Department of Orthodontics, University Hospital Regensburg, 93053 Regensburg, Germany.
Department of Orthodontics, University of Bonn, 53111 Bonn, Germany.
Int J Mol Sci. 2020 Dec 15;21(24):9530. doi: 10.3390/ijms21249530.
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.
正畸牙齿移动（OTM）在牙周韧带中产生压缩和拉伸应变，导致循环障碍。已经表明，缺氧诱导因子 1α（HIF-1α）在机械应变期间主要通过压缩而不是缺氧在牙周韧带成纤维细胞（PDLF）中稳定，这是 OTM 的关键调节因子。本研究旨在阐明肝素硫酸整合素相互作用及其下游激酶磷酸化在压缩和拉伸应变下稳定 HIF-1α的作用，以及下游 VEGF 和前列腺素的合成在 PDLF 模拟 OTM 模型中依赖于 HIF-1α的程度。将 PDLF 置于压缩或拉伸应变下 48 小时。在各种设置中，实验稳定（DMOG）或不稳定（YC-1）HIF-1α，并通过 surfen 和 genistein 抑制机械转导。我们发现，HIF-1α不受拉伸应变的稳定，而是受压缩应变的稳定。HIF-1α 的稳定对前列腺素和 VEGF 的合成具有诱导作用。正如预期的那样，HIF-1α 的不稳定降低了 VEGF 的表达，而前列腺素的合成增加了。通过 surfen 或 genistein 抑制整合素机械转导可防止 HIF-1α的稳定。观察到 VEGF 表达减少，但前列腺素合成没有增加。通过整合素机械转导和下游激酶磷酸化稳定 HIF-1α似乎是 PDLF 在压缩（而不是拉伸）正畸应变期间诱导 VEGF 但不是前列腺素合成所必需的。
