The Proteasome Inhibitor Bortezomib Inhibits Inflammatory Response of Periodontal Ligament Cells and Ameliorates Experimental Periodontitis in Rats

• Published in: Journal of periodontology (1970) 2017-05, Vol.88 (5), p.473-483
• Main Authors: Jiang, Lin, Song, Jinlin, Hu, Xiaolei, Zhang, Hongmei, Huang, Enyi, Zhang, Yan, Deng, Feng, Wu, Xiaomian
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Anti‐inflammatory agents; bone resorption; Bortezomib - therapeutic use; cell biology; Child; Dentistry; Disease Models, Animal; Female; Humans; Inflammation - drug therapy; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Interleukin-8 - metabolism; Male; periodontal ligament; Periodontal Ligament - cytology; Periodontal Ligament - drug effects; periodontitis; Periodontitis - drug therapy; proteasome inhibitors; Proteasome Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-3492; 1943-3670
• DOI: 10.1902/jop.2016.160396

Background: Periodontitis is a chronic inflammatory disease initiated by bacteria and their virulence factors. Bortezomib (BTZ) is the first proteasome inhibitor for clinical treatment of malignancies. Its anticancer activity is accompanied by an anti‐inflammatory effect. However, there are few reports about its anti‐inflammatory effect and underlying mechanism in periodontal disease, especially on human periodontal ligament cells (hPDLCs), which are considered a promising cell‐based therapy for treating periodontitis. Methods: hPDLCs were treated with lipopolysaccharide (LPS) and pretreated with BTZ. mRNA and protein levels of tumor necrosis factor (TNF)‐alpha, interleukin (IL)‐1β, IL‐6, and IL‐8 were determined. The anti‐inflammatory mechanism of BTZ was studied. Further, experimental rat periodontitis was induced with ligature and LPS injection, and simultaneously and locally treated with BTZ (three injections/week). Four weeks after treatment, microcomputed tomography, immunohistochemical, and histopathologic analyses were performed. Results: Bortezomib administration at safe concentrations (≤1 nM) inhibited production of proinflammatory cytokines in LPS‐stimulated hPDLCs via nuclear factor (NF)‐kappa B, p38/extracellular signal‐regulated kinase, and mitogen‐activated protein kinase/activator protein‐1 pathways. Moreover, in the LPS and ligature‐induced periodontitis rat model, BTZ suppressed expression of TNF‐α, IL‐1β, IL‐6, and IL‐8, reduced the ratio of receptor activator of NF‐κB ligand/osteoprotegerin, and prevented alveolar bone absorption. Conclusion: These findings demonstrate the anti‐inflammatory activity of BTZ against periodontal inflammatory response and present BTZ as a promising therapy for periodontal disease.