title: The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation.
abstract: OBJECTIVE
  Periodontitis is a severe chronic inflammatory disease and one of the most prevalent non-communicable chronic diseases that affects the majority of the world's adult population. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno-associated virus (AAV) expressing cathepsin K (Ctsk) small hairpin (sh)RNA (AAV-sh-Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease.
  
  
  METHODS
  We used a known mouse model of periodontitis, in which wild-type BALB/cJ mice were infected with Porphyromonas gingivalis W50 in the maxillary and mandibular periodontium to induce the disease. AAV-sh-Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess progression of the disease.
  
  
  RESULTS
  AAV-mediated Ctsk silencing drastically protected mice (> 80%) from P. gingivalis-induced bone resorption by osteoclasts. In addition, AAV-sh-Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T-cell and dendritic cell numbers in periodontal lesions.
  
  
  CONCLUSIONS
  AAV-mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV-sh-Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV-mediated local silencing of Ctsk as an important therapeutic strategy for effectively treating periodontal disease.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|The State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors.forename: B
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|The State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors.forename: L
authors.initials: L
authors.lastname: Hao
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jules
authors.affiliation: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: MacDougall
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology and Infectious Disease, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: The State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Li
mesh_terms: D016301:Alveolar Bone Loss / Q000473:pathology; D000818:Animals; D001862:Bone Resorption / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D056657:Cathepsin K / Q000235:genetics* / Q000494:pharmacology* / Q000502:physiology; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts; D010510:Periodontal Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D010518:Periodontitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010519:Periodontium / Q000382:microbiology / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000472:pathogenicity; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D056657:Cathepsin K
keywords: adeno-associated virus; alveolar bone loss; cathepsin K; gene therapy; periodontal diseases