Mechanobiology of tooth movement
Department of Orthodontics and Oral Biology, Radboud University Nijmegen Medical Centre, The Netherlands
Address for correspondence J. W. Von den Hoff, Department of Orthodontics and Oral Biology, Radboud University Nijmegen Medical Centre, 309 Tandheelkunde, Postbus 9101, 6500 HB Nijmegen, The Netherlands, E-mail:h.vondenhoff{at}dent.umcn.nl
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Summary |
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 Top Summary IntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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This review describes the mechanical and biological signalling pathways during orthodontic tooth movement and provides an update of the current literature. A theoretical model is introduced to elucidate the complex cascade of events after the application of an orthodontic force to a tooth. In this model, the events are divided into four stages: matrix strain and fluid flow, cell strain, cell activation and differentiation, and remodelling. Each stage is explained in detail and discussed using recent literature.
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Introduction |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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Since the first extended reports at the end of the 19th century (Kingsley, 1880
; Angle, 1900), there have been tremendous developments in the field of orthodontics. The acquired knowledge is being used to treat an increasing number of subjects with malocclusions that seek orthodontic solutions for their psychosocial, functional, or dental problems (Proffit, 2000).
A law in orthodontics is that a tooth can be moved through the alveolar bone when an appropriate orthodontic force is applied. This is based on the principle that a change in mechanical loading of a biological system results in strain, which subsequently leads to cellular responses aiming at adaptation of the system to the changed conditions. As a result of this principle, remodelling of the periodontal ligament (PDL) and the alveolar bone around a tooth takes place during orthodontic force application. It is possible to find detailed descriptions of processes occurring during orthodontic tooth movement in the literature (Krishnan and Davidovitch, 2006; Masella and Meister, 2006) but a concise overview of the induction processes is still lacking. Therefore, the aim of this review is to describe the mechanical and biological processes taking place during orthodontic tooth movement and to provide an update of the current literature. To elucidate the complex cascade of events after the application of an orthodontic force on a tooth, a new theoretical model based on the existing knowledge is introduced.
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Terminology |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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In orthodontics, the two sides of a tooth during tooth movement are normally called the pressure and tension side. The term ‘pressure’ suggests a loading of the PDL and the bone by the orthodontic force. However, this is not what occurs. The apparent contradiction can be explained by two phenomena. First, the presence of collagen fibres of the PDL that connect the tooth with the alveolar bone. At the so-called pressure side, these fibres are unloaded leading to unloading of the alveolar bone, resulting in its resorption (Melsen, 2001
). Second, a redistribution of fluid in the PDL leads to a rapid return to normal tissue fluid pressure within the periodontal space. The above explains the importance of the correct use of terminology in orthodontics. To avoid further confusion, the more accurate terms resorption and apposition side instead of pressure and tension side will be used. |
Theoretical model |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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The model shown in Figure 1 demonstrates the main processes taking place after the application of an orthodontic force. In this model, the force is assumed to be exerted on a single tooth leading to bodily tooth movement. A period of arrest in movement often takes place after application of a force, caused by local tissue necrosis (Rygh, 1973
; Brudvik and Rygh, 1994). Tooth movement through the bone can only start after the removal of this necrotic or hyalinized tissue by phagocytic cells such as macrophages, foreign body giant cells, and possibly osteoclasts (Okumura, 1982; Nakamura et al., 2001). Since it is not essential for the bone remodelling process during tooth movement and, for the sake of clarity, this hyalinization period and the subsequent inflammatory reaction is not included in the model. The attachment of the tooth to the bone is schematically shown in Figure 2. A visualization of the changes in the system that take place after external force application is also shown.
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The theoretical model describes four stages in the induction of tooth movement. These stages are as follows: (1) Matrix strain and fluid flow (Figure 1a). Immediately after the application of an external force, strain in the matrix of the PDL and the alveolar bone results in fluid flow in both tissues. (2) Cell strain (Figure 1b). As a result of matrix strain and fluid flow, the cells are deformed. (3) Cell activation and differentiation (Figure 1c). In response to the deformation, fibroblasts and osteoblasts in the PDL as well as osteocytes in the bone are activated. (4) Remodelling (Figure 1d). A combination of PDL remodelling and the localized apposition and resorption of alveolar bone enables the tooth to move. These stages will be described in more detail in the following sections.
