Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan; Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan.
Bone. 2021 Aug;149:115969. doi: 10.1016/j.bone.2021.115969. Epub 2021 Apr 21.
During tooth movement in orthodontic treatment, bone formation and resorption occur on the tension and compression sides of the alveolar bone, respectively. Although the bone formation activity increases in the periodontal ligament (PDL) on the tension side, the PDL itself is not ossified and maintains its homeostasis, indicating that there are negative regulators of bone formation in the PDL. Our previous report suggested that scleraxis (Scx) has an inhibitory effect on ossification of the PDL on the tension side through the suppression of calcified extracellular matrix formation. However, the molecular biological mechanisms of Scx-modulated inhibition of ossification in the tensioned PDL are not fully understood. The aim of the present study is to clarify the inhibitory role of Scx in osteoblast differentiation of PDL cells and its underlying mechanism. Our in vivo experiment using a mouse experimental tooth movement model showed that Scx expression was increased during early response of the PDL to tensile force. Scx knockdown upregulated expression of alkaline phosphatase, an early osteoblast differentiation marker, in the tensile force-loaded PDL cells in vitro. Transforming growth factor (TGF)-β1-Smad3 signaling in the PDL was activated by tensile force and inhibitors of TGF-β receptor and Smad3 suppressed the tensile force-induced Scx expression in PDL cells. Tensile force induced ephrin A2 (Efna2) expression in the PDL and Efna2 knockdown upregulated alkaline phosphatase expression in PDL cells under tensile force loading. Scx knockdown eliminated the tensile force-induced Efna2 expression in PDL cells. These findings suggest that the TGF-β1-Scx-Efna2 axis is a novel molecular mechanism that negatively regulates the tensile force-induced osteoblast differentiation of PDL cells.
在正畸治疗中牙齿移动时，牙槽骨的张力和压缩侧分别发生骨形成和骨吸收。尽管张力侧牙周韧带（PDL）中的骨形成活性增加，但 PDL 本身不会骨化并保持其体内平衡，这表明 PDL 中有骨形成的负调节剂。我们之前的报告表明，粘连蛋白（Scx）通过抑制钙化细胞外基质的形成，对张力侧 PDL 的骨化具有抑制作用。然而，Scx 调节张力侧 PDL 成骨抑制的分子生物学机制尚不完全清楚。本研究旨在阐明 Scx 在 PDL 细胞成骨分化中的抑制作用及其潜在机制。我们使用小鼠实验性牙齿移动模型的体内实验表明，Scx 表达在 PDL 对张力的早期反应中增加。Scx 敲低可上调体外受力 PDL 细胞中碱性磷酸酶的表达，碱性磷酸酶是成骨细胞分化的早期标志物。TGF-β1-Smad3 信号通路在 PDL 中被张力激活，TGF-β 受体和 Smad3 的抑制剂可抑制 PDL 细胞中张力诱导的 Scx 表达。张力诱导 PDL 中的 Ephrin A2（Efna2）表达，Efna2 敲低可上调受力 PDL 细胞中碱性磷酸酶的表达。Scx 敲低消除了 PDL 细胞中张力诱导的 Efna2 表达。这些发现表明，TGF-β1-Scx-Efna2 轴是一种负调节 PDL 细胞张力诱导成骨分化的新分子机制。
