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Published on: March 18, 2019
GalNAc-Conjugated siRNA Targeting Complement C3 Inhibits Osteoclast Activation in Periodontitis
Yingyi Chen1,2, Yitong Liu1,2, Zhongguo Fu3
1Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, People's Republic of China.
Objective:
The complement cascade plays an important role in the inflammation amplification and tissue destruction of periodontitis. Importantly, complement C3 was proved to be the central element of complement cascade. Thus, targeting inhibition of C3 has become one of the focuses of treatment method development and exploration.
Methods:
The siRNAs targeting C3 were designed and screened for in vitro potency. The selected siRNA was conjugated to GalNAc (GalNAc-C3 siRNA) for liver-specific delivery. The mouse model of periodontitis was established by silk ligation. Stereomicroscopy, Micro-CT, histological and histochemical assessment, and immunofluorescence staining were performed to evaluate the level of bone destructive and osteoclast activity. The influence of GalNAc-C3 siRNA on inflammatory reactions was determined by qRT-PCR, ELISA, and flow cytometry.
Results:
GalNAc-C3 siRNA showed great in vivo potency and durability to silence hepatic C3 mRNA expression. GalNAc-C3 siRNA treatment could effectively inhibit the production of inflammatory cytokines (IL-17A, TNF-α, IL-6, and IFN-γ) and restrain Th17 differentiation. Importantly, the expression of RANKL and differentiation of osteoclast were inhibited by GalNAc-C3 siRNA.
Conclusion:
GalNAc-C3 siRNA could efficiently play a role in bone protection by inhibiting inflammatory responses and osteoclast activities. This therapeutic siRNA may become an effective treatment strategy for periodontitis.
Insights
This study shows that GalNAc-C3 siRNA effectively silences complement C3, reducing inflammation and osteoclast activity. This offers a promising new treatment strategy for periodontitis bone loss.
Area of Science:
- Immunology
- Periodontology
- RNA Therapeutics
Background:
- The complement cascade, particularly complement C3, is central to periodontitis-associated inflammation and tissue destruction.
- Targeting complement C3 is a key strategy for developing novel periodontitis treatments.
Purpose of the Study:
- To evaluate the efficacy of GalNAc-C3 siRNA, a liver-targeted therapeutic, in a mouse model of periodontitis.
- To assess its impact on inflammatory responses and osteoclast activity for potential periodontitis treatment.
Main Methods:
- siRNAs targeting C3 were designed and screened; the selected siRNA was conjugated to GalNAc for liver delivery (GalNAc-C3 siRNA).
- A mouse model of periodontitis was induced. Bone destruction and osteoclast activity were assessed using stereomicroscopy, Micro-CT, histology, and immunofluorescence.
- Inflammatory reactions were analyzed via qRT-PCR, ELISA, and flow cytometry.
Main Results:
- GalNAc-C3 siRNA demonstrated potent and durable in vivo silencing of hepatic C3 mRNA.
- Treatment inhibited inflammatory cytokines (IL-17A, TNF-α, IL-6, IFN-γ) and Th17 differentiation.
- Expression of RANKL and osteoclast differentiation were significantly inhibited.
Conclusions:
- GalNAc-C3 siRNA effectively protects bone by suppressing inflammation and osteoclast activity in periodontitis.
- This therapeutic siRNA presents a potential new treatment strategy for periodontitis.
