title: Sustained mitogen-activated protein kinase activation with Aggregatibacter actinomycetemcomitans causes inflammatory bone loss.
abstract: Aggregatibacter actinomycetemcomitans is a gram-negative facultative capnophile involved in pathogenesis of aggressive forms of periodontal disease. In the present study, we interrogated the ability of A. actinomycetemcomitans to stimulate innate immune signaling and cytokine production and established that A. actinomycetemcomitans causes bone loss in a novel rat calvarial model. In vitro studies indicated that A. actinomycetemcomitans stimulated considerable production of soluble cytokines, tumor necrosis factor-α, interleukin-6 and interleukin-10 in both primary bone marrow-derived macrophages and NR8383 macrophages. Immunoblot analysis indicated that A. actinomycetemcomitans exhibits sustained activation of all major mitogen-activated protein kinase (MAPK) pathways, as well as the negative regulator of MAPK signaling, MAPK phosphatase-1 (MKP-1), for at least 8 h. In a rat calvarial model of inflammatory bone loss, high and low doses of formalin-fixed A. actinomycetemcomitans were microinjected into the supraperiosteal calvarial space for 1-2 weeks. Histological staining and micro-computed tomography of rat calvariae revealed a significant increase of inflammatory and fibroblast infiltrate and increased bone resorption as measured by total lacunar pit formation. From these data, we provide new evidence that fixed whole cell A. actinomycetemcomitans stimulation elicits a pro-inflammatory host response through sustained MAPK signaling, leading to enhanced bone resorption within the rat calvarial bone.
authors.affiliation: Department of Craniofacial Biology and the Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dunmyer
authors.forename: B
authors.initials: B
authors.lastname: Herbert
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Zinna
authors.forename: K
authors.initials: K
authors.lastname: Martin
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: K L
authors.initials: KL
authors.lastname: Kirkwood
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000201:enzymology* / Q000276:immunology; D000818:Animals; D058491:Bacterial Load; D001862:Bone Resorption / Q000276:immunology / Q000382:microbiology*; D002452:Cell Count; D018929:Cell Culture Techniques; D002460:Cell Line; D004789:Enzyme Activation; D005347:Fibroblasts / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000382:microbiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology; D010010:Osteoclasts / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012886:Skull / Q000276:immunology / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D055114:X-Ray Microtomography
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases