Strain-dependent up-regulation of ephrin-B2 protein in periodontal ligament fibroblasts contributes to osteogenesis during tooth movement

During orthodontic tooth movement, the application of adequate orthodontic forces allows teeth to be moved through the alveolar bone. These forces are transmitted through the periodontal ligaments (PDL) to the supporting alveolar bone and lead to deposition or resorption of bone, depending on whether the tissues are exposed to a tensile or compressive mechanical strain. Fibroblasts within the PDL (PDLF) are considered to be mechanoresponsive. The transduction mechanisms from mechanical loading of the PDLF to the initiation of bone remodeling are not clearly understood. Recently, members of the ephrin/Eph family have been shown to be involved in the regulation of bone homeostasis. For the first time, we demonstrate that PDLF exposed to tensile strain induce the expression of ephrin-B2 via a FAK-, Ras-, ERK1/2-, and SP1-dependent pathway. Osteoblasts of the alveolar bone stimulated with ephrin-B2 increased their osteoblastogenic gene expression and showed functional signs of osteoblastic differentiation. In a physiological setting, ephrin-B2-EphB4 signaling between PDLF and osteoblasts of the alveolar bone might contribute to osteogenesis at tension sites during orthodontic tooth movement.     

The Biomechanical Function of Periodontal Ligament Fibres in Orthodontic Tooth Movement

Orthodontic tooth movement occurs as a result of resorption and formation of the alveolar bone due to an applied load, but the stimulus responsible for triggering orthodontic tooth movement remains the subject of debate. It has been suggested that the periodontal ligament (PDL) plays a key role. However, the mechanical function of the PDL in orthodontic tooth movement is not well understood as most mechanical models of the PDL to date have ignored the fibrous structure of the PDL. In this study we use finite element (FE) analysis to investigate the strains in the alveolar bone due to occlusal and orthodontic loads when PDL is modelled as a fibrous structure as compared to modelling PDL as a layer of solid material. The results show that the tension-only nature of the fibres essentially suspends the tooth in the tooth socket and their inclusion in FE models makes a significant difference to both the magnitude and distribution of strains produced in the surrounding bone. The results indicate that the PDL fibres have a very important role in load transfer between the teeth and alveolar bone and should be considered in FE studies investigating the biomechanics of orthodontic tooth movement.     

Expression of genes for gelatinases and tissue inhibitors of metalloproteinases in periodontal tissues during orthodontic tooth movement

Orthodontic tooth movement progresses by a combination of periodontal ligament (PDL) tissue and alveolar bone remodeling processes. Besides the remodeling of alveolar bone around the moving teeth, the major extracellular matrix (ECM) components of PDLs, collagens, are degenerated, degraded, and restructured. Matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), act in a co-ordinated fashion to regulate the remodeling of periodontal tissues. We hypothesized that the expression levels of the genes for MMP-2, MMP-9, and TIMPs 1–3 are increased transiently in the periodontal tissue during orthodontic tooth movement. To test this hypothesis, we employed an animal model of tooth movement using rats, as well as in situ hybridization to analyze the expression levels of Mmp-2, Mmp-9, and Timps 1-3. The expression levels of these genes increased transiently in cells of periodontal tissues, which include cementoblasts, fibroblasts, osteoblasts, and osteoclasts, at the compression side of the moving teeth. The transient increases in gene expression at the tension side were mainly limited to osteoblasts and cementoblasts. In conclusion, the expression levels of Mmp-2, Mmp-9, and Timps 1-3 increase transiently during orthodontic tooth movement at both the tension and compression sides. The expression of these genes is regulated differentially in the periodontal tissue of the tension side and compression side. This altered pattern of gene expression may determine the rate and extent of remodeling of the collagenous ECM in periodontal tissues during orthodontic tooth movement.     

