Palmitate-Triggered COX2/PGE2-Related Hyperinflammation in Dual-Stressed PdL Fibroblasts Is Mediated by Repressive H3K27 Trimethylation

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

Oleic acid-related anti-inflammatory effects in force-stressed PdL fibroblasts are mediated by H3 lysine acetylation associated with altered IL10 expression

The initiation of a spatially and temporally limited inflammation is essential for tissue and bone remodelling by the periodontal ligament (PdL) located between teeth and alveolar bone. Nutritional components may cause alterations in the inflammatory response of PdL fibroblasts to mechanical stress such as those occurring during orthodontic tooth movement (OTM). Recently, we reported an attenuated pro-inflammatory response of human PdL fibroblasts (HPdLFs) to compressive forces when stimulated with oleic acid (OA), a monounsaturated fatty acid particularly prominent in the Mediterranean diet. Fatty acids could serve as alternative source of acetyl-CoA, thereby affecting epigenetic histone marks, such as histone 3 lysine acetylation (H3Kac) in a lipid metabolism-dependent manner. In this study, we aimed to investigate the extent to which OA exerts its anti-inflammatory effect in compressed HPdLFs via changes in H3Kac. Six-hour compressed HPdLFs showed increased H3Kac when cultured with OA. Inhibition of histone deacetylases resulted in a comparable IL10-increase as observed in compressed OA-cultures. In contrast, inhibition of histone acetyltransferases, particularly p300/CBP, in compressed HPdLFs exposed to OA normalized the inflammatory response to control levels. OA-dependent increased association of H3Kac to IL10 promoter regions in compressed HPdLFs further strengthened the assumption that OA exhibits its anti-inflammatory properties via modulation of this epigenetic mark. In conclusion, our study strongly suggests that nutritional components can directly affect PdL cells via changes in their epigenetic code. Since epigenetic inhibitors are already widely used clinically, they may hold promise for novel approaches for personalized orthodontic treatment that incorporates nutritional and metabolism-related changes