title: RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease.
abstract: 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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhang
authors.forename: Byron
authors.initials: B
authors.lastname: Tucker
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.forename: Shengmei
authors.initials: S
authors.lastname: Feng
authors.forename: Hongliang
authors.initials: H
authors.lastname: Ci
authors.forename: Junqing
authors.initials: J
authors.lastname: Ma
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Stashenko
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010510:Periodontal Diseases / Q000150:complications / Q000235:genetics* / Q000382:microbiology / Q000628:therapy*; D010519:Periodontium / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000502:physiology; D034622:RNA Interference; D013601:T-Lymphocytes / Q000166:cytology; D014161:Transduction, Genetic; D025262:Vacuolar Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics*
chemical_list: C484226:Atp6ap1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases