title: The Proteasome Inhibitor Bortezomib Inhibits Inflammatory Response of Periodontal Ligament Cells and Ameliorates Experimental Periodontitis in Rats.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These findings demonstrate the anti-inflammatory activity of BTZ against periodontal inflammatory response and present BTZ as a promising therapy for periodontal disease.
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.|Department of Preventive Dentistry, College of Stomatology, Chongqing Medical University.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.|Department of Orthodontics, College of Stomatology, Chongqing Medical University.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Song
authors.affiliation: Key Laboratory of Clinical Laboratory Science, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Hu
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.
authors.forename: Enyi
authors.initials: E
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.|Department of Orthodontics, College of Stomatology, Chongqing Medical University.
authors.forename: Feng
authors.initials: F
authors.lastname: Deng
authors.affiliation: Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, College of Stomatology, Chongqing Medical University, Chongqing, China.|Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University.|Department of Orthodontics, College of Stomatology, Chongqing Medical University.
authors.forename: Xiaomian
authors.initials: X
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000818:Animals; D000069286:Bortezomib / Q000627:therapeutic use*; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects*; D010518:Periodontitis / Q000188:drug therapy*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib
keywords: Anti-inflammatory agents; bone resorption; cell biology; periodontal ligament; periodontitis; proteasome inhibitors