Effects of lipopolysaccharides on periodontal ligament fibroblasts under compressive force via Eph-ephrin signaling

Abstract

Orthodontic treatment is performed to correct a malocclusion to obtain a functional occlusion and favourable facial profile. However, active periodontitis, a common problem among adult patients, can cause pathological bone resorption, which is a contraindication and challenge for adult orthodontics. Therefore, it is believed that active periodontitis has negative effects on the efficacy and velocity of orthodontic tooth movement (OTM). Since the number of adults seeking orthodontic therapy is growing due to the increasing needs for the improvement of facial aesthetics, inflammation controlling that is required to stabilise the periodontitis before orthodontic treatment begins has become a key topic of contemporary studies. Even though periodontal inflammation controlling is strongly recommended to secure OTM, the underlying mechanism of the bone homeostasis-associated cellular response to inflammation controlling and the recovery of periodontal ligament fibroblasts (PDLFs) after previous exposure to inflammatory stimuli has not been thoroughly elucidated. Studies have confirmed the importance of Eph-ephrin bidirectional signaling in various biological processes. Amongst, it is recently reported that EphA2-ephrinA2 and EphB4-ephrinB2 interactions coordinate bone remodeling in bone cells and PDLFs. But the multifunctional activities of this two couplings of Eph-ephrin involved in regulation between periodontitis and orthodontics have not yet been explored. Thus, for the first time, we aimed to evaluate the effects of lipopolysaccharides (LPS) on PDLFs under compressive force (CF) via Eph-ephrin signaling. First, we systematically reviewed the in-vitro approaches used to apply mechanical force to PDLFs and the cellular response to force-induced bone modeling. With the CF magnitude determined from the systematic review, we then stimulated primary human PDLFs isolated from extracted healthy premolars with Porphyromonas gingivalis LPS, with or without the combination of static CF. The results revealed that both the P. gingivalis LPS and the CF stimulus alone could alter the expression of EphA2-ephrinA2 and EphB4-ephrinB2 signaling in PDLFs. However, the compressed PDLFs previously exposed to P. gingivalis LPS behaved differently from those upon ongoing P. gingivalis LPS treatment, including the expression level of osteogenic and osteoclastogenic markers, as well as the osteoblastic differentiation of PDLFs and its ability to induce osteoclastic formation in co-culture with osteoclast precursors. Finally, the positive and negative management of Ephs and ephrins disclosed that the bone remodeling regulated by P. gingivalis LPS and CF stimulation was dependent on EphA2-ephrinA2 and EphB4-ephrinB2 communication. Overall, the in-vitro experiment suggests that P. gingivalis LPS-induced inflammatory effects on the PDLFs upon physical CF leads to dysregulation and dysfunction of the balance between osteogenic and osteoclastogenic activities, and inflammation controlling before the application of mechanical CF can mediate these activities, which rely in part on regulation of the EphA2-ephrinA2 and EphB4-ephrinB2 signaling pathways. Elucidating of the cellular mechanism behind inflammation controlling may facilitate the development of a novel vision for orthodontic treatment in patients with periodontitis.