Abstract
Orthodontic tooth movement (OTM) creates compressive and tensile strain in the periodontal ligament, causing circulation disorders. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be primarily stabilised by compression, but not hypoxia in periodontal ligament fibroblasts (PDLF) during mechanical strain, which are key regulators of OTM. This study aimed to elucidate the role of heparan sulfate integrin interaction and downstream kinase phosphorylation for HIF-1α stabilisation under compressive and tensile strain and to which extent downstream synthesis of VEGF and prostaglandins is HIF-1α-dependent in a model of simulated OTM in PDLF. PDLF were subjected to compressive or tensile strain for 48 h. In various setups HIF-1α was experimentally stabilised (DMOG) or destabilised (YC-1) and mechanotransduction was inhibited by surfen and genistein. We found that HIF-1α was not stabilised by tensile, but rather by compressive strain. HIF-1α stabilisation had an inductive effect on prostaglandin and VEGF synthesis. As expected, HIF-1α destabilisation reduced VEGF expression, whereas prostaglandin synthesis was increased. Inhibition of integrin mechanotransduction via surfen or genistein prevented stabilisation of HIF-1α. A decrease in VEGF expression was observed, but not in prostaglandin synthesis. Stabilisation of HIF-1α via integrin mechanotransduction and downstream phosphorylation of kinases seems to be essential for the induction of VEGF, but not prostaglandin synthesis by PDLF during compressive (but not tensile) orthodontic strain.
Highlights
To improve dental health and aesthetics, orthodontic treatment strives to correct malpositioned teeth, as malocclusions may provoke diseases such as caries or periodontitis [1,2]
Gene expression of prostaglandin synthase 2 (PTGS-2) was elevated by DMOG treatment in the absence (p < 0.0001) and presence of pressure application (p = 0.0052; Figure 2c)
PTGS-2 gene expression and prostaglandin E2 (PG-E2) secretion were both elevated by compressive strain without and with the addition of surfen (PTGS-2: p = 0.0054; PG-E2: p < 0.0001; Figure 4e,f), indicating that Hypoxia-inducible factor 1α (HIF-1α) is not involved in the upregulation of PTGS-2/PG-E2
Summary
To improve dental health and aesthetics, orthodontic treatment strives to correct malpositioned teeth, as malocclusions may provoke diseases such as caries or periodontitis [1,2]. For orthodontic tooth movement (OTM), mechanical forces are applied to a tooth in the direction of movement using removable or fixed orthodontic appliances This induces tension and pressure zones in the periodontal ligament, a connective tissue rich in collagenous fibres connecting the tooth to its surrounding alveolar bone, thereby affecting local perfusion via a compression of blood vessels [2,3]. This is accompanied by a sterile inflammatory response, which is distinguished by an increased release of cytokines and chemokines, leading to further attraction of inflammatory and immune cells into the periodontal ligament [3,4,5,6]. Most of the cellular and chemical adaptations occurring in pressure zones of the periodontal ligament aim to recruit osteoclast precursor cells and to differentiate them into osteoclasts that resorb the adjacent alveolar bone and remove the necrotic hyalinised tissue caused by hypoxia, enabling tooth movement
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