title: Ac45 silencing mediated by AAV-sh-Ac45-RNAi prevents both bone loss and inflammation caused by periodontitis.
abstract: OBJECTIVE
  Periodontitis induced by oral pathogens leads to severe periodontal tissue damage and osteoclast-mediated bone resorption caused by inflammation. On the basis of the importance of Ac45 in osteoclast formation and function, we performed this study to evaluate the therapeutic potential of periodontitis by local adeno-associated virus (AAV)-mediated Ac45 gene knockdown.
  
  
  METHODS
  We used AAV-mediated short hairpin RNAi knockdown of Ac45 gene expression (AAV-sh-Ac45) to inhibit bone erosion and gingival inflammation simultaneously in a well-established periodontitis mouse model induced by Porphyromonas gingivalis W50. Histological studies were performed to evaluate the bone protection of AAV-sh-Ac45. Immunochemistry, ELISA and qRT-PCR were performed to reveal the role of Ac45 knockdown on inflammation, immune response and expression of cytokine.
  
  
  RESULTS
  We found that Ac45 knockdown impaired osteoclast-mediated extracellular acidification and bone resorption in vitro and in vivo. Furthermore, local administration of AAV-sh-Ac45 protected mice from bone erosion by >85% and attenuated inflammation and decreased infiltration of T cells, dendritic cells and macrophages in the periodontal lesion. Notably, the expression of pro-inflammatory cytokines was also reduced.
  
  
  CONCLUSIONS
  Local AAV-sh-Ac45 gene therapy efficiently protects against periodontal tissue damage and bone erosion through both inhibition of osteoclast function and attenuating inflammation, and may represent a powerful new treatment strategy for periodontitis.
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.|Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.|Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D016301:Alveolar Bone Loss / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D000818:Animals; D016866:Bacteroidaceae Infections / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005891:Gingivitis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000502:physiology; D010518:Periodontitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000276:immunology / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics
chemical_list: C484226:Atp6ap1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D025262:Vacuolar Proton-Translocating ATPases
keywords: AAV-mediated RNAi knockdown; Ac45; alveolar bone resorption; gene therapy; gingival inflammation; osteoclast immunology; periodontal disease