CN117482239B - Yap通路干预剂在制备抑制牙根吸收的药物中的应用 - Google Patents
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Abstract
本发明涉及牙根吸收治疗药物技术领域，具体为一种YAP通路干预剂在制备抑制牙根吸收的药物中的应用。其中，YAP通路干预剂包括YAP通路抑制剂，所述YAP通路抑制剂选自维替泊芬和/或YAP‑TEAD Inhibitor 1。本发明通过建立动物力学引起牙根吸收模型发现YAP通路抑制剂可明显抑制牙根吸收，通过组织学染色发现YAP通路抑制剂可抑制牙骨质表面的TRAP阳性破骨细胞/破牙骨质细胞，并且可以调控巨噬细胞的破骨向分化。本发明为制备正畸治疗引起牙根吸收的治疗药物提供了技术支持，也为破骨细胞相关疾病的治疗提供了技术支持。
Description
技术领域
本发明涉及牙根吸收治疗药物技术领域，特别是涉及一种YAP通路干预剂在制备抑制牙根吸收的药物中的应用。
背景技术
牙根吸收是牙本质、牙骨质和牙髓组织受损的生理或病理过程。表现为牙根逐渐缩小、萎缩、吸收。牙根吸收分为正常的生理性牙根吸收和病理性牙根吸收。生理性牙根吸收常见于儿童的换牙；病理性牙根吸收则常常见于细菌感染、物理或化学刺激。牙根吸收危害很大，会造成牙齿疼痛、咀嚼无力等问题，严重的牙根吸收甚至可以导致牙齿脱落。
错颌畸形是指牙齿、颌骨、颅面的畸形，影响人们的口腔健康及颜面部的美观，需要进行正畸治疗。正畸治疗的基础是适当的机械力引起的牙周膜和牙槽骨改建，然而长期过重的力学刺激可能会造成一些正畸患者出现牙根吸收，且正畸重力去除后牙根也难以修复，是正畸治疗的常见并发症。如何治疗正畸治疗中的牙根吸收意义重大，目前研究发现治疗牙根吸收的方式主要分为激光治疗、超声治疗、干细胞治疗、基因治疗等，但在由于其操作复杂，尚未进行临床应用。因此如何高效、无创治疗重力引起的牙根吸收是本领域亟待解决的问题之一。
发明内容
本发明要解决的技术问题是提供一种YAP通路干预剂在制备抑制牙根吸收的药物中的应用。
为了解决上述技术问题，本申请提供了如下技术方案：
YAP通路干预剂或含有YAP通路干预剂的组合物在制备抑制牙根吸收的药物中的应用。
其中，所述YAP通路干预剂包括YAP通路抑制剂。
进一步的，所述YAP通路抑制剂选自维替泊芬（Verteporfin）和/或YAP-TEADInhibitor 1。
进一步的，所述牙根吸收为力学引起的牙根吸收。
进一步的，所述牙根吸收为正畸重力引起的牙根吸收。
进一步的，所述YAP通路干预剂作用于破骨前体细胞的巨噬细胞上，能够直接影响破骨细胞/破牙骨质细胞形成和破骨相关因子表达。
本发明还提供了YAP通路干预剂或含有YAP通路干预剂的组合物在制备破骨细胞相关疾病的药物中的应用，所述YAP通路干预剂包括YAP通路抑制剂，所述YAP通路抑制剂选自维替泊芬和/或YAP-TEAD Inhibitor 1。
与现有技术相比，本发明的YAP通路干预剂在制备抑制牙根吸收的药物中的应用至少具有以下有益效果：
本发明发现YAP通路高度参与急性炎症环境并能促进牙根吸收，YAP通路抑制剂维替泊芬（Verteporfin）被证明可抑制牙骨质表面TRAP阳性破骨细胞/破牙骨质细胞的激活，这显示维替泊芬（Verteporfin）可抑制正畸牙根吸收。
本发明提供了YAP通路干预剂在制备抑制牙根吸收药物中的应用，尤其是YAP通路抑制剂在抑制力学引起的牙根吸收的应用，本发明通过体内研究发现YAP通路抑制剂可减少牙骨质表面TRAP阳性破骨细胞/破牙骨质细胞数量，从而抑制力学引起的牙根吸收。
下面结合附图对本发明的YAP通路干预剂在制备抑制牙根吸收的药物中的应用作进一步说明。
附图说明
图1为轻力和重力分别作用牙根7、14天后的牙根情况。通过研究观察第一磨牙远中根的近中侧牙根吸收情况，发现重力14天后可见明显牙根吸收陷窝且TRAP阳性破骨细胞/破牙骨质细胞数量增加，说明重力作用14天的模型是理想的牙根吸收模型。
图2为轻力和重力分别作用牙根7、14天后压力侧牙周膜中巨噬细胞的YAP表达。与轻力组相比，重力作用后可见YAP入核，且14天后YAP入核明显，这提示YAP表达与牙根吸收严重程度成正相关。其中，CD68为巨噬细胞标志物，DAPI为4',6-二脒基-2-苯基吲哚。
图3为体外对巨噬细胞RAW264.7加不同力值的静压力后YAP表达情况，发现力值越大YAP表达水平越高。
图4为YAP通路干预剂对力学引起牙根吸收的影响。YAP通路抑制剂维替泊芬（Verteporfin）会减少牙根吸收面积，减少TRAP阳性破骨细胞/破牙骨质细胞数量。
图5为YAP通路干预剂对力学引起牙根吸收牙周膜中巨噬细胞破骨向分化的影响。YAP通路抑制剂YAP-TEAD Inhibitor 1会抑制牙周膜中巨噬细胞破骨向分化，抑制ROS产生。
具体实施方式
实施例1
为了验证力学对牙根吸收的影响，通过建立小鼠力学引起牙根吸收模型进行验证。
实验组中将弹簧绑于小鼠右侧切牙和第一磨牙之间，使弹簧力量为25g和45g。此模型作用是对小鼠第一磨牙产生向前的拉力使第一磨牙向前移动。加力7天、14天后取小鼠颌骨进行固定，后进行micro-CT扫描。扫描后用mimics软件对牙根部分进行抠取，并画出牙根吸收区域。
TRAP染色实验方法为：将小鼠牙槽骨用石蜡包埋、切片，用二甲苯及梯度酒精进行脱蜡后用TRAP固定液固定，用索莱宝TRAP孵育液浸染60分钟，甲基绿复染，封片。
结果显示：对小鼠第一磨牙施加重力会造成明显的牙根吸收，轻力则未见明显牙根吸收；重力作用14天的牙根吸收程度高于加力7天，加力7天后可见牙根吸收区域附近TRAP阳性破骨细胞/破牙骨质细胞出现，而14天后牙根吸收区域附近破骨细胞/破牙骨质细胞数量明显增加，见图1。
结论：
重力刺激会造成小鼠牙根吸收，且牙根吸收区域TRAP阳性破骨细胞/破牙骨质细胞数量增加。
实施例2
为了验证牙根吸收过程中YAP通路水平的变化，对小鼠牙槽骨进行组织切片免疫荧光染色。
收集固定好的小鼠牙槽骨，对其进行EDTA脱钙处理14天，每天换新的脱钙液。脱钙后将牙槽骨进行15%蔗糖处理6小时，30%蔗糖处理过夜，并用OCT包埋剂对其进行冰冻包埋和冷冻切片。切好的片用水冲洗OCT包埋剂，滴加3%过氧化氢后用胎牛血清进行封闭，一抗YAP和CD68孵育4℃过夜。第二天加入荧光二抗室温孵育30分钟，DAPI封片剂封片。共聚焦显微镜对组织进行观察和拍摄。
结果显示：重力会造成小鼠牙根吸收区域巨噬细胞YAP通路水平增加，且加力14天的YAP通路水平明显高于加力7天，见图2。
结论：
重力会造成小鼠牙根吸收区域牙周膜中YAP通路水平增加。