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Matrix strain and fluid flow (Figure 1a) |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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Immediately after the application of a force, the tooth moves within its socket for a certain distance. The amount of movement depends on the biomechanical properties and the dimensions of the PDL. This movement leads to a positive strain (tensional deformation) within the PDL at the future apposition side of the root (Reitan, 1951
) and, therefore, a stretching of the collagen fibres, which connect the tooth to the bone (Rygh et al., 1986; Melsen, 1999). At the future resorption side of the root, a negative strain (compressive deformation) is induced within the PDL (Reitan, 1951) and, consequently, the fibres are relaxed (Melsen, 1999; Binderman et al., 2002). The strain depends on the material properties of the PDL and the applied force. The material properties of the PDL have been analysed by measuring tooth displacement in relation to an applied load in both animal and human experimental settings (Chiba and Komatsu, 1993; van Driel et al., 2000; Yoshida et al., 2001; Komatsu et al., 2004; Cronau et al., 2006). However, these studies have yielded highly variable results. The data have been used in finite element models in an attempt to calculate the strain distribution within the PDL under specific loading conditions (van Driel et al., 2000; Natali et al., 2004; Cattaneo et al., 2005). Increasing evidence exists for a non-linear and time-dependent relationship between force and displacement, indicating that the PDL is viscoelastic (Yoshida et al., 2001; Cronau et al., 2006). This behaviour can be described with the viscoelastic properties of only the PDL fibres (Sasano et al., 1992; van Driel et al., 2000; Komatsu et al., 2004; Natali et al., 2004), but a two-phase fibre-reinforced viscoelastic model seems to be more realistic. The latter model predicts an almost immediate fluid flow in the PDL after force application at both the apposition and resorption sides, followed by an increasing strain of the viscoelastic matrix, which is mainly determined by the collagen fibres. This model can very well explain in vivo data on the mechanical behaviour of the PDL (unpublished data).
In addition, the external force also results in a strain in the alveolar bone at the apposition side through the collagen fibre bundles that connect the tooth to the bone (Cronau et al., 2006; Meikle, 2006). An important theory that describes the reaction of bone to strain involves the effect of fluid flow on bone cells (Weinbaum et al., 1994; Cowin et al., 1995; Mak et al., 1997). This fluid shear stress theory is based on the presence of osteocytes entrapped in lacunae within the bone. These cells are interconnected by protrusions that run through tiny channels in the bone called canaliculi. The strain of the bone results in a fluid flow through the canaliculi leading to shear stress on the osteocytes, which are then activated. It has been suggested that in areas of reduced canalicular fluid flow, apoptosis of osteocytes occurs, which subsequently attracts osteoclasts to the site (Burger et al., 2003; Tan et al., 2006). This could be the case at the resorption side of the tooth where an unloading of the bone might result in a reduction of fluid flow. Indeed, it has been shown in mice that unloading of bone leads to increased osteocyte apoptosis followed by bone resorption (Aguirre et al., 2006). This concept of mechanosensing of osteocytes by strain-derived canalicular fluid flow is supported by in vitro data (Klein-Nulend et al., 1995c; Ajubi et al., 1996; Owan et al., 1997; Westbroek et al., 2000; Tan et al., 2006). Studies in animal models also support this theory (Pitsillides et al., 1995; Turner et al., 1995) and the actual canalicular fluid flow itself has been shown in the rat tibia (Knothe Tate et al., 2000).
Two alternatives for the fluid flow theory have been proposed. The first assumes a direct mechanical stimulus on cells within the bone by an external force (Kimmel, 1993; Mullender and Huiskes, 1995). This direct loading effect is supported by in vitro studies. However, the strains used were much higher than those believed to occur in bone (Harter et al., 1995; Brand et al., 2001). Direct mechanical loading with strain levels similar to those measured in vivo evokes no cellular reaction in human osteocytes in vitro (Owan et al., 1997; You et al., 2000).
