The Hippo Pathway Effectors YAP/TAZ Are Essential for Mineralized Tissue Homeostasis in the Alveolar Bone/Periodontal Complex.
The Hippo Pathway Effectors YAP/TAZ Are Essential for Mineralized Tissue Homeostasis in the Alveolar Bone/Periodontal Complex.
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DOI：
10.3390/jdb10010014
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发表时间：
2022-03-01
影响因子：
2.7
通讯作者：
Diekwisch TGH
中科院分区：
文献类型：
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作者：
Pandya M;Gopinathan G;Tillberg C;Wang J;Luan X;Diekwisch TGH
YAP 和 TAZ 是 Hippo 通路的重要转录共激活因子和下游效应子，调节细胞增殖、器官生长和组织稳态。为了探究 Hippo 通路如何影响高度依赖于矿化沉积和吸收的严格稳态控制的组织中的矿化组织稳态，我们确定了 YAP/TAZ 失调对牙周组织牙槽骨、牙根牙骨质和牙周膜的影响。 YAP/TAZ 的缺失与牙骨质和牙槽骨中矿化组织密度的降低、I 型胶原蛋白、碱性磷酸酶和 RUNX2 基因表达的下调、吸收标记物 TRAP 和组织蛋白酶 K 的增加以及 TRAP 染色的破骨细胞数量的增加有关。对牙周膜细胞施加循环应变导致 YAP 核定位，这种效应在阻断 YAP 后被消除。硫酸乙酰肝素蛋白聚糖集聚蛋白对 YAP 信号的拯救导致核 YAP 信号的恢复。细胞外基质 YAP 激活剂集聚蛋白逆转了 YAP 抑制相关的矿化相关基因的下调，这说明了 YAP 对矿化基因表达的关键作用。应用无对抗的小鼠磨牙模型将牙周膜转变为无负载状态并促进牙齿的远端漂移，导致矿化相关基因表达总体增加，而在 Wnt1Cre/YAP/TAZ 突变小鼠中，这种效应减少了 10-20%。 Wnt1Cre/YAP/TAZ突变小鼠中无对抗磨牙模型的无负荷状态也导致破骨细胞数量显着增加三倍，骨/牙骨质吸收显着增加，牙周膜透明化明显，牙周纤维束增厚。总之，这些数据表明，YAP/TAZ 信号传导通过调节矿化基因表达并防止牙槽复合体身体运动过程中的过度吸收，对于牙周组织微结构的完整性至关重要。
YAP and TAZ are essential transcriptional co-activators and downstream effectors of the Hippo pathway, regulating cell proliferation, organ growth, and tissue homeostasis. To ask how the Hippo pathway affects mineralized tissue homeostasis in a tissue that is highly reliant on a tight homeostatic control of mineralized deposition and resorption, we determined the effects of YAP/TAZ dysregulation on the periodontal tissues alveolar bone, root cementum, and periodontal ligament. Loss of YAP/TAZ was associated with a reduction of mineralized tissue density in cellular cementum and alveolar bone, a downregulation in collagen I, alkaline phosphatase, and RUNX2 gene expression, an increase in the resorption markers TRAP and cathepsin K, and elevated numbers of TRAP-stained osteoclasts. Cyclic strain applied to periodontal ligament cells resulted in YAP nuclear localization, an effect that was abolished after blocking YAP. The rescue of YAP signaling with the heparan sulfate proteoglycan agrin resulted in a return of the nuclear YAP signal. Illustrating the key role of YAP on mineralization gene expression, the YAP inhibition-related downregulation of mineralization-associated genes was reversed by the extracellular matrix YAP activator agrin. Application of the unopposed mouse molar model to transform the periodontal ligament into an unloaded state and facilitate the distal drift of teeth resulted in an overall increase in mineralization-associated gene expression, an effect that was 10–20% diminished in Wnt1Cre/YAP/TAZ mutant mice. The unloaded state of the unopposed molar model in Wnt1Cre/YAP/TAZ mutant mice also caused a significant three-fold increase in osteoclast numbers, a substantial increase in bone/cementum resorption, pronounced periodontal ligament hyalinization, and thickened periodontal fiber bundles. Together, these data demonstrated that YAP/TAZ signaling is essential for the microarchitectural integrity of the periodontium by regulating mineralization gene expression and preventing excessive resorption during bodily movement of the dentoalveolar complex.