title: RNA interference-mediated silencing of Atp6i prevents both periapical bone erosion and inflammation in the mouse model of endodontic disease.
abstract: Dental caries is one of the most prevalent infectious diseases in the United States, affecting approximately 80% of children and the majority of adults. Dental caries may lead to endodontic disease, where the bacterial infection progresses to the root canal system of the tooth, leading to periapical inflammation, bone erosion, severe pain, and tooth loss. Periapical inflammation may also exacerbate inflammation in other parts of the body. Although conventional clinical therapies for this disease are successful in approximately 80% of cases, there is still an urgent need for increased efficacy of treatment. In this study, we applied a novel gene-therapeutic approach using recombinant adeno-associated virus (AAV)-mediated Atp6i RNA interference (RNAi) knockdown of Atp6i/TIRC7 gene expression to simultaneously target periapical bone resorption and periapical inflammation. We found that Atp6i inhibition impaired osteoclast function in vitro and in vivo and decreased the number of T cells in the periapical lesion. Notably, AAV-mediated Atp6i/TIRC7 knockdown gene therapy reduced bacterial infection-stimulated bone resorption by 80% in the mouse model of endodontic disease. Importantly, Atp6i(+/-) mice with haploinsufficiency of Atp6i exhibited protection similar to that in mice with bacterial infection-stimulated bone erosion and periapical inflammation, which confirms the potential therapeutic effect of AAV-small hairpin RNA (shRNA)-Atp6i/TIRC7. Our results demonstrate that AAV-mediated Atp6i/TIRC7 knockdown in periapical tissues can inhibit endodontic disease development, bone resorption, and inflammation, indicating for the first time that this potential gene therapy may significantly improve the health of those who suffer from endodontic disease.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Junqing
authors.initials: J
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhang
authors.forename: Byron
authors.initials: B
authors.lastname: Tucker
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.forename: Hajime
authors.initials: H
authors.lastname: Sasaki
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Ci
authors.forename: Hongbing
authors.initials: H
authors.lastname: Jiang
authors.forename: Philip
authors.initials: P
authors.lastname: Stashenko
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000473:pathology / Q000517:prevention & control; D001862:Bone Resorption / Q000473:pathology* / Q000517:prevention & control*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000378:metabolism; D010485:Periapical Periodontitis / Q000473:pathology / Q000517:prevention & control; D011671:Pulpitis / Q000473:pathology* / Q000517:prevention & control*; D034622:RNA Interference; D013601:T-Lymphocytes / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C484226:Atp6ap1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases