Small molecule mediated restoration of periodontal homeostasis through the YAP1 pathway

摘要 牙周组织再生，包括形成新的牙槽骨，以及 产生新的结缔组织附着一直是牙周组织的终极目标 自20世纪80年代以来的研究和治疗。在这里我们已经确定了高度选择性的SETD7 甲基转移酶活性抑制物(R)-PFI-2(PFI-2)作为一种强大的小分子调节剂 改善牙周炎症程度，明显促进新生牙槽骨形成 形成，新的牙骨质形成，和牙周膜重新附着。当PFI-2是 应用于我们的啮齿动物模型中的牙周缺陷，有1.7倍的大幅增加 牙槽骨高度相当于附着水平垂直骨增加3 mm 与对照组相比。这些初步数据表明，PFI-2可能代表着一种新的 牙周再生的答案和一种能够倾倒牙周的分子 动态平衡有利于合成代谢方面的平衡。解释PFI-2的作用机制 影响牙周干细胞功能，我们的初步数据表明，PFI-2治疗 YAP1核易位和下游基因表达增加，提示PFI-2 通过一种新的途径影响炎症条件下牙周基因的表达 包括甲基转移酶SETD7和河马途径成员YAP1。基于这些 令人兴奋的初步数据，我们现在假设PFI-2上调YAP1靶基因 通过核转位表达，导致牙周祖细胞增殖改善 和分化，并减少炎症条件下的牙周骨丢失。我们 预计这些研究将导致新型小分子化合物的发展 治疗牙周病和抗击相关的牙周病丢失 牙周组织，这将有助于执业牙周病医生。

Abstract Regeneration of periodontal tissues including formation of new alveolar bone, and generation of new connective tissue attachment have been the ultimate goals of periodontal research and therapy since the 1980ies. Here we have identified the highly selective SETD7 methyltransferase activity inhibitor (R)-PFI-2 (PFI-2) as a powerful small molecule modulator that ameliorated the severity of periodontal inflammation and significantly promoted new alveolar bone formation, new cementum formation, and periodontal ligament re-attachment. When PFI-2 was applied to periodontal defects in our rodent model, there was a substantial 1.7-fold increase in alveolar bone height equivalent to a 3 mm gain in vertical bone of attachment levels in humans when compared to controls. These preliminary data indicate that PFI-2 might represent a new answer to the quest for periodontal regeneration and a molecule capable of tipping the periodontal homeostasis balance in favor of the anabolic side. Explaining the mechanisms by which PFI-2 affects periodontal stem cell function, our preliminary data have demonstrated that PFI-2 treatment increased YAP1 nuclear translocation and downstream gene expression, suggesting that PFI-2 affects periodontal gene expression under inflammatory conditions through a novel pathway that includes the methyltransferase SETD7 and the Hippo pathway member YAP1. Based on these exciting preliminary data we have now hypothesized that PFI-2 upregulates YAP1 target gene expression through nuclear translocation, resulting in improved periodontal progenitor proliferation and differentiation, and reduced periodontal bone loss under inflammatory conditions. We anticipate that these studies will result in the development of novel small molecule-based therapeutics for the treatment of periodontal disease and to combat the associated loss of periodontal tissue that will aid the practicing periodontist.