Date of Award

2016

Embargo Period

8-1-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Oral Health Sciences

College

College of Graduate Studies

First Advisor

Keith Kirkwood

Second Advisor

Michael J. Kern

Third Advisor

Courtney Haycraft

Fourth Advisor

Sakamuri Reddy

Fifth Advisor

Bei Liu

Abstract

In the United States, 47% of the adult population has periodontal disease. As periodontal disease progresses, inflammation can ultimately lead to irreversible bone and tooth loss. Mitogen activated protein kinases (MAPKs) modulate the innate host inflammatory response during periodontal disease. MAPK-activated protein kinase 2 (MK2), a downstream target of p38 MAPK, regulates inflammation in macrophages and osteoclast formation in aggressive periodontal disease animal models. Both macrophages and osteoclasts are derived from a monocyte lineage that expresses surface chemokine receptors critical for chemotaxis from circulation to peripheral sites of infection. Previous results from our laboratory show that Aggregatibacter actinomycetemcomitans, an aggressive periodontal disease pathogen, and lipopolysaccharide (LPS) from A. actinomycetemcomitans activate MK2. In an A. actinomycetemcomitans LPS challenged rat model, MK2 positively regulates inflammatory infiltration and bone loss. These studies support a role for MK2 as a regulator of macrophage differentiation and chemokine expression during A. actinomycetemcomitans infection in murine pre-clinical models. We utilized 2 murine models for experimentation: the A. actinomycetemcomitans-driven calvarial model and the bone marrow transplant model to create chimeric MK2 mice followed by A. actinomycetemcomitans infection in the dorsal air pouch. These animal models as well as in vitro studies enabled us to assess the role of hematopoietic and non-hematopoietic MK2 signaling in monocyte chemotaxis. MK2 signaling was critical for pathologic regulation of cytokines, chemokines, and macrophage infiltrate. MK2 signaling also regulated osteoclastogenesis, which was supported by a decrease in A. actinomycetemcomitans driven calvarial pit formation and receptor activator of nuclear factor kappa-B ligand (RANKL) gene expression in vivo. Furthermore, the mechanism of MK2 signaling in RANKL-induced osteoclastogenesis in vitro showed that defined osteoclast progenitor cells with CD11blo cell surface expression (dOCPlo) were the most osteoclastogenic and regulated by MK2 signaling in male mice. In dOCPlo cells, MK2 positively regulated dendritic cell-specific transmembrane protein (DC-STAMP) and osteoclast stimulatory transmembrane protein (OC-STAMP) gene expression in male murine derived osteoclasts. In conclusion, MK2 signaling regulates chemokine signaling pathways, monocyte plasticity and differentiation, and osteoclastogenesis mechanisms during host-pathogen interactions.

Rights

All rights reserved. Copyright is held by the author.

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