Roles of CCL2 in peri-implantitis and its potential as a treatment target: An animal study

Abstract

Background

CC-chemokine ligand 2 (CCL2) plays pivotal roles in many osteoimmune disorders, while its role in peri-implantitis is unknown. The main research question aimed to address in this study is investigating the specific roles of CCL2 in peri-implantitis and assessing the preventive and therapeutic effects of bindarit on experimental peri-implantitis.

Methods

Firstly, the expression profile of CC-chemokine receptor 2 ligands in human peri-implantitis was ascertained by processing and analyzing datasets from the Gene Expression Omnibus database. Then the experimental peri-implantitis model was established in mice by suture ligation, and the soft tissue inflammation and hard tissue resorption were compared in CCL2 knockout (Ccl2^−/−) mice and wild-type mice with experimental peri-implantitis to evaluate the impact of CCL2 in vivo by visual examination, microcomputed tomography, hematoxylin-eosin staining, tartrate-resistant acid phosphatase staining, immunohistochemistry staining, flow cytometry, and quantitative real-time polymerase chain reaction. Furthermore, using both preventive and therapeutic administration routes, the effectiveness of bindarit, which inhibited the expression of CCL2, was evaluated in experimental peri-implantitis.

Results

CCL2 demonstrated a significant predominant expression among the ligands of CC-chemokine receptor 2 in human peri-implantitis. CCL2 was significantly upregulated in the ligature-induced peri-implantitis model (p = 0.0007), and CCL2 deficiency resulted in significantly decreased monocytes/macrophages infiltration in peri-implant tissue (CD45⁺CD11b⁺Ly6C^hi, p = 0.0019; CD45⁺CD11b⁺F4/80⁺, p = 0.0261), significantly reduced proinflammatory cytokine production (TNF-α, p = 0.0333; IL-6, p = 0.0194; IL-1β, p = 0.0090), and significant impaired osteoclast activity (TRAP⁺ cells, p = 0.0240; RANKL, p = 0.0047), ultimately leading to attenuated mucosal inflammation and bone resorption in peri-implantitis. Moreover, treatment with bindarit demonstrated promising preventive and therapeutic effects in experimental peri-implantitis through inhibiting CCL2.

Conclusions

The findings of this study suggest that CCL2 may serve as a potential target for peri-implantitis treatment by mediating peri-implant host immune response to modulate local inflammation and bone resorption, offering a new direction for the development of immunotherapeutic drugs for this condition.

Plain language summary

Peri-implantitis, an inflammatory condition that impacts the longevity of dental implants, poses considerable challenges due to the limited effectiveness of current treatment methods. This study aimed to understand the role of CC-chemokine ligand 2 (CCL2) in this condition. In our study, CCL2 was discovered to be the primary ligand of CC-chemokine receptor 2 in peri-implantitis. Lab tests using a mouse model revealed that in the absence of CCL2, inflammation and bone loss were reduced. Furthermore, this study confirmed the effect of a drug called bindarit, which inhibits CCL2, in treating experimental peri-implantitis. Investigating the specific roles of CCL2 and assessing the potential benefits of bindarit in managing peri-implantitis provide a scientific foundation for exploring new treatment strategies.