Ac45 silencing mediated by AAV‐sh‐Ac45‐RNAi prevents both bone loss and inflammation caused by periodontitis

Abstract

Aim Periodontitis induced by oral pathogens leads to severe periodontal tissue damage and osteoclast-mediated bone resorption caused by inflammation. Based on 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. Material and 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.

CDG and immune response: From bedside to bench and back

“…ATP6AP1 deficiency is associated with immune‐related complications that include recurrent bacterial infections. However, in the context of periodontitis, ATP6AP1 silencing resulted in decreased inflammation with diminished infiltration of T cells, DCs, macrophages and expression of pro‐inflammatory cytokines in the periodontal lesion . Other variables influencing and influenced by glycans are the developmental stage, protein/cell activation status and aging …”

“…However, in the context of periodontitis, ATP6AP1 silencing resulted in decreased inflammation with diminished infiltration of T cells, DCs, macrophages and expression of pro-inflammatory cytokines in the periodontal lesion. 260 Other variables influencing and influenced by glycans are the developmental stage, protein/cell activation status and aging. 54,75,199,261 The paradoxical activity of glycans in the immune response can be clearly demonstrated by their ambiguity in host-pathogen interaction and recognition.…”

The function of dendritic cells in modulating the host response

“…Oral infection with P. gingivalis in mice increases the number of cDCs, which is positively correlated with the generation of a Th17 response 47,49 . Oral infection with P. gingivalis and Fusobacterium nucleatum stimulate migration of cDCs to the lymph nodes and gingiva and is associated with increased IL-17 levels, as well as other pro-inflammatory factors such as TNF, IL-6 and IL-1β, which contribute to alveolar bone loss 4,50 .…”

Effects of Standardised Fermented Papaya Gel on Clinical Symptoms, Inflammatory Cytokines, and Nitric Oxide Metabolites in Patients with Chronic Periodontitis: An Open Randomised Clinical Study

“…The chronic inflammation of periodontal disease is induced by polymicrobial infection [ 10 , 11 ], with a leading pathogen being Porphyromonas gingivalis [ 12 ]. The several hundred of microbes hosted in the oral cavity are commonly organised in “complexes,” that is, associations typically forming biofilms in gingival pockets and supragingival plaque [ 13 ], which makes microbes more pathogenic and less sensitive to traditional antibiotic therapies [ 14 ].…”