The second alternative theory is based on the principle that bone microdamage evokes a cellular response (Mori and Burr, 1993; Taylor and Lee, 2003). This microdamage theory developed from the hypothesis that microcracks occur in the bone as a result of material fatigue. This might lead to apoptosis of osteocytes around the cracks which, as mentioned previously, attracts osteoclasts to the site (Noble et al., 1997; Noble 2005). Animal studies show increased amounts of apoptotic osteocytes in combination with increased numbers of osteoclasts after mechanical loading of bone (Noble et al., 2003; Clark et al., 2005). Furthermore, increased numbers of microcracks have been found at the resorption side during the initial phase of orthodontic tooth movement in pigs (Verna et al., 2004). This suggests that not only reduced fluid flow but also microcracks might cause apoptosis of osteocytes. The microcracks reflect the initial damage of the bone that is subsequently remodelled.
In summary, the application of an external force to a tooth strains the matrix of the PDL and evokes a fluid flow in the tissue. Simultaneously, according to the fluid flow theory, a strain in the bone induces canalicular fluid flow, which results in a shear stress on osteocytes. In addition, microdamage of the bone after force application might be involved.
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Cell strain (Figure 1b) |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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Direct deformation of PDL cells is possible via transduction of strain through cell-matrix attachments (Beertsen et al., 1997
) and indirect deformation might be induced by fluid flow (Davidovitch, 1991). The cell-matrix attachments are formed by binding of the extracellular domains of integrins to extracellular matrix (ECM) proteins. Integrins are transmembrane proteins with an extra- and intracellular domain. Inside the cell, the cytoplasmic domains of the integrins connect to the cytoskeleton via a multiprotein complex (Goldmann, 2002). This focal adhesion complex not only transduces matrix strain to the cytoskeleton but also activates protein kinases that initiate a variety of intracellular signalling pathways (Hynes, 1992; Wang and Thampatty, 2006). It is not exactly clear how signal transduction after indirect deformation by fluid flow takes place, although the cytoskeleton is probably also involved. Alternatively, specific flow receptors on the cell surface have been proposed (Cherian et al., 2005; Wall and Banes, 2005).
Whatever the exact mechanism, PDL cells need to be highly sensitive to mechanical stimuli. This is indeed shown by in vitro studies, in which PDL fibroblasts react to direct deformation by the production of cytokines and other mediators, and matrix metalloproteinases (MMPs) that degrade collagen (Von den Hoff, 2003; Yamaguchi et al., 2004; Snoek-van Beurden and Von den Hoff, 2005). Some important mediators will be discussed in the next section.
Many in vitro studies have employed culture dishes with a flexible bottom that is stretched, which directly deforms the cells (Banes et al., 1985). Indirect mechanical deformation has been performed in vitro by the application of a pulsating fluid flow. These data show that not only direct cell deformation but also fluid flow-induced deformation leads to cellular responses in PDL fibroblasts (van der Pauw et al., 2000). In vivo, mechanical stimulation by orthodontic forces also increased the levels of mediators in the PDL such as interleukins (Davidovitch et al., 1988; Alhashimi et al., 2001). Besides fibroblasts, osteoblasts within the PDL are also sensitive to mechanical stimulation. Mechanosensing of osteoblasts was shown by the release of signalling molecules such as prostaglandins by human osteoblasts after direct and indirect deformation (Bakker et al., 2003; Mullender et al., 2004; Tang et al., 2006).
It was assumed that a shear stress on osteocytes occurs within the bone as a result of canalicular fluid flow during orthodontic force application. Similar to the activation of PDL cells by fluid flow, the signal might be transduced to the osteocytes through specific receptors or through deformation of the cytoskeleton (Duncan and Turner, 1995). Osteocytes respond to fluid flow in vitro by the production of mediators such as nitric oxide (NO) and prostaglandins (Klein-Nulend et al., 1995b; Westbroek et al., 2000).
In summary, after force application both matrix strain and fluid flow in the PDL and the bone cause deformation of cells. Through integrin signalling and other transduction pathways, mediators are produced that activate several types of cells.
