title: Inhibition of GSK3 abolishes bacterial-induced periodontal bone loss in mice.
abstract: The tissue destruction that characterizes periodontitis is driven by the host response to bacterial pathogens. Inhibition of glycogen synthase kinase 3β (GSK3β) in innate cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines under nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 transcriptional control and promotion of cyclic adenosine monophosphate response element-binding (CREB)-dependent gene activation. Therefore, we hypothesized that the cell permeable GSK3-specific inhibitor, SB216763, would protect against alveolar bone loss induced by the key periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), in a murine model. B6129SF2/J mice either were infected orally with P. gingivalis ATCC 33277; or treated with SB216763 and infected with P. gingivalis; sham infected; or exposed to vehicle only (dimethyl sulfoxide [DMSO]); or to GSK3 inhibitor only (SB216763). Alveolar bone loss and local (neutrophil infiltration and interleukin [IL]-17) and systemic (tumor necrosis factor [TNF], IL-6, Il-1β and IL-12/IL-23 p40) inflammatory indices also were monitored. SB216763 unequivocally abrogated mean P. gingivalis-induced bone resorption, measured at 14 predetermined points on the molars of defleshed maxillae as the distance from the cementoenamel junction to the alveolar bone crest (p < 0.05). The systemic cytokine response, the local neutrophil infiltration and the IL-17 expression were suppressed (p < 0.001). These data confirm the relevance of prior in vitro phenomena and establish GSK3 as a novel, efficacious therapeutic preventing periodontal disease progression in a susceptible host. These findings also may have relevance to other chronic inflammatory diseases and the systemic sequelae associated with periodontal infections.
authors: Center for Oral Health and Systemic Disease, University of Louisville, Louisville, Kentucky 40292, United States of America.
authors: Karina
authors: K
authors: Adamowicz
authors: Huizhi
authors: H
authors: Wang
authors: Ravi
authors: R
authors: Jotwani
authors: Iris
authors: I
authors: Zeller
authors: Jan
authors: J
authors: Potempa
authors: David A
authors: DA
authors: Scott
mesh_terms: D016301:Alveolar Bone Loss / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D008437:Maxilla / Q000187:drug effects / Q000473:pathology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D016966:Porphyromonas gingivalis / Q000187:drug effects / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D007211:Indoles; D020381:Interleukin-17; D008301:Maleimides; C417521:SB 216763; D051193:Toll-Like Receptors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3