Investigation of effective intrusion and extrusion force for maxillary canine using finite element analysis

Abstract

Orthodontic tooth movement is mainly regulated by the biomechanical responses of loaded periodontal ligament (PDL). We investigated the effective intervals of orthodontic force in pure maxillary canine intrusion and extrusion referring to PDL hydrostatic stress and logarithmic strain. Finite element analysis (FEA) models, including a maxillary canine, PDL and alveolar bone, were constructed based on computed tomography (CT) images of a patient. The material properties of alveolar bone were non-uniformly defined using HU values of CT images; PDL was assumed to be a hyperelastic–viscoelastic material. The compressive stress and tensile stress ranging from 0.47 to 12.8?kPa and 18.8 to 51.2?kPa, respectively, were identified as effective for tooth movement; a strain 0.24% was identified as the lower limit of effective strain. The stress/strain distributions within PDL were acquired in canine intrusion and extrusion using FEA; root apex was the main force-bearing area in intrusion–extrusion movements and was more prone to resorption. Owing to the distinction of PDL biomechanical responses to compression and tension, the effective interval of orthodontic force was substantially lower in canine intrusion (80–90?g) than in canine extrusion (230–260?g). A larger magnitude of force remained applicable in canine extrusion. This study revised and complemented orthodontic biomechanical behaviours of tooth movement with intrusive–extrusive force and could further help optimize orthodontic treatment.     

Mass acquisition of human periodontal ligament stem cells

The periodontal ligament (PDL) is an essential fibrous tissue for tooth retention in the alveolar bone socket. PDL tissue further functions to cushion occlusal force, maintain alveolar bone height, allow orthodontic tooth movement, and connect tooth roots with bone. Severe periodontitis, deep caries, and trauma cause irreversible damage to this tissue, eventually leading to tooth loss through the destruction of tooth retention. Many patients suffer from these diseases worldwide, and its prevalence increases with age. To address this issue, regenerative medicine for damaged PDL tissue as well as the surrounding tissues has been extensively investigated regarding the potential and effectiveness of stem cells, scaffolds, and cytokines as well as their combined applications. In particular, PDL stem cells (PDLSCs) have been well studied. In this review, I discuss comprehensive studies on PDLSCs performed in vivo and contemporary reports focusing on the acquisition of large numbers of PDLSCs for therapeutic applications because of the very small number of PDLSCs available in vivo.     

Focal adhesion kinase mediates β-catenin signaling in periodontal ligament cells

Periodontal ligament (PDL) cells convert the orthodontic forces into biological responses by secreting signaling molecules to induce modeling of alveolar bone and tooth movement. Beta-catenin pathway is activated in response to mechanical loading in PDL cells. The upstream signaling pathways activated by mechanical loading resulting in the activation of β-catenin pathway through Wnt-independent mechanism remains to be characterized. We hypothesized that mechanical loading induces activation of β-catenin signaling by mechanisms that dependent on focal adhesion kinase (FAK) and nitric oxide (NO). We found that mechanical or pharmacological activation of β-catenin signaling in PDL cells upregulated the expression of β-catenin target genes. Pre-treatment of PDL cells with FAK inhibitor-14 prior to mechanical loading abolished the mechanical loading-induced phosphorylation of Akt and dephosphorylation of β-catenin. PDL cells pre-treated with NO donor or NO inhibitor and subjected to mechanical loading. Western blot analysis showed that the mechanical loading or pre-treatment with NO donor increased the levels of dephosphorylated β-catenin, pAkt, and pGSK-3β. Pre-treatment with NO inhibitor blocked the mechanical loading-induced phosphorylation of Akt and dephosphorylation of β-catenin. These data indicate that mechanical loading-induced β-catenin stabilization in PDL cells involves phosphorylation of Akt by two parallel pathways requiring FAK and NO.     

A visco-elastic model for the prediction of orthodontic tooth movement

This study presents a biomechanical model of orthodontic tooth movement. Although such models have already been presented in the literature, most of them incorporate computationally expensive finite elements (FE) methods to determine the strain distribution in the periodontal ligament (PDL). In contrast, the biomechanical model presented in this work avoids the use of FE methods. The elastic deformation of the PDL is modelled using an analytical approach, which does not require setting up a 3D model of the tooth. The duration of the lag phase is estimated using the calculated hydrostatic stresses, and bone remodelling is predicted by modelling the alveolar bone as a viscous material. To evaluate the model, some typically used motion patterns were simulated and a sensitivity analysis was carried out on the parameters. Results show that despite some shortcomings, the model is able to describe commonly used motion patterns in orthodontic tooth movement, in both single- and multi-rooted teeth.     