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Cell activation and differentiation ( Figure 1c) |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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As mentioned, the production of mediators by PDL and bone cells during mechanical stimulation indicates that these cells become activated. In frame c, the arrows indicate which cellular processes are induced by the mediators. Arrow 1 indicates the effect that activated osteocytes have on cells in the PDL. Precursors in the PDL are stimulated to differentiate into osteoblasts through factors produced by activated osteocytes (Dereka et al., 2006
). Examples of these factors are bone morphogenic proteins (2, 6, and 9) and platelet-derived growth factor that also stimulate osteoblast activity (Cheng et al., 2003; Singhatanadgit et al., 2006). Osteocytes also respond to strain in vitro by the production of cytokines, NO, prostaglandins, and tumour necrosis factor-
(Klein-Nulend et al., 1995b,a; Ajubi et al., 1996; Westbroek et al., 2000; Kurata et al., 2006). These in vitro studies support the theory that certain cytokines produced by osteocytes activate osteoclast precursors in the PDL at the resorption side, while NO inhibits the activity of osteoclasts at the apposition side in rats (Yoo et al., 2004).
The activation of osteoclast precursors and the differentiation into osteoclasts by factors produced by PDL cells are represented by arrow 2. At the resorption side, soluble factors such as colony-stimulating factor, receptor activator of nuclear factor kappa β ligand (RANKL), osteoprotegerin, and bone morphogenic proteins regulate osteoclast differentiation has been shown in vitro (Nomura and Takano-Yamamoto, 2000; Zhao et al., 2002; Kurata et al., 2006) and, in vivo, during orthodontic tooth movement in rats (Shiotani et al., 2001). These factors are produced by osteocytes present in the alveolar bone and by osteoblasts and fibroblast present in the PDL (Oshiro et al., 2002). Colony-stimulating factor is of importance during the first steps of differentiation. RANKL, and its receptor RANK, stimulate the further differentiation of osteoclasts. Osteoprotegerin is a decoy receptor for RANKL that prevents its binding to RANK and thereby further differentiation (Theoleyre et al., 2004).
Before actual resorption of bone can take place, osteoblasts have to degrade the non-mineralized layer of the osteoid (arrow 3). Only after degradation of this layer through MMP activity, can the differentiated osteoclasts attach to the bone surface (Birkedal-Hansen et al., 1993). This attachment is mediated by specific integrins (vβ3; Gay and Weber, 2000), and it is stimulated by osteopontin (OPN) produced by osteoblasts and osteocytes. During orthodontic tooth movement, increased levels of OPN have been found at the resorption side (Terai et al., 1999).
Bone formation at the apposition side of the tooth is a combination of ECM synthesis and mineralization (arrow 4). In vitro studies show that loading of PDL cells results in an increased production of alkaline phosphatase, osteocalcin, and other non-collagenous matrix proteins (Matsuda et al., 1998; Ozaki et al., 2005; Yang et al., 2006). These factors might stimulate precursors in the PDL to differentiate into osteoblasts, leading to subsequent bone deposition. After mechanical stimulation in vitro, osteoblasts produce NO, which is, among others, a mediator of bone formation (Owan et al., 1997; You et al., 2000; Burger et al., 2003; Mullender et al., 2004).
The production of factors that regulate ECM degradation by PDL cells is represented by arrow 5. PDL fibroblasts and osteoblasts react to mechanical stress in vitro by the production of inflammatory mediators such as prostaglandins and enzymes such as MMPs and cathepsins that stimulate ECM degradation through autocrine and paracrine actions (Owan et al., 1997; Howard et al., 1998; You et al., 2000; Yamaguchi et al., 2004). In vitro studies have also shown that not only the unloading of PDL but also dermal fibroblasts leads to a reduction of collagen synthesis and an increased expression of ECM-degrading MMPs (Langholz et al., 1995; Xu and Clark, 1996; Von den Hoff, 2003). It is clear that degradation of the ECM of periodontal tissues after orthodontic force application takes place both after loading and unloading of cells. This is also supported by the presence of increased MMP levels at both the resorption and apposition sides during orthodontic tooth movement (Apajalahti et al., 2003; Takahashi et al., 2003,2006; Ingman et al., 2005).
