Abstract
The interrelationships between periodontal disease, obesity-related hyperlipidemia and mechanical forces and their modulating effects on the epigenetic profile of periodontal ligament (PdL) cells are assumed to be remarkably complex. The PdL serves as a connective tissue between teeth and alveolar bone and is involved in pathogen defense and the inflammatory responses to mechanical stimuli occurring during tooth movement. Altered inflammatory signaling could promote root resorption and tooth loss. Hyperinflammatory COX2/PGE2 signaling was reported for human PdL fibroblasts (HPdLFs) concomitantly stressed with Porphyromonas gingivalis lipopolysaccharides and compressive force after exposure to palmitic acid (PA). The aim of this study was to investigate the extent to which this was modulated by global and gene-specific changes in histone modifications. The expression of key epigenetic players and global H3Kac and H3K27me3 levels were quantitatively evaluated in dual-stressed HPdLFs exposed to PA, revealing a minor force-related reduction in repressive H3K27me3. UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory responses of dual-stressed PA cultures characterized by increased COX2 expression, PGE2 secretion and THP1 adhesion. The reduced expression of the gene encoding the anti-inflammatory cytokine IL-10 and the increased presence of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between the different stimuli to which the PdL is exposed.
Highlights
Genetic predisposition, unfavorable environmental conditions and an unhealthy lifestyle are important risk factors for the onset and progression of periodontal disease, but they cannot fully account for individual susceptibility [1]
We recently reported that palmitic acid (PA)-stimulated human periodontal ligament (PdL) fibroblasts (HPdLFs) showed an excessive inflammatory response to simultaneous stimulation with P. gingivalis LPS and compressive force, mainly through the enhanced secretion of prostaglandin E2 (PGE2) [39], which is regulated by cyclooxygenase 2 (COX2) [40]
To elucidate the role of histone 3 (H3) lysine acetylation (H3Kac) in the regulation of the hyperinflammatory responses of PA-exposed HPdLFs simultaneously stimulated by mechanical and bacterialinduced stress, we first examined the expression of relevant H3K9/14/18/23/27 acetylation (H3Kac) regulators (Figure 1a,b), which are associated with PdL properties, periodontal disease and hyperlipidemia [48–52]
Summary
Unfavorable environmental conditions and an unhealthy lifestyle are important risk factors for the onset and progression of periodontal disease, but they cannot fully account for individual susceptibility [1]. In light of the high prevalence of this chronic, non-communicable disease and its subsequent economic and healthcare implications [2], the investigation of additional key regulatory mechanisms has been the focus of recent periodontitis research. This has drawn attention to epigenetic regulatory mechanisms as important factors in the pathogenesis of the disease [3]. With regard to the inflammatory aspects of periodontal disease, post-translational modifications (PTMs) to histone tail amino acids have been thoroughly investigated [5]. Regarding the expression of key factors regulating PTMs, a number of comparative studies have shown differences between periodontal patients and healthy subjects [5], presumably caused by the pathogenic infections and possibly linked to excesses of bacterial metabolites, such as short-chain fatty acids [8]
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