Differential expression of osteoblast and osteoclast chemmoatractants in compression and tension sides during orthodontic movement

Orthodontic tooth movement is achieved by the remodeling of alveolar bone in response to mechanical loading, and is supposed to be mediated by several host mediators, such as chemokines. In this study we investigated the pattern of mRNAs expression encoding for osteoblast and osteoclast related chemokines, and further correlated them with the profile of bone remodeling markers in palatal and buccal sides of tooth under orthodontic force, where tensile (T) and compressive (C) forces, respectively, predominate. Real-time PCR was performed with periodontal ligament mRNA from samples of T and C sides of human teeth submitted to rapid maxillary expansion, while periodontal ligament of normal teeth were used as controls. Results showed that both T and C sides exhibited significant higher expression of all targets when compared to controls. Comparing C and T sides, C side exhibited higher expression of MCP-1/CCL2, MIP-1α/CCL3 and RANKL, while T side presented higher expression of OCN. The expression of RANTES/CCL5 and SDF-1/CXCL12 was similar in C and T sides. Our data demonstrate a differential expression of chemokines in compressed and stretched PDL during orthodontic tooth movement, suggesting that chemokines pattern may contribute to the differential bone remodeling in response to orthodontic force through the establishment of distinct microenvironments in compression and tension sides.     

Low-Intensity Pulsed Ultrasound Accelerates Tooth Movement via Activation of the BMP-2 Signaling Pathway

The present study was designed to determine the underlying mechanism of low-intensity pulsed ultrasound (LIPUS) induced alveolar bone remodeling and the role of BMP-2 expression in a rat orthodontic tooth movement model. Orthodontic appliances were placed between the homonymy upper first molars and the upper central incisors in rats under general anesthesia, followed by daily 20-min LIPUS or sham LIPUS treatment beginning at day 0. Tooth movement distances and molecular changes were evaluated at each observation point. In vitro and in vivo studies were conducted to detect HGF (Hepatocyte growth factor)/Runx2/BMP-2 signaling pathways and receptor activator of NFκB ligand (RANKL) expression by quantitative real time PCR (qRT-PCR), Western blot and immunohistochemistry. At day 3, LIPUS had no effect on the rat orthodontic tooth movement distance and BMP-2-induced alveolar bone remodeling. However, beginning at day 5 and for the following time points, LIPUS significantly increased orthodontic tooth movement distance and BMP-2 signaling pathway and RANKL expression compared with the control group. The qRT-PCR and Western blot data in vitro and in vivo to study BMP-2 expression were consistent with the immunohistochemistry observations. The present study demonstrates that LIPUS promotes alveolar bone remodeling by stimulating the HGF/Runx2/BMP-2 signaling pathway and RANKL expression in a rat orthodontic tooth movement model, and LIPUS increased BMP-2 expression via Runx2 regulation.     

The divergent expression of periostin mRNA in the periodontal ligament during experimental tooth movement

A novel 90-kDa protein named periostin, which is preferentially expressed in the periosteum and the periodontal ligament (PDL), may play a role in bone metabolism and remodeling. However, the precise role of periostin in the PDL remains unclear. Therefore, we examined the expression of periostin mRNA during experimental tooth movement. Experimental tooth movement was achieved in 7-week-old male Sprague-Dawley rats. In control specimens without tooth movement, the expression of periostin mRNA was uniformly observed in the PDL surrounding the mesial and distal roots of the upper molars and was weak in the PDL of the root furcation area. The periostin mRNA-expressing cells were mainly fibroblastic cells in the PDL and osteoblastic cells on the alveolar bone surfaces. The divergent expression of periostin mRNA in the PDL began to be observed at 3 h and continued up to 96 h after tooth movement. The maximum changes, which showed stronger staining in the pressure sites than in the tension sites, were observed at 24 h. The expression of periostin mRNA in the PDL 168 h after tooth movement exhibited a similar distribution to that of the control specimens. These results suggest that periostin is one of the local contributing factors in bone and periodontal tissue remodeling following mechanical stress during experimental tooth movement.     

