The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation
The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation
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DOI：
10.1111/jre.12345
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发表时间：
2016-10-01
影响因子：
3.5
通讯作者：
Li, Y. -P.
中科院分区：
文献类型：
--
作者：
Chen, W.;Gao, B.;Li, Y. -P.
背景和目的：牙周炎是一种严重的慢性炎症性疾病，是影响世界上大多数成年人的最普遍的非传染性慢性疾病之一。虽然人们已经付出了很大的努力来了解牙周炎的发病机制，但仍然迫切需要开发针对这种可怕疾病的有效治疗策略。在这项研究中，我们利用腺相关病毒（AAV）表达组织蛋白酶K（Ctsk）小发夹（sh）RNA，（AAV-sh-Ctsk）在体内沉默Ctsk，随后评估其作为该疾病的潜在治疗策略在牙周炎中的影响。我们使用了一种已知的牙周炎小鼠模型，其中野生型BALB/cJ小鼠在上颌和下颌牙周组织中感染牙龈卟啉单胞菌W50以诱发疾病。结果：AAV介导的Ctsk沉默显著保护小鼠（>80%）免受牙龈卟啉单胞菌诱导的破骨细胞骨吸收。此外，AAV-sh-Ctsk管理通过影响许多炎性细胞因子的表达以及牙周病损中T细胞和树突状细胞的数量而显著减少炎症。结论：AAV介导的Ctsk沉默可以通过其对免疫细胞和破骨细胞功能的抑制作用同时靶向与牙周炎相关的炎症和骨吸收。因此，AAV-sh-Ctsk施用可以有效地保护牙周组织损伤和牙槽骨损失，建立这种AAV介导的Ctsk局部沉默作为有效治疗牙周病的重要治疗策略。
Background and Objective: Periodontitis is a severe chronic inflammatory disease and one of the most prevalent non-communicable chronic diseases that affects the majority of the world's adult population. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno-associated virus (AAV) expressing cathepsin K (Ctsk) small hairpin (sh) RNA (AAV-sh-Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease.Material and Methods: We used a known mouse model of periodontitis, in which wild-type BALB/cJ mice were infected with Porphyromonas gingivalis W50 in the maxillary and mandibular periodontium to induce the disease. AAV-sh-Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess progression of the disease.Results: AAV-mediated Ctsk silencing drastically protected mice (>80%) from P. gingivalis-induced bone resorption by osteoclasts. In addition, AAV-sh-Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T-cell and dendritic cell numbers in periodontal lesions.Conclusion: AAV-mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV-sh-Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV-mediated local silencing of Ctsk as an important therapeutic strategy for effectively treating periodontal disease.