Targeting MAPK/MKP signaling as a therapeutic axis in periodontal disease

Periodontal pathogens stimulate inflammatory cytokine and chemokine production within the periodontal microenvironment producing chronic inflammation and subsequent bone loss. In stimulated cells, the maximal induction of cytokine/chemokine expression requires activation of the p38 mitogen-activated protein kinase (MAPK) pathways. The clinical relevance of p38 MAPK activation was demonstrated by our group where excessive MAPK correlated with human periodontal disease severity. Importantly, MAPK signaling contributes toward the expression of multiple gene targets including (interleukin)-1Β, IL-6, tumor necrosis factor (TNF)-a, matrix metalloproteinase (MMP)-13, receptor activator of nuclear factor kappa-? (RANKL), and other inflammatory mediators that can contribute toward periodontal inflammation and bone destruction. Once MAPK activation and substrate phosphorylation occur, MAPK inactivation occurs through specific phosphatase activity via a family of dual-specificity MAPK phosphatases (MKPs) that target the regulatory sites of these kinases. In this chapter, the therapeutic potential to control the MAPK/MKP signaling axis of innate immunity is explored through various therapeutic platforms including small molecule inhibitors, RNA interference, gene therapy, and nanoparticle encapsulation of small molecules.