Periodontitis is a chronic inflammatory disease related to tooth loss in adults. Infliximab is a chimeric monoclonal antibody against TNF-α and is prescribed for the treatment of systemic inflammatory diseases. This study aimed to investigate the role of infliximab on experimental periodontal disease (EPD). EPD was induced by passing a 3.0 nylon thread around the upper left second molar in Wistar rats. Animals were either treated with intravenous infliximab (1, 5, 7, and 10 mg/kg) or saline solution 30 min before the periodontitis induction and were followed until they were sacrificed on the 11th day. A subset of rats was euthanized on the third day for analysis of gingival myeloperoxidase (MPO) and the blood MPO granulocyte index. In addition, we analyzed the bone loss index (BLI), the periodontal histopathological score, and the periodontal collagen network using confocal microscopy. We also analyzed metalloproteinase-1/-8, RANK, RANK-L, and osteoprotegerin in maxillary tissue by immunohistochemistry Gingival MPO, IL-1β, TNF-α were measured by ELISA. EPD caused leukocytosis, significant increases in BLI and gingival pro-inflammatory cytokines and cell infiltrates, with worse histopathological scores and periodontal collagen derangement. Infliximab (5 mg/kg) reduced granulocyte blood counts, gingival IL-1β, TNF-α, and MPO levels, diminished MMP-1/-8, RANK, and RANK-L bone immunolabeling with better periodontal histopathological scores and collagen network in comparison with the challenged saline group. We concluded that infliximab had significant anti-inflammatory and bone-protective effects in Wistar rats challenged by periodontitis.
PapapanouPN. Epidemiology of periodontal diseases: an update. J Int Acad Periodontol1999; 1: 110–6.
2.
KornmanKS. Mapping the pathogenesis of periodontitis: a new look. J Periodontol2008; 79: 1560–8.
3.
SoukosNSGoodsonJM. Photodynamic therapy in the control of oral biofilms. Periodontol 20002011; 55: 143–166.
4.
ArmitageGC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol1999; 4: 1–6.
5.
ArweilerNBPietruskaMSkurskaADolinskaEPietruskiJKBlasMAuschillTMSculeanA. Nonsurgical treatment of aggressive periodontitis with photodynamic therapy or systemic antibiotics. Three-month results of a randomized, prospective, controlled clinical study. Schweiz Monatsschr Zahnmed2013; 123: 532–44.
6.
BartoldPMCantleyMDHaynesDR. Mechanisms and control of pathologic bone loss in periodontitis. Periodontol 20002010; 53: 55–69.
7.
AzumaYKajiKKatogiRTakeshitaSKudoA. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem2000; 275: 4858–64.
8.
FullerKMurphyCKirsteinBFoxSWChambersTJ. TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology2002; 143: 1108–18.
9.
GravalleseEM. Bone destruction in arthritis. Ann Rheum Dis2002; 61: ii84–6.
10.
KhoslaS. Minireview: the OPG/RANKL/RANK system. Endocrinology2001; 142: 5050–5.
11.
DougallWCGlaccumMCharrierKRohrbachKBraselKDeSTDaroESmithJTometskoMEMaliszewskiCRArmstrongAShenVBainSCosmanDAndersonDMorrisseyPJPeschonJJSchuhJ. RANK is essential for osteoclast and lymph node development. Genes Dev1999; 13: 2412–24.
12.
OdgrenPRKimNMacKayCAMason-SavasAChoiYMarksSCJr. The role of RANKL (TRANCE/TNFSF11), a tumor necrosis factor family member, in skeletal development: effects of gene knockout and transgenic rescue. Connect Tissue Res2003; 44: 264–71.
13.
LeibbrandtAPenningerJM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci2008; 1143: 123–50.
14.
KaoDWFiorelliniJP. Regenerative periodontal therapy. Front Oral Biol2012; 15: 149–59.
15.
PerdrigerA. Infliximab in the treatment of rheumatoid arthritis. Biologics2009; 3: 183–91.
16.
TraceyDKlareskogLSassoEHSalfeldJGTakPP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther2008; 117: 244–79.
17.
EissnerGKirchnerSLindnerHKolchWJanoschPGrellMScheurichPAndreesenRHollerE. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J Immunol2000; 164: 6193–8.
18.
MayerYBalbir-GurmanAMachteiEE. Anti-tumor necrosis factor-alpha therapy and periodontal parameters in patients with rheumatoid arthritis. J Periodontol2009; 80: 1414–20.
19.
BezerraMMdeLVAlencarVBVieiraIBBritoGARibeiroRARochaFA. Selective cyclooxygenase-2 inhibition prevents alveolar bone loss in experimental periodontitis in rats. J Periodontol2000; 71: 1009–14.
20.
PageRCSchroederHE. Current status of the host response in chronic marginal periodontitis. J Periodontol1981; 52: 477–91.
21.
Lima-Junior RC, Figueiredo AA, Freitas HC, Melo ML, Wong DV, Leite CA, Medeiros RP, Marques-Neto RD, Vale ML, Brito GA, Oria RB, Souza MH, Cunha FQ, Ribeiro RA. Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. Cancer Chemother Pharmacol 2011:931–42.
22.
AzoubelMCMenezesAMBezerraDOriaRBRibeiroRABritoGA. Comparison of etoricoxib and indomethacin for the treatment of experimental periodontitis in rats. Braz J Med Biol Res2007; 40: 117–25.
23.
LeitaoRFRibeiroRAChavesHVRochaFALimaVBritoGA. Nitric oxide synthase inhibition prevents alveolar bone resorption in experimental periodontitis in rats. J Periodontol2005; 76: 956–63.
24.
MonacoCRossiEMilazzoDCitterioFGinnettiFD'OnofrioGCianfloneDCreaFBiasucciLMMaseriA. Persistent systemic inflammation in unstable angina is largely unrelated to the atherothrombotic burden. J Am Coll Cardiol2005; 45: 238–43.
25.
HuangHZhaoNXuXXuYLiSZhangJYangP. Dose-specific effects of tumor necrosis factor alpha on osteogenic differentiation of mesenchymal stem cells. Cell Prolif2011; 44: 420–7.
26.
GilbertLCChenHLuXNanesMS. Chronic low dose tumor necrosis factor-alpha (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. Bone2013; 56: 174–83.
27.
LimaVVidalFDRochaFABritoGARibeiroRA. Effects of tumor necrosis factor-alpha inhibitors pentoxifylline and thalidomide on alveolar bone loss in short-term experimental periodontal disease in rats. J Periodontol2004; 75: 162–8.
28.
KawamuraHAraiMTogariA. Inhibitory effect of chlorpromazine on RANKL-induced osteoclastogenesis in mouse bone marrow cells. J Pharmacol Sci2011; 117: 54–62.
29.
deLVBezerraMMde Menezes AlencarVBVidalFDda RochaFAde Castro BritoGAde AlbuquerqueRR. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci2000; 108: 123–9.
30.
AkmanSAArikanCSozenGOzturkCYagciRV. Infliximab treatment of pediatric refractory Crohn's disease: a case report. Turk J Gastroenterol2006; 17: 133–6.
31.
Van DykeTESerhanCN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J Dent Res2003; 82: 82–90.
32.
Becker AK. Interpretación del hemograma. Rev Chilena Ped 2001;72:460–5.
33.
Schwarz BC, Hoven RV, Schwendenwein I. Diagnostic value of the neutrophil myeloperoxidase index in horses with systemic inflammation. Vet J 2011:72–8.
34.
PersJOSarauxAPierreRYouinouP. Anti-TNF-alpha immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis. J Periodontol2008; 79: 1645–51.
35.
BoyceBFLiPYaoZZhangQBadellIRSchwarzEMO'KeefeRJXingL. TNF-alpha and pathologic bone resorption. Keio J Med2005; 54: 127–31.
BoyceBFXingL. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther2007; 9: S1–S1.
38.
PoubellePEChakravartiAFernandesMJDoironKMarceauAA. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther2007; 9: R25–R25.
39.
BoyceBFXingL. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys2008; 473: 139–46.
40.
RinconJCYoungWGBartoldPM. The epithelial cell rests of Malassez–a role in periodontal regeneration?J Periodontal Res2006; 41: 245–52.
41.
HasegawaNKawaguchiHOgawaTUchidaTKuriharaH. Immunohistochemical characteristics of epithelial cell rests of Malassez during cementum repair. J Periodontal Res2003; 38: 51–6.
42.
KookSHJangYSLeeJC. Human periodontal ligament fibroblasts stimulate osteoclastogenesis in response to compression force through TNF-alpha-mediated activation of CD4+ T cells. J Cell Biochem2011; 112: 2891–901.
43.
KatoRIshiharaYKawanabeNSumiyoshiKYoshikawaYNakamuraMImaiYYanagitaTFukushimaHKamiokaHTakano-YamamotoTYamashiroT. Gap-junction-mediated communication in human periodontal ligament cells. J Dent Res2013; 92: 635–40.
44.
WeiSSiegalGP. Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic targets. Pathol Res Pract2008; 204: 695–706.
45.
DahanMNawrockiBElkaimRSoellMBolcato-BelleminALBirembautPTenenbaumH. Expression of matrix metalloproteinases in healthy and diseased human gingiva. J Clin Periodontol2001; 28: 128–36.
46.
KinaneDFDarbyIBSaidSLuotoHSorsaTTikanojaSMantylaP. Changes in gingival crevicular fluid matrix metalloproteinase-8 levels during periodontal treatment and maintenance. J Periodontal Res2003; 38: 400–4.
47.
LagervallMJanssonLBergstromJ. Systemic disorders in patients with periodontal disease. J Clin Periodontol2003; 30: 293–9.
48.
Havemose-PoulsenAWestergaardJStoltzeKSkjodtHDanneskiold-SamsoeBLochtHBendtzenKHolmstrupP. Periodontal and hematological characteristics associated with aggressive periodontitis, juvenile idiopathic arthritis, and rheumatoid arthritis. J Periodontol2006; 77: 280–8.
49.
KeaneJGershonSWiseRPMirabile-LevensEKasznicaJSchwietermanWDSiegelJNBraunMM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med2001; 345: 1098–104.
50.
PappKADekovenJParsonsLPirzadaSRobernMRobertsonLTanJK. Biologic therapy in psoriasis: perspectives on associated risks and patient management. J Cutan Med Surg2012; 16: 153–68.