Experimental model of tooth mobility in the human "in vivo"]

The aim of the present study was to investigate experimentally the mechanical properties of tooth deflection under external loading. These properties have a significant impact on tooth movement during orthodontic treatment. The stresses and strains caused by tooth movement influence bone remodelling, which is the basis of orthodontic treatment. The movement of a tooth as a direct reaction to the forces acting on it is termed "initial" movement. It is nonlinear and has a clearly time-dependent component. While the initial tooth movement represents the totality of the reaction mechanisms of all the tissues of the tooth unit, it is determined primarily by the mechanical properties of the periodontal ligament (PDL). The PDL is the softest tissue of the tooth unit and is therefore subject to the largest deformations when forces act on the crown of the tooth. The objective of orthodontic treatment is to achieve as precise and rapid tooth movement as possible, without provoking such undesired effects as bone and root resorption. To enable the implementation of an optimal orthodontic force system that meets these requirements, a thorough knowledge of the biomechanics of tooth movement is a must.     

Histochemical examination of cathepsin K,MMP1 and MMP2 in compressed periodontal ligament during orthodontic tooth movement in periostin deficient mice

The purpose of this study was to investigate immunolocalization of collagenolytic enzymes including cathepsin K, matrix metalloproteinase (MMP) 1 and 2 in the compressed periodontal ligament (PDL) during orthodontic tooth movement using a periostin deficient (Pn-/-) mouse model. Twelve-week-old male mice homozygous for the disrupted periostin gene and their wild type (WT) littermates were used in these experiments. The tooth movement was performed according to Waldo’s method, in which elastic bands of 0.5 mm thickness were inserted between the first and second upper molars of mice under anesthesia. At 1 and 3 days after orthodontic force application, mice were fixed with transcardial perfusion of 4 % paraformaldehyde in 0.1 M phosphate buffer (pH 7.4), and the first molars and peripheral alveolar bones were extracted for histochemical analyses. Compared with WT mice, immunolocalization of cathepsin K, MMP1 and MMP2 was significantly decreased at 1 and 3 days after orthodontic tooth movement in the compressed PDL of Pn-/- mice, although MMP1-reactivity and MMP2-reactivity decreased at different amounts. Very little cathepsin K-immunoreactivity was observed in the assessed regions of Pn-/- mice, both before and after orthodontic force application. Furthermore, Pn-/- mice showed a much wider residual PDL than WT mice. Taken together, we concluded that periostin plays an essential role in the function of collagenolytic enzymes like cathepsin K, MMP1 and MMP2 in the compressed PDL after orthodontic force application.     

Effect of variable periodontal ligament thickness and its non-linear material properties on the location of a tooth’s centre of resistance

In orthodontics, the 3D translational and rotational movement of a tooth is determined by the force–moment system applied and the location of the tooth’s centre of resistance (CR). Because of the practical constraints of in-vivo experiments, the finite element (FE) method is commonly used to determine the CR. The objective of this study was to investigate the geometric model details required for accurate CR determination, and the effect of material non-linearity of the periodontal ligament (PDL). A FE model of a human lower canine derived from a high-resolution µCT scan (voxel size: 50 µm) was investigated by applying four different modelling approaches to the PDL. These comprised linear and non-linear material models, each with uniform and realistic PDL thickness. The CR locations determined for the four model configurations were in the range 37.2–45.3% (alveolar margin: 0%; root apex: 100%). We observed that a non-linear material model introduces load-dependent results that are dominated by the PDL regions under tension. Load variation within the range used in clinical orthodontic practice resulted in CR variations below 0.3%. Furthermore, the individualized realistic PDL geometry shifted the CR towards the alveolar margin by 2.3% and 2.8% on average for the linear and non-linear material models, respectively. We concluded that for conventional clinical therapy and the generation of representative reference data, the least sophisticated modelling approach with linear material behaviour and uniform PDL thickness appears sufficiently accurate. Research applications that require more precise treatment monitoring and planning may, however, benefit from the more accurate results obtained from the non-linear constitutive law and individualized realistic PDL geometry.     

