The role of mechanotransductively-induced HIF1α stabilization for the regulation of orthodontic tooth movement

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For orthodontic tooth movement, a sterile-inflammatory, immunological process at the cellular-molecular level, a mechanical force is transmitted to a tooth. This creates pressure and tension zones in the periodontal ligament (PDL), where bone resorption and bone building processes take place, which enable tooth movement in the direction of force. In our own preparatory work within the framework of the DFG project KI2105/1-1, we examined in the rat (in vivo) and in human PDL fibroblasts (in vitro), whether the hypoxia-associated transcription factor HIF-1α is stabilized during orthodontic force application and tooth movement in the PDL and whether this stabilization continues to increase under the influence of nicotine, which may explain the previously observed potentiation of periodontal bone loss. In addition, the project investigated whether HIF-1α is rather regulated by hypoxia or rather non-hypoxically (e.g. by mechanotransduction / inflammation). Our results indicate a significant increase in HIF1α stabilization in the PDL during force application (tooth movement) compared to controls. Surprisingly, nicotine did not have an additive effect on this HIF1α induction either with or without force application, so that the previously observed potentiation in the PDL cannot be explained by an increased expression of HIF1α or hypoxic states. Further in vitro results indicate that the regulation of HIF1α in the PDL in the context of tooth movement is predominantly controlled by the force application itself (mechanotransduction), whereas hypoxic effects seem to play only a minor role. In addition to human PDL fibroblasts, macrophages also play an important role as immune cells, on the one hand through secretion of cytokines and chemokines, on the other hand as direct progenitor cells of osteoclasts. In the context of the proposed project, the actual role and significance of HIF1α for orthodontic tooth movement and its regulation at the molecular-cellular level is to be clarified. To this end, the extent, localization, effects and a possible mechanism of a mechanotransductively induced stabilization or inhibition (siRNA silencing) of the transcription factor HIF1α in human PDL fibroblasts and macrophages or in the (peri)dental tissue is to be investigated in established in vitro and in vivo models of orthodontic tooth movement. Because HIF1α regulates more than 100 genes by transcriptional activation, which are in part already described in relation to orthodontic tooth movement (cell proliferation and migration, angiogenesis, inflammation, osteoclastogenesis), and since HIF1α also seems to have an inhibitory effect on force-induced bone formation, it can be assumed that HIF1α plays a key role in the regulation of orthodontic tooth movement.