Symmank, J. | bioRxiv Science

bioRxiv2026

GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts

Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.

cell biology↗

bioRxiv2022

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 remodeling by the periodontal ligament (PdL) located between teeth and alveolar bone. Obesity-associated hyperlipidemic changes may impair PdL fibroblast (PdLF) functions, disturbing their inflammatory response to mechanical stress such as those occurring during orthodontic tooth movement (OTM). Recently, we reported an attenuated pro-inflammatory response of human PdLF (HPdLF) to compressive forces when stimulated with monounsaturated oleic acid (OA). Fatty acids, including OA, 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 therefore aimed to investigate the extent to which OA exerts its anti -inflammatory effect via changes in H3Kac. Six-hour compressed HPdLF 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 HPdLF exposed to OA led to an inflammatory response comparable to compressed control cells. OA-dependent increased association of H3Kac to IL10 promoter regions in force-stressed HPdLF further strengthened the assumption that OA exhibits its anti-inflammatory properties via modulation of this epigenetic mark. In conclusion, our study strongly suggests that obesity-related hyperlipidemia affect the functions of PdL cells via alterations in their epigenetic code. Since epigenetic inhibitors are already widely used clinically, they may hold promise for novel approaches to limit obesity-related risks during OTM.

molecular biology↗