The alveolar bone provides structural support against compressive and tensile forces generated during mastication as well as during orthodontic treatment. To avoid abnormal alveolar bone resorption and tooth loss, a balanced bone turnover by bone-degrading osteoclasts and bone-generating osteoblasts is of great relevance. Unlike its contradictory role in regulating osteoclast and osteoblast cell differentiation, the TGF-β/BMP-family member GDF15 is well known for its important functions in the regulation of cell metabolism, as well as cell fate and survival in response to cellular stress. Here, we provide first evidence for a potential role of GDF15 in translating mechanical stimuli into cellular changes in immature osteoblasts. We detected enhanced levels of GDF15 in vivo in periodontal ligament cells after the simulation of tooth movement in rat model system as well as in vitro in mechanically stressed human periodontal ligament fibroblasts. Moreover, mechanical stimulation enhanced GDF15 secretion by periodontal ligament cells and the stimulation of human primary osteoblast with GDF15 in vitro resulted in an increased transcription of osteogenic marker genes like RUNX2, osteocalcin (OCN) and alkaline phosphatase (ALP). Together, the present data emphasize for the first time a potential function of GDF15 in regulating differentiation programs of immature osteoblasts according to mechanical stimulation.

The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases (DNMTs), mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mitotic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.

Periodontitis is characterized by bacterially induced inflammatory destruction of periodontal tissue. This also affects fibroblasts of the human periodontal ligaments (HPdLF), which play a coordinating role in force-induced tissue and alveolar bone remodeling. Excessive inflammation in the oral tissues has been observed with simultaneous stimulation by pathogens and mechanical forces. Recently, elevated levels of growth differentiation factor 15 (GDF15), an immuno-modulatory member of the transforming growth factor (TGFB) superfamily, were detected under periodontitis-like conditions and in force-stressed PdL cells. In view of the pleiotropic effects of GDF15 in various tissues, this study aims to investigate the role of GDF15 in P. gingivalis-related inflammation of HPdLF and its effect on the excessive inflammatory response to concurrent compressive stress. To this end, the expression and secretion of cytokines (IL6, IL8, COX2/PGE2, TNFα) and the activation of THP1 monocytic cells were analyzed in GDF15 siRNA-treated HPdLF stimulated with P. gingivalis lipopolysaccharides alone and in combination with compressive force. GDF15 knockdown significantly reduced cytokine levels and THP1 activation in LPS-stimulated HPdLF, which was less pronounced with additional compressive stress. Overall, our data suggest a pro-inflammatory role for GDF15 in periodontal disease and demonstrate that GDF15 partially modulates the force-induced excessive inflammatory response of PdLF under these conditions.

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.

Alveolar bone (AB) remodeling is necessary for the adaption to mechanical stimuli occurring during mastication and orthodontic tooth movement (OTM). Thereby, bone degradation and assembly are strongly regulated processes that can be altered in obese patients. Further, increased fatty acids (FA) serum levels affect bone remodeling cells and we, therefore, investigated whether they also influence the function of periodontal ligament fibroblast (PdLF). PdLF are a major cell type regulating the differentiation and function of osteoblasts and osteoclasts localized in the AB. We stimulated human PdLF (HPdLF) in vitro with palmitic (PA) or oleic acid (OA) and analyzed their metabolic activity, growth, survival and expression of osteogenic markers and calcium deposits. Our results emphasize that PA increased cell death of HPdLF, whereas OA induced their osteoblastic differentiation. Moreover, quantitative expression analysis of OPG and RANKL revealed altered levels in mechanically stimulated PA-treated HPdLF. Furthermore, osteoclasts stimulated with culture medium of mechanical stressed FA-treated HPdLF revealed significant changes in cell differentiation upon FA-treatment. For the first time, our results highlight a potential role of specific FA in the function of HPdLF-modulated AB remodeling and help to elucidate the complex interplay of bone metabolism, mechanical stimulation and obesity-induced alterations.

In obese patients, enhanced serum levels of free fatty acids (FFA), such as palmitate (PA) or oleate (OA), are associated with an increase in systemic inflammatory markers. Bacterial infection during periodontal disease also promotes local and systemic low-grade inflammation. How both conditions concomitantly impact tooth movement is largely unknown. Thus, the aim of this study was to address the changes in cytokine expression and the secretion of human periodontal ligament fibroblasts (HPdLF) due to hyperlipidemic conditions, when additionally stressed by bacterial and mechanical stimuli. To investigate the impact of obesity-related hyperlipidemic FFA levels on HPdLF, cells were treated with 200 µM PA or OA prior to the application of 2 g/cm² compressive force. To further determine the additive impact of bacterial infection, HPdLF were stimulated with lipopolysaccharides (LPS) obtained from Porphyromonas gingivalis. In mechanically compressed HPdLF, PA enhanced COX2 expression and PGE2 secretion. When mechanically stressed HPdLF were additionally stimulated with LPS, the PGE2 and IL6 secretion, as well as monocyte adhesion, were further increased in PA-treated cultures. Our data emphasize that a hyperlipidemic condition enhances the susceptibility of HPdLF to an excessive inflammatory response to compressive forces, when cells are concomitantly exposed to bacterial components.