Besides the degradation of ECM, new ECM is also synthesized during remodelling of the periodontal structures around the tooth (arrow 6). Increased levels of collagen synthesis were found at both the resorption and apposition sides after orthodontic force application in humans (Bumann et al., 1997). Several mediators produced by activated PDL and bone cells stimulate ECM synthesis and reduce its degradation. Examples are members of the transforming growth factor-β (TGF-β) superfamily (Nahm et al., 2004). Increased levels of transforming growth factor-β, cathepsins B and L, and interleukin-1 beta were also found in the crevicular fluid of orthodontically moved teeth in humans and at the apposition side of rat teeth after orthodontic force application (Uematsu et al., 1996a,b; Wang et al., 2000; Iwasaki et al., 2001; Yamaguchi et al., 2004). In addition, ECM breakdown is also inhibited by the tissue inhibitors of MMPs produced by PDL cells (Nahm et al., 2004; Verstappen and Von den Hoff, 2006).
In summary, fibroblasts, osteoblasts, osteocytes, and osteoclasts are part of a complex regulatory network that induces PDL and bone remodelling during orthodontic tooth movement.
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Remodelling (Figure 1d) |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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Under physiological conditions, the synthesis and degradation of the periodontal structures is at a low level to maintain tissue homeostasis (Figure 2a). After the application of an external force, this balance is disturbed and increased remodelling of both PDL and bone leads to tooth movement (Figure 2b,c). At the resorption side, PDL tissue and alveolar bone is degraded to create space for the moving tooth while new PDL tissue is simultaneously formed to maintain the attachment. The extensive remodelling of the PDL matrix takes place after the activation of fibroblasts in the PDL. Meanwhile, osteoclast precursors migrate to the bone surface and differentiate into osteoclasts. After differentiation, the activated osteoclasts attach to the bone surface by means of specific integrins (Gay and Weber, 2000
). The attached osteoclasts undergo morphological changes and develop specific functional characteristics. The clear zone seals off the bone surface from its environment, the body of the osteoclast contains an extensive lysosomal system, and the ruffled border is the site where the actual resorption takes place (Hill, 1998). The osteoclast releases hydrogen ions at the ruffled border, which dissolve the anorganic matrix and, after the organic matrix is resorbed by enzymes such as cathepsins and MMPs (Teitelbaum et al., 1997; Phan et al., 2004), the attachment of the principal fibres of the PDL to the bone is lost. The non-functional fibres that mainly contain type I collagen are degraded and replaced by a loose connective tissue mainly containing type III collagen (Pilon, 1996).
At the apposition side, the principal fibres are stretched and remodelling of the PDL takes place. New bone is formed by the activated osteoblasts that first produce new ECM and then mineralize this in a unidirectional manner. At a later stage, when the new layer of bone becomes thicker, some osteoblasts will become entrapped in the bone and turn into osteocytes. The principal fibres of the PDL will also be entrapped in the newly formed bone as Sharpey's fibres. In the meantime, new PDL matrix is formed to maintain the width of the PDL and the attachment of the tooth to the alveolar bone. This new PDL contains thick principal fibres of mainly type I collagen for correct attachment of the tooth to the bone. Both the resorption and apposition sides show upregulation of collagen synthesis after orthodontic force application (Bumann et al., 1997) but the type of collagen is different. A much higher increase of collagen type I was found at the apposition side compared with the resorption side after orthodontic force application in rats (Nakagawa et al., 1994).
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Conclusion |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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The introduced theoretical model (Figure 1) is a schematic overview of the processes taking place after the application of an orthodontic force. The strain in the matrix of the PDL and the alveolar bone immediately after force application, resulting in a fluid flow in both tissues is represented by (a). As a result of matrix strain and fluid flow, cells are deformed (b). In response to the deformation, fibroblasts and osteoblasts in the PDL as well as osteocytes in the bone are activated (c). In d, a combination of PDL remodelling, and the localized apposition and resorption of alveolar bone enables the tooth to move. This model might offer the clinician a better insight into the processes taking place during orthodontic tooth movement and a greater understanding of the biological consequences of orthodontic treatment.
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References |
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TopSummaryIntroductionTerminologyTheoretical modelMatrix strain and fluid...Cell strain (Figure 1b)Cell activation and...Remodelling (Figure 1d)ConclusionReferences |
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