨原基的形成。这些发现表明，RUNX2足以在胚胎发生过程中将间充质细胞引导至成骨细胞并导致膜内骨形成：Runx2在早期阶段抑制软骨细胞分化； Runx2 在胚胎发生过程中以适当的水平、时间和空间表达对于骨骼发育至关重要。 (C) 2011 Elsevier Inc. 保留所有权利。
RUNX2 is an essential transcription factor for osteoblast differentiation, because osteoblast differentiation is completely blocked in Runx2-deficient mice. However, it remains to be clarified whether RUNX2 is sufficient for osteoblast differentiation during embryogenesis. To address this issue, Runx2 transgenic mice were generated under the control of the Prrx1 promoter, which directs the transgene expression to mesenchymal cells before the onset of bone development. The transgene expression was detected in the cranium, limb buds, and the region from the mandible to anterior chest wall. The skull became small and the limbs were shortened depending on the levels of the transgene expression. Early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis as shown by the closure of sutures and fontanelles on E18.5. Col1a1 and Spp1 expressions were detected in the mineralized regions on E12.5-13.5. The limb bones were hypoplastic and fused, and ectopic bones were formed in the hands and feet. Col2a1 expression was inhibited but Col1a1 expression was induced in the limb buds on E12.5. In the anterior chest wall, ectopic bones were formed through the process of intramembranous ossification, interrupting the formation of cartilaginous anlagen of sternal manubrium. These findings indicate that RUNX2 is sufficient to direct mesenchymal cells to osteoblasts and lead to intramembranous bone formation during embryogenesis: Runx2 inhibits chondrocyte differentiation at an early stage; and that Runx2 expression at appropriate level, times and spaces during embryogenesis is essential for skeletal development. (C) 2011 Elsevier Inc. All rights reserved.