RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease.
RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease.
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DOI：
10.1371/journal.pone.0058599
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li YP
中科院分区：
文献类型：
--
作者：
Jiang H;Chen W;Zhu G;Zhang L;Tucker B;Hao L;Feng S;Ci H;Ma J;Wang L;Stashenko P;Li YP
牙周病影响美国约80%的成年人，其特征在于口腔细菌感染引起的牙龈炎症、口腔骨吸收和牙齿脱落。牙周炎还与其他疾病有关，如类风湿性关节炎、糖尿病和心脏病。尽管已经做出了许多努力来开发针对这种疾病的有效疗法，但没有一种是非常有效的，仍然迫切需要更好的治疗和预防策略。在此，我们首次探索了腺相关病毒（AAV）介导的RNAi敲除可用于治疗牙周病并提高疗效的可能性。为此，我们使用AAV介导的Atp 6 i/TIRC 7基因表达的RNAi敲低来同时靶向骨吸收和牙龈炎症。用口腔病原菌牙龈卟啉单胞菌（Porphyromonas gingivalis）W50感染小鼠上颌牙周组织，诱导牙周炎。我们发现，Atp 6 i耗竭损害细胞外酸化和破骨细胞介导的骨吸收。此外，将AAV-shRNA-Atp 6 i/TIRC 7局部注射到体内牙周组织中保护小鼠免受牙龈卟啉单胞菌感染刺激的骨吸收>85%，并减少牙周组织中的T细胞数量。值得注意的是，AAV介导的Atp 6 i/TIRC 7敲低也降低了破骨细胞标志物基因和炎症诱导的细胞因子基因的表达。Atp 6 i +/−单倍型功能不全的小鼠同样受到牙龈卟啉单胞菌感染刺激的骨丢失和牙龈炎症的保护。这表明AAV-shRNA-Atp 6 i/TIRC 7治疗性治疗可以显著改善数百万患有牙龈卟啉单胞菌介导的牙周病的人的健康。
Periodontal disease affects about 80% of adults in America, and is characterized by oral bacterial infection-induced gingival inflammation, oral bone resorption, and tooth loss. Periodontitis is also associated with other diseases such as rheumatoid arthritis, diabetes, and heart disease. Although many efforts have been made to develop effective therapies for this disease, none have been very effective and there is still an urgent need for better treatments and preventative strategies. Herein we explored for the first time the possibility that adeno-associated virus (AAV)-mediated RNAi knockdown could be used to treat periodontal disease with improved efficacy. For this purpose, we used AAV-mediated RNAi knockdown of Atp6i/TIRC7 gene expression to target bone resorption and gingival inflammation simultaneously. Mice were infected with the oral pathogen Porphyromonas gingivalis W50 (P. gingivalis) in the maxillary periodontium to induce periodontitis. We found that Atp6i depletion impaired extracellular acidification and osteoclast-mediated bone resorption. Furthermore, local injection of AAV-shRNA-Atp6i/TIRC7 into the periodontal tissues in vivo protected mice from P. gingivalis infection-stimulated bone resorption by >85% and decreased the T-cell number in periodontal tissues. Notably, AAV-mediated Atp6i/TIRC7 knockdown also reduced the expression of osteoclast marker genes and inflammation-induced cytokine genes. Atp6i+/− mice with haploinsufficiency were similarly protected from P. gingivalis infection-stimulated bone loss and gingival inflammation. This suggests that AAV-shRNA-Atp6i/TIRC7 therapeutic treatment may significantly improve the health of millions who suffer from P. gingivalis-mediated periodontal disease.
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DOI：
10.1155/2012/308943
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Li Q;Valerio MS;Kirkwood KL
通讯作者：
Kirkwood KL
影响因子：
82.9
作者：
Hommel, JD;Sears, RM;DiLeone, RJ
通讯作者：
DiLeone, RJ
影响因子：
15.3
作者：
HAN, J;BROWN, T;BEUTLER, B
通讯作者：
BEUTLER, B
影响因子：
168.9
作者：
Kaplitt, Michael G.;Feigin, Andrew;During, Matthew J.
通讯作者：
During, Matthew J.
影响因子：
12.4
作者：
Gasmi, Mehdi;Herzog, Christopher D.;Bartus, Raymond T.
通讯作者：
Bartus, Raymond T.