Lin Jiang1,2,3, Jinlin Song1,2,4, Xiaolei Hu5, Hongmei Zhang1,2, Enyi Huang1,2, Yan Zhang1,2, Feng Deng1,2,4, Xiaomian Wu1,2,4. 1. Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China. 2. Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University. 3. Department of Preventive Dentistry, College of Stomatology, Chongqing Medical University. 4. Department of Orthodontics, College of Stomatology, Chongqing Medical University. 5. Key Laboratory of Clinical Laboratory Science, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University.
Abstract
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.
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 ratperiodontitis 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 periodontitisrat 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.