Abstract
Apart from periodontal ligament fibroblasts, immune cells like macrophages also play an important mediating role in orthodontic tooth movement (OTM). Upon orthodontic force application to malpositioned teeth, macrophages in the periodontal ligament get exposed to both mechanical strain and hypoxic conditions (via a compression of blood vessels). In this study, we assessed the relative impact of orthodontically induced mechanical strain and hypoxic conditions on macrophages for the mediation and regulation of OTM. Macrophages were stimulated with physiological orthodontic compressive forces of 2 g/cm2 for 4 h and 24 h on gas-impermeable or gas-permeable cell culture plates under normoxic or hypoxic cell culture conditions. We quantified expression of genes involved in inflammation (Tnf, Il-6, and Cox-2), extracellular remodelling (Mmp-9), and angiogenesis (Vegf) by RT-qPCR. Furthermore, we analysed HIF-1α, prostaglandin-E2, and VEGF protein expression via immunoblotting or ELISA. Mechanical strain and oxygen supply both differentially affected expression of genes and proteins involved in inflammation and angiogenesis. In this context, we found that HIF-1α protein levels were elevated by combined mechanical strain and hypoxic conditions, whereas gas-permeable plates providing sufficient oxygen supply prevented HIF-1α stabilization at the protein level after pressure application on macrophages. Our results thus indicate that macrophages involved in the mediation of OTM are affected by and respond differently to hypoxic conditions and mechanical compressive strain, which occur concomitantly during OTM, than periodontal ligament fibroblasts (PDLF), thus indicating different roles of these cells in the regulation of OTM at the cellular-molecular level. We further observed that contrary to PDLF HIF-1α stabilization in macrophages is rather induced via the decreased oxygen supply associated with OTM than via mechanotransduction by mechanical strain.
Highlights
Carl Sandstedt examined tissue remodelling during orthodontic treatments aimed at correcting malocclusions and malpositioned teeth over 100 years ago and found that the alveolar bone adapts to the pressure and tension zones created within the periodontal ligament by the application of therapeutic orthodontic forces to teeth [1]
Effects of compressive force treatment compared to oxygen supply on macrophages are so far unknown. As these immune cells constitute an important cell population within the periodontal ligament and are involved in the regulation and instigation of orthodontic tooth movement (OTM) at the cellular-molecular level [8], the aim of this work was to clarify the relative impact of orthodontically induced mechanical strain and hypoxic conditions in the periodontal ligament on macrophages for the mediation and regulation of OTM focusing on hypoxia inducible factor 1α (HIF-1α) expression and its stabilization as well as on genes and proteins involved in the inflammatory processes occurring during OTM
Mechanical compressive strain as occurring during OTM in pressure zones of the periodontal ligament has a mechanotransductive effect on compressed cells and reduces oxygen supply by compression of blood vessels
Summary
Carl Sandstedt examined tissue remodelling during orthodontic treatments aimed at correcting malocclusions and malpositioned teeth over 100 years ago and found that the alveolar bone adapts to the pressure and tension zones created within the periodontal ligament by the application of therapeutic orthodontic forces to teeth [1]. Cytokines and other inflammatory markers are secreted into the periodontal tissue by periodontal fibroblasts [3, 4] or immune cells [5] to attract additional leukocytes and macrophages [6, 7] inducing a “pseudoinflammatory process” [1]. This process is characterized by a promotion of inflammation but may accelerate other noninflammatory processes mediated by periodontal ligament cells [1]. To fibroblasts, which make up the main cell population in the periodontal ligament, immune cells like macrophages are present, which will be exposed to mechanical strain and changing oxygen supply during
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