实施例3
为了验证YAP通路抑制剂维替泊芬抑制牙根吸收，通过建立小鼠力学引起牙根吸收模型进行验证。
实验组中将弹簧绑于小鼠右侧切牙和第一磨牙之间，使弹簧力量为45g。分别对小鼠牙周组织隔天进行注射0.9% NaCl，5 mg/kg维替泊芬，14天后取小鼠颌骨进行固定，后进行micro-CT扫描。TRAP染色方法同实施例1。
结果显示：
YAP通路抑制剂维替泊芬可明显减少牙根吸收体积，并减少牙根吸收陷窝附近破骨细胞/破牙骨质细胞数量，见图4。
结论：
YAP通路抑制剂可减少力学引起的牙根吸收及破骨细胞/破牙骨质细胞数量。
实施例4
聚焦力学引起牙根吸收中发挥重要的细胞——巨噬细胞，探究力学对巨噬细胞中YAP表达的变化，对巨噬细胞进行体外加力，后观察其骨架变化、ROS水平变化及YAP表达变化。
将小鼠巨噬细胞RAW264.7培养至六孔板中，贴壁加入静压力装置（玻璃片铺在细胞上，上方放置EP管盖子，盖子中装入不同质量的钢珠），24小时后进行荧光检测。
ROS检测：用PBS洗细胞3次后加入荧光探针DCFH-DA，在共聚焦显微镜下拍摄，绿色荧光代表ROS。细胞骨架染色：PBS洗细胞3次后加入细胞固定液固定细胞，加入triton-100破细胞膜，加入FITC标记鬼笔环肽孵育细胞，后清洗细胞并用含DAPI的封片剂对细胞进行封片，在共聚焦显微镜下拍摄。
YAP检测：PBS洗细胞3次后加入细胞固定液固定细胞，加入triton-100破细胞膜，用5%BSA封闭细胞后加入YAP一抗过夜孵育，第二天清洗一抗后加入荧光二抗，清洗后用含DAPI的封片剂对细胞进行封片，在共聚焦显微镜下拍摄。
结果显示：
对RAW264.7给予梯度静压力后，随着力值的增加细胞ROS表达增加，细胞形态从圆形变成长梭形，YAP入核的细胞数量逐渐增加，见图3。
结论：
重力容易激活YAP通路，伴随ROS表达增加，细胞形态从圆形变成长梭形。
实施例5
为了验证YAP通路抑制剂YAP-TEAD Inhibitor 1对巨噬细胞破骨向分化的影响，对RAW264.7进行体外加力，加入 YAP通路抑制剂YAP-TEAD Inhibitor 1后观察破骨细胞/破牙骨质细胞数量变化。
加力方法同实施例4，破骨细胞/破牙骨质细胞诱导：将RAW264.7培养至十二孔板中，贴壁加入静压力装置24小时，后进行破骨诱导。加入100ug/L RANKL，隔天换液，8天后固定细胞，进行TRAP染色，显微镜下观察并拍摄。
结果显示：
YAP通路抑制剂YAP-TEAD Inhibitor 1可减少ROS表达，且抑制YAP后RAW264.7 经8天破骨诱导，破骨细胞/破牙骨质细胞数量明显低于单纯加力组，见图5。
结论：
YAP通路抑制剂可抑制RAW264.7向破骨向分化。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (1)
1.YAP通路抑制剂或含有YAP通路抑制剂的组合物在制备抑制牙根吸收的药物中的应用，其特征在于：所述YAP通路抑制剂选自维替泊芬；所述牙根吸收为正畸重力引起的牙根吸收；所述YAP通路抑制剂作用于破骨前体细胞的巨噬细胞上直接影响TRAP阳性破骨细胞/破牙骨质细胞形成和破骨相关因子表达。
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