Mechanisms of peroxisome proliferator-activated receptor-alpha regulation in peridontitis

Ada Forsyth Institute, Inc., Cambridge MA

Investigators

Abstract

Project Summary This application is for the extension of our current R03 grant titled “Pathogenic role of peroxisome proliferator- activated receptor alpha in periodontitis”, which has produced 2 published and 1 under review publications so far. Our studies have focused on the pathogenic role of PPARα in periodontal inflammation and bone resorption. Specifically, we demonstrated that PPARα not PPARβ or PPARγ had decreased expression levels in gingival cells stimulated with periodontitis antigens and in gingival tissue of mouse experimental periodontitis, and PPARα agonist treatment significantly reduces inflammation and bone loss in experimental periodontitis. While the mechanism of how activated PPARα regulates these pathology of periodontitis is largely unknown. Our recent data demonstrated that activation of PPARα inhibited the NF-kB (p65) signaling and increased the anti- inflammatory cytokines IL-10 and its secretion factor CD36 in the macrophages. The Wnt pathway was aberrantly activated in the macrophage during periodontitis in vivo and activated PPARα decreased Wnt/β-catinin/TCF-4 activity and induced a binding of β-catenin with PPARα in in vitro studies. Together with the previously published findings by others, we hypothesize that PPARα is an effective macrophage modulator through diversion the Wnt/β-catenin signaling via competing with TCF4 for binding to β-catenin, enhancing the CD36/IL-10 mediated anti-inflammatory transcriptional activities and suppressing the TCF4 mediated pro- inflammatory transcriptional activities. In this proposal, we will first determine if PPARα agonist’s periodontitis protective effect is via modulating macrophage polarization through a PPARα agonist dependent mechanism (Aim 1); Then we will explore the underlying mechanism by which PPARα modulates macrophage in the periodontitis (Aim 2). Successful completion of this project will generate conceptual advances in our understanding of the etiology of the disease by highlighting previously poorly understood pathways of inflammation. If our hypothesis is correct, these studies will broaden our insights into the potential role of PPARα in the regulation of macrophages in the inflammation of periodontal disease, as well as other immune-mediated osteolytic conditions such as osteoporosis or rheumatoid arthritis.