Sustained MAPK Activation with Aggregatibacter actinomycetemcomitans Causes Inflammatory Bone Loss

• Published in: Molecular oral microbiology 2012-07, Vol.27 (5), p.397-407
• Main Authors: Dunmyer, Joni, Herbert, Bethany, Li, Qiyan, Zinna, Robert, Martin, Kylie, Yu, Hong, Kirkwood, Keith L.
• Format: Article
• Language: English
• ISSN: 2041-1006; 2041-1014
• DOI: 10.1111/j.2041-1014.2012.00656.x

Aggregatibacteractinomycetemcomitans 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 then 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, TNF-α, IL-6, and IL-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 hours. In a rat calvarial model of inflammatory bone loss, high and low doses of formalin fixed A. actinomycetemcomitans were microinjected into the supraperiostealcalvarial space for 1 to 2 weeks.Histological staining and micro-computed tomography (μCT) of rat calvariae revealed a significant increase of inflammatoryand fibroblast infiltrate and increased bone resorptionas measured by total lacunar pit formation.From these data, we provide new evidence thatfixed 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.