Inhibiting periapical lesions through AAV-RNAi silencing of cathepsin K.

Abstract

Dental caries, one of the most prevalent infectious diseases worldwide, affects approximately 80% of children and the majority of adults. Dental caries may result in endodontic disease, leading to dental pulp necrosis, periapical inflammation and bone resorption, severe pain, and tooth loss. Periapical inflammation may also increase inflammation in other parts of the body. Although many studies have attempted to develop therapies for this disease, there is still an urgent need for effective treatments. In this study, we applied a novel gene therapeutic approach using recombinant adeno-associated virus (AAV)-mediated RNAi knockdown of Cathepsin K (Ctsk) gene expression, to target osteoclasts and periapical bone resorption in a mouse model. We found that AAV-sh-Cathepsin K (AAV-sh-Ctsk) impaired osteoclast function in vivo and furthermore reduced bacterial infection-stimulated bone resorption by 88%. Reduced periapical lesion size was accompanied by decreases in mononuclear leukocyte infiltration and inflammatory cytokine expression. Our study shows that AAV-RNAi silencing of Cathepsin K in periapical tissues can significantly reduce endodontic disease development, bone destruction, and inflammation in the periapical lesion. This is the first demonstration that AAV-mediated RNAi knockdown gene therapy may significantly reduce the severity of endodontic disease.

• Authors: B Gao, W Chen, L Hao, G Zhu, S Feng, H Ci, X Zhou, P Stashenko, Y P Li
• Journal: Journal of dental research (J Dent Res) Vol. 92 Issue 2 Pg. 180-6 (Feb 2013) ISSN: 1544-0591 [Electronic] United States
• PMID: 23166044 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Inflammation Mediators
• Interleukins
• RNA, Small Interfering
• Recombinant Proteins
• Cathepsin K
• Ctsk protein, mouse

Topics

• Alveolar Bone Loss (microbiology, prevention & control)
• Animals
• Cathepsin K (genetics)
• Cell Culture Techniques
• Dental Pulp Exposure (microbiology)
• Dependovirus (genetics)
• Disease Models, Animal
• Female
• Gene Expression Regulation (genetics)
• Gene Knockdown Techniques
• Gene Silencing (physiology)
• Genetic Therapy
• Genetic Vectors (genetics)
• Gram-Negative Bacterial Infections (microbiology)
• Inflammation Mediators (analysis)
• Interleukins (analysis)
• Leukocytes, Mononuclear (pathology)
• Mice
• Mice, Inbred BALB C
• Osteoclasts (pathology)
• Periapical Diseases (microbiology, prevention & control)
• RNA, Small Interfering (genetics)
• Recombinant Proteins
• T-Lymphocytes (pathology)