Mechanical responses of the periodontal ligament based on an exponential hyperelastic model: a combined experimental and finite element method

The V–W exponential hyperelastic model is adopted to describe the instantaneous elastic response of the periodontal ligament (PDL). The general theoretical framework of constitutive modeling is described based on nonlinear continuum mechanics, and the elasticity tensor used to develop UMAT subroutine is formulated. Nanoindentation experiment is performed to characterize mechanical properties of an adult pig PDL specimen. Then the experiment is simulated by using the finite element (FE) analysis. Meanwhile, the optimized material parameters are identified by the inverse FE method. The good agreement between the simulated results and experimental data demonstrates that the V–W model is capable of describing the mechanical behavior of the PDL. Therefore, the model and its implementation into FE code are validated. By using the model, we simulate the tooth movement under orthodontic loading to predict the mechanical responses of the PDL. The results show that local concentrations of stress and strain in the PDL are found.     

正畸牙移动相关信号通路研究进展

<正>畸牙移动是在机械力的作用下,通过对牙周膜产生牵张或压缩的力来引起牙周组织在生理限度内的组织改建,从而达到牙齿移动、矫治畸形的目的。由于没有明显的年龄限制,正畸矫治在全球范围已变得越来越普遍。因此,相关的研究也日益增多。牙齿移动的生物学基础是正畸力作用于牙周组织激活一系列信号转导通路,进而引起牙周膜的修复改建。为指导临床、加速正畸矫治疗程提供新的思路,本文综述了近年来有关正畸牙移动相关信号通路的研究进展。发现最新的研究集中在MAPK信号通路,Wnt/β-catenin信号通路,PI3K/AKt/m TOR信号通路,BMP-2信号通路,Caspase-3介导的凋亡通路较多。但是正畸牙移动引起的牙周组织改建是一个多种生物力学信号转导通路相互调节相互作用的过程,对于上述信号通路之间的相互关系还有待于我们更进一步的探索。     

Finite element simulation of the behavior of the periodontal ligament: A validated nonlinear contact model

Due to its significance in tooth movement, the stress/deformation field of periodontium and the alveolar bone remodeling process, periodontal ligament (PDL) cannot be excluded from the studies investigating dental biomechanics regarding its excessive deformability. Therefore, many analytical and numerical researches are carried out to simulate its response and to create a constitutive model via experiments intending to discover the material properties of PDL. The aim of this study is to formulate a user specified contact model that can be used in conjunction with finite element (FE) software and reflects PDL’s influence on neighboring structures based on the currently available information, without requiring an actual volumetric finite element mesh of ligament. The results show good agreement with available experimental tooth mobility data. Smooth stress fields are obtained on the tooth root and alveolar bone, which is a significant aspect in bone-remodeling studies. The advantage of simulating PDL as a contact model at the interface of tooth root and the alveolar process instead of a solid-meshed FE model with poor geometric morphology and/or very dense mesh is expected to save pre/post-processing workforce, to increase the accuracy and to contribute to the smoothness of interface stress distributions.     

Tension force-induced bone formation in orthodontic tooth movement via modulation of the GSK-3β/β-catenin signaling pathway

Orthodontic force-induced osteogenic differentiation and bone formation at tension sites play a critical role in orthodontic tooth movement. However, the molecular mechanism underlying this phenomenon is poorly understood. In the current study, we investigated the involvement of the GSK-3β/β-catenin signaling pathway, which is critical for bone formation during tooth movement. We established a rat tooth movement model to test the hypothesis that orthodontic force may stimulate bone formation at the tension site of the moved tooth and promote the rate of tooth movement via regulation of the GSK-3β/β-catenin signaling pathway. Our results showed that continued mechanical loading increased the distance between the first and second molar in rats. In addition, the loading force increased bone formation at the tension site, and also increased phospho-Ser9-GSK-3β expression and β-catenin signaling pathway activity. Downregulation of GSK-3β activity further increased bone parameters, including bone mineral density, bone volume to tissue volume and trabecular thickness, as well as ALP- and osterix-positive cells at tension sites during tooth movement. However, ICG-001, the β-catenin selective inhibitor, reversed the positive effects of GSK-3β inhibition. In addition, pharmaceutical inhibition of GSK-3β or local treatment with β-catenin inhibitor did not influence the rate of tooth movement. Based on these results, we concluded that GSK-3β/β-catenin signaling contributes to the bone remodeling induced by orthodontic forces, and can be used as a potential therapeutic target in clinical dentistry.