Role and Regulation of Mechanotransductive HIF-1α Stabilisation in Periodontal Ligament Fibroblasts

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.

Myeloid HIF1α Is Involved in the Extent of Orthodontically Induced Tooth Movement

“…This could be due to a possible compensatory role of periodontal ligament fibroblasts during orthodontic tooth movement, which react to compressive force with increased Ptgs2 gene expression [7,21]. The by tendency observed increase of Ptgs2 gene expression in Hif1α ∆myel mice during OTM, however, would be in accordance with previous research, showing that Ptgs2 expression is regulated by Hif1α [32,33]. In macrophages, on the other hand, an uncoupling of compressive force and oxygen supply in vitro reduced HIF1α stabilisation without affecting Ptgs2 gene expression or prostaglandin E2 release [17].…”

“…Therefore, this study demonstrates that myeloid HIF1α seems to have a bone-protective role during orthodontic tooth movement. A targeted stabilisation of myeloid HIF1α during orthodontic treatment, as was done experimentally via DMOG (dimethyloxallyl glycine) [32], might thus in the future be a possible therapeutic approach to reduce treatment-related periodontal hazards, which needs to be investigated in further studies.…”

MAPK and β-Catenin signaling: implication and interplay in orthodontic tooth movement

“…Focal adhesions which sited with integrin receptors attach the PDL fibroblasts to each other [34]. Therefore, integrins transmit forces across the cell membrane, and integrin receptors are candidates of mechanoreceptors [35]. The stimulation of appropriate orthodontic force leads to periodontal tissue reconstruction by adaptive changes at the molecular level in different microenvironments, including the extracellular matrix, cell membrane, cytoskeleton, nucleoprotein and genome [36].…”

Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

“…The hypoxia-inducible PD-L1 expression has been revealed in multiple primary and various carcinoma cell types [15,16]. The hypoxia-induced transcription factors (HIF) are crucial regulators of the transcriptional responses to orthodontic forces [17] and have been reported to regulate the apoptosis process of cementoblasts [2]. However, it is currently largely unknown whether HIF-1α regulates PD-L1 expression in cementoblasts.…”