Jie Pan1, Jue Wang2, Liang Hao2, Guochun Zhu2, Diep N Nguyen2, Qian Li3, Yuehua Liu4, Zhihe Zhao5, Yi-Ping Li6, Wei Chen7. 1. Department of Orthodontics, Shanghai Stomatological Disease Centre, Shanghai, People's Republic of China; Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 2. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 3. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Life Science College, Zhejiang University, Hangzhou, People's Republic of China. 4. Department of Orthodontics, Shanghai Stomatological Disease Centre, Shanghai, People's Republic of China. 5. State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China. 6. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: yipingli@uabmc.edu. 7. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: weichen@uabmc.edu.
Abstract
INTRODUCTION: Dental caries is the most widespread chronic infectious disease. Inflammation in pulp tissues caused by dental caries will lead to periapical granulomas, bone erosion, loss of the tooth, and severe pain. Despite numerous efforts in recent studies to develop effective treatments for dental caries, the need for a potent therapy is still urgent. METHODS: In this study, we applied a gene-based therapy approach by administering recombinant adeno-associated virus (AAV)-mediated Atp6v0d2 (d2) RNA interference knockdown of d2 gene expression to prevent periapical bone loss and suppress periapical inflammation simultaneously. RESULTS: The results showed that d2 depletion is simultaneously capable of reducing bone resorption with 75% protection through reducing osteoclasts, enhancing bone formation by increasing osterix expression, and inhibiting inflammation by decreasing T-cell infiltration. Notably, AAV-mediated gene therapy of d2 knockdown significantly reduced proinflammatory cytokine expression, including tumor necrosis factor α, interferon-γ, interleukin-1α, and interleukin 6 levels in periapical diseases caused by bacterial infection. Quantitative real-time polymerase chain reaction revealed that d2 knockdown reduced osteoclast-specific functional genes (ie, Acp5 and Ctsk) and increased osteoblast marker genes (ie, Osx and Opg) in periapical tissues. CONCLUSIONS: Collectively, our results showed that AAV-mediated d2 depletion in the periapical lesion area can prevent the progression of endodontic disease and bone erosion while significantly reducing the inflammatory over-response. These findings show that the depletion of d2 simultaneously reduces bone resorption, enhances bone formation, and inhibits inflammation caused by periapical diseases and provide significant insights into the potential effectiveness of AAV-sh-d2-mediated d2 silencing gene therapy as a major endodontic treatment.
INTRODUCTION: Dental caries is the most widespread chronic infectious disease. Inflammation in pulp tissues caused by dental caries will lead to periapical granulomas, bone erosion, loss of the tooth, and severe pain. Despite numerous efforts in recent studies to develop effective treatments for dental caries, the need for a potent therapy is still urgent. METHODS: In this study, we applied a gene-based therapy approach by administering recombinant adeno-associated virus (AAV)-mediated Atp6v0d2 (d2) RNA interference knockdown of d2 gene expression to prevent periapical bone loss and suppress periapical inflammation simultaneously. RESULTS: The results showed that d2 depletion is simultaneously capable of reducing bone resorption with 75% protection through reducing osteoclasts, enhancing bone formation by increasing osterix expression, and inhibiting inflammation by decreasing T-cell infiltration. Notably, AAV-mediated gene therapy of d2 knockdown significantly reduced proinflammatory cytokine expression, including tumornecrosis factor α, interferon-γ, interleukin-1α, and interleukin 6 levels in periapical diseases caused by bacterial infection. Quantitative real-time polymerase chain reaction revealed that d2 knockdown reduced osteoclast-specific functional genes (ie, Acp5 and Ctsk) and increased osteoblast marker genes (ie, Osx and Opg) in periapical tissues. CONCLUSIONS: Collectively, our results showed that AAV-mediated d2 depletion in the periapical lesion area can prevent the progression of endodontic disease and bone erosion while significantly reducing the inflammatory over-response. These findings show that the depletion of d2 simultaneously reduces bone resorption, enhances bone formation, and inhibits inflammation caused by periapical diseases and provide significant insights into the potential effectiveness of AAV-sh-d2-mediated d2 silencing gene therapy as a major endodontic treatment.
Authors: Jie Pan; Jiajia Deng; Liming Yu; Yuhui Wang; Weihua Zhang; Xinxin Han; Pedro H C Camargo; Jiale Wang; Yuehua Liu Journal: J Mater Sci Mater Med Date: 2019-12-05 Impact factor: 3.896