Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells
Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells
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DOI：
10.1093/hmg/ddy386
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发表时间：
2019-03-15
影响因子：
3.5
通讯作者：
Komori, Toshihisa
中科院分区：
文献类型：
--
作者：
Qin, Xin;Jiang, Qing;Komori, Toshihisa
锁骨颅骨发育不良（CCD，#119600），其特征在于发育不全的锁骨，开放的<$门，多生牙和身材矮小，是由RUNX 2杂合突变引起的。然而，目前尚不清楚CCD患者缝线闭合严重受损的原因。Runx 2（+/-）小鼠后额叶（PF）缝和矢状缝（SAG）的闭合完全中断，缝间充质细胞的增殖及其凝聚程度低于野生型小鼠。为了阐明潜在的分子机制，通过微阵列和实时逆转录聚合酶链反应分析鉴定了野生型和Runx 2（+/-）PF和SAG缝线之间的差异表达基因。Runx 2直接调控的hedgehog、Fgf、Wnt和Pthlh信号通路基因Gli 1、Ptch 1、Ihh、Fgfr 2、Fgfr 3、Tcf 7、Wnt 101 b和Pth 1 r在骨缝中的表达降低，但在Runx 2（+/-）小鼠颅骨组织中的表达没有降低。在具有hedgehog、Fgf、Wnt和Pthlh信号传导的配体或激动剂的Runx 2（+/-）颅骨的器官培养物中，骨形成和缝合闭合得到增强，而在具有其拮抗剂的野生型颅骨的器官培养物中，它们受到抑制并且缝合间充质细胞增殖降低。这些结果表明，缝线间充质细胞的增殖、它们的凝聚和向成骨细胞系细胞的定型以及缝线中hedgehog、Fgf、Wnt和Pthlh信号通路基因表达的诱导需要超过一半剂量的Runx 2，但颅骨组织中不需要，并且hedgehog、Fgf、Wnt和Pthlh信号通路的激活对于缝线闭合是必要的。
Cleidocranial dysplasia (CCD, #119600), which is characterized by hypoplastic clavicles, open fontanelles, supernumerary teeth and a short stature, is caused by heterozygous mutations in RUNX2. However, it currently remains unclear why suture closure is severely impaired in CCD patients. The closure of posterior frontal (PF) and sagittal (SAG) sutures was completely interrupted in Runx2(+/-) mice, and the proliferation of suture mesenchymal cells and their condensation were less than those in wild-type mice. To elucidate the underlying molecular mechanisms, differentially expressed genes between wild-type and Runx2(+/-) PF and SAG sutures were identified by microarray and real-time reverse transcription polymerase chain reaction analyses. The expression of hedgehog, Fgf, Wnt and Pthlh signaling pathway genes, including Gli1, Ptch1, Ihh, Fgfr2, Fgfr3, Tcf7, Wnt101b and Pth1r, which were directly regulated by Runx2, was reduced in the sutures, but not the calvarial bone tissues of Runx2(+/-) mice. Bone formation and suture closure were enhanced in an organ culture of Runx2(+/-) calvariae with ligands or agonists of hedgehog, Fgf, Wnt and Pthlh signaling, while they were suppressed and suture mesenchymal cell proliferation was decreased in an organ culture of wild-type calvariae with their antagonists. These results indicate that more than a half dosage of Runx2 is required for the proliferation of suture mesenchymal cells, their condensation and commitment to osteoblast-lineage cells, and the induction of hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in sutures, but not in calvarial bone tissues, and also that the activation of hedgehog, Fgf, Wnt and Pthlh signaling pathways is necessary for suture closure.