Effect of Tension on Human Periodontal Ligament Cells: Systematic Review and Network Analysis

Abstract

Orthodontic tooth movement is based on the remodeling of tooth-surrounding tissues in response to mechanical stimuli. During this process, human periodontal ligament cells (hPDLCs) play a central role in mechanosensing and mechanotransduction. Various in vitro models have been introduced to investigate the effect of tension on hPDLCs. They provide a valuable body of knowledge on how tension influences relevant genes, proteins, and metabolites. However, no systematic review summarizing these findings has been conducted so far. Aim of this systematic review was to identify all related in vitro studies reporting tension application on hPDLCs and summarize their findings regarding force parameters, including magnitude, frequency and duration. Expression data of genes, proteins, and metabolites was extracted and summarized. Studies’ risk of bias was assessed using tailored risk of bias tools. Signaling pathways were identified by protein-protein interaction (PPI) networks using STRING and GeneAnalytics. According to our results, Flexcell Strain Unit® and other silicone-plate or elastic membrane-based apparatuses were mainly adopted. Frequencies of 0.1 and 0.5 Hz were predominantly applied for dynamic equibiaxial and uniaxial tension, respectively. Magnitudes of 10 and 12% were mostly employed for dynamic tension and 2.5% for static tension. The 10 most commonly investigated genes, proteins and metabolites identified, were mainly involved in osteogenesis, osteoclastogenesis or inflammation. Gene-set enrichment analysis and PPI networks gave deeper insight into the involved signaling pathways. This review represents a brief summary of the massive body of knowledge in this field, and will also provide suggestions for future researches on this topic.

Effect of Different Parameters of In Vitro Static Tensile Strain on Human Periodontal Ligament Cells Simulating the Tension Side of Orthodontic Tooth Movement

“…Interestingly, TNFRSF11B gene expression was below the detection limit in all experimental conditions in this study. In contrast, upregulation of TNFRSF11B has been reported previously in hPDLCs after exposure to static tensile strain for 12 h but not for longer periods of time [16,54,57]. Thus, one might assume that the TNFRSF11B gene is already upregulated by tensile strain in shorter time periods than covered in the present study.…”

“…Similar results were obtained considering the specific anatomy of the PDL in vivo: application of 1 N and 3 N forces to incisors led to an increase in PDL width of ~12% [38]. A recent systematic review reported 10% tensile strain as the most frequently applied magnitude [16]. Herein, 10% tensile strain was selected as being equivalent to a physiological force exposure, whereas 20% cell stretching is commonly used to investigate the influence of pathogenic stimuli on cellular mechanotransduction in hPDLCs [39][40][41] and therefore was considered the upper limit of tensile strain in this study.…”

“…Therefore, the effect of tension on hPDLCs has been widely addressed in numerous in vitro studies, which have been recently reviewed [16,31]. In most of these in vitro studies, the effects of exclusively one specific tensile strain magnitude were analyzed, commonly for a maximum of 48 h using tension devices based on cells growing on a flexible membrane, similar to the one proposed in this study [16]. However, the combined effects of different magnitudes together with various durations on hPDLCs have rarely been compared.…”

“…In a recently published systematic review [16], different sources were identified to deduce clinical relevant tensile strain magnitudes for in vitro studies: (1) tensile strain derived from mastication or OTM [32][33][34][35], (2) finite element simulation including biomechanical confirmation [36,37], (3) the specific anatomy of the periodontium including the PDL width [38], or (4) previously published studies [39][40][41]. Based on finite element simulations and biomechanical testing, it was shown that bodily movement of a premolar tooth with 1 N pressure induced 1% strain in the PDL on the tension side [36], whereas strains of 6-7% for intrusive and 8-25% for horizontal tooth movement in the PDL were reported after application of 3 N intrusive loading [37].…”

“…To gain improved insight into the effects of therapeutic forces on the expression and regulation of relevant genes involved in tooth movement and bone remodeling, different in vitro force application models have been suggested specifically in terms of compressive forces [7,[13][14][15]. Regarding tension, different in vitro models have been applied addressing distinct issues [16][17][18], i.e., apoptosis [19,20], pyroptosis [21], angiogenesis [22], osteogenesis [23] and inflammation [24], but most of these studies focused on specific tension magnitudes only. Even in those studies considering different magnitudes, tension was only applied for a single period of time [25][26][27][28].…”