Inhibitory regulation of osteogenesis in sutures of mammalian skull

探讨颅缝形成和维持的分子机制。我们的研究表明，缝的形成和维持需要不同组织中不同分子的时空表达，在缝的形成过程中，需要一个基本的螺旋-环-螺旋型转录因子Twist 1，用于缝间充质细胞的增殖和调节发育中的颅骨周围的前成骨细胞的未分化状态。脑膜层调控颅骨的生长，我们发现骨形态发生蛋白信号在这一过程中发挥了一定的作用。成纤维细胞生长因子（FGF）受体优先在成骨细胞谱系中表达，增强的FGF信号传导是加速骨生成的原因，这导致缝线的不成熟融合。我们发现，应用不同的FGF浸泡珠引起不同的反应，胎鼠冠状缝，FGF浸泡珠诱导成骨标志物的表达，但诱导矿化取决于应用FGF。我们目前正试图用成纤维细胞生长因子信号下游分子的组合来解释这种差异。牙周韧带也保持成纤维细胞的条件，以响应咬合力。牙周膜的形成与牙根的形成密切相关。因此，我们研究了牙根的形成。我们发现，音刺猬信号是所需的根伸长，但它不调节牙周膜的形成。相反，FGF信号似乎参与韧带形成以及根形成。将FGF珠应用于移植在肾囊中的冠形成的牙芽上也显示出对根形成的不同结果，这取决于使用哪种FGF。基于这些观察结果，我们计划调查的功能，成纤维细胞生长因子信号在牙周组织的形成，包括牙齿。

Molecular mechanism of formation and maintenance of calvarial sutures was investigated. Our study suggests that spatio- temporal expression of various molecules in different tissues is required for suture formation and suture maintenance.During suture formation, a basic helix-loop-helix type transcription factor, Twist 1, is required for cell proliferation of sutural mesenchyme and regulation of undifferentiated condition of preosteoblast at the periphery of the developing skull bone. Meningeal layer regulates the growth of the overlying calvarial bone and we found that bone morphogenetic protein signals play partly in this process. Fibroblast growth factor (FGF) receptors are preferentially expressed in osteoblast cell lineage and enhanced FGF signaling is responsible for acceleration of osteogenesis, which leads to immature fusion of the suture. We found that application of different FGF-soaked beads cause different reaction in fetal mouse coronal suture, FGF-soaked beads induced expression of osteogenic markers but induction of mineralization depends on which FGF was applied. We are now currently trying to explain this difference using combination of downstream molecules of Fgf signaling.Periodontal ligament also maintains fibroblastic condition in response to occlusal force. Formation of the periodontal ligament is closely associated with tooth root formation. We have therefore investigated tooth root formation. We found that sonic hedgehog signaling is required for root elongation but it does not regulate the formation of the periodontal ligament. In contrast, Fgf signaling appears to be involved in ligament formation as well as root formation. FGF beads application onto the crown formed tooth buds grafted in kidney capsule also showed different consequence on root formation depends on which FGF was used. Based on these observations we plan to investigate functions of Fgf signaling in periodontal tissue formation including teeth.