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The Role of Tumor Necrosis Factor Receptor Type 1 in Orthodontic Tooth Movement
I. Andrade, Jr.1,
T.A. Silva2,*,
G.A.B. Silva3,
A.L. Teixeira4 and
M.M. Teixeira5
1 Department of Orthodontics, Pontifícia Universidade Católica de Minas Gerais (PUC-Minas), Faculty of Dentistry, Belo Horizonte/MG, Brazil;
2 Department of Oral Pathology, Universidade Federal de Minas Gerais, Faculty of Dentistry, Av. Antônio Carlos 6627, CEP 31.270-901, Belo Horizonte/MG, Brazil;
3 Department of Morphology, Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Belo Horizonte/MG, Brazil;
4 Department of Clinical Medicine, Universidade Federal de Minas Gerais, Faculty of Medicine, Belo Horizonte/MG, Brazil; and
5 Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte/MG, Brazil
Correspondence: * corresponding author, tarcilia{at}odonto.ufmg.br
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ABSTRACT
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Orthodontic tooth movement is dependent on osteoclast activity. Tumor necrosis factor (TNF)- plays an important role, directly or via chemokine release, in osteoclast recruitment and activation. This study aimed to investigate whether the TNF receptor type 1 (p55) influences these events and, consequently, orthodontic tooth movement. An orthodontic appliance was placed in wild-type mice (WT) and p55-deficient mice (p55–/–). Levels of TNF- and 2 chemokines (MCP-1/CCL2, RANTES/CCL5) were evaluated in periodontal tissues. A significant increase in CCL2 and TNF- was observed in both groups after 12 hrs of mechanical loading. However, CCL5 levels remained unchanged in p55–/– mice at this time-point. The number of TRAP-positive osteoclasts in p55–/– mice was significantly lower than that in WT mice. Also, there was a significantly smaller rate of tooth movement in p55–/– mice. Analysis of our data suggests that the TNFR-1 plays a significant role in orthodontic tooth movement that might be associated with changes in CCL5 levels.
Key Words: orthodontic tooth movement • mechanical loading • bone remodeling • TNF- • chemokines
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INTRODUCTION
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Bone remodeling is a lifelong process, and it is achieved by bone resorption at compression sites and new bone formation on the tension sides (Thilander et al., 2000; Klein-Nulend et al., 2005). The availability of transgenic-mutated mice, including those with genes related to bone metabolism, for investigating the effect of mechanical loading on bone remodeling is of great interest to enhance our understanding of the process of orthodontic tooth movement.
Orthodontic tooth movement is achieved by the process of osteoclastic bone resorption and osteoblastic bone formation. Numerous substances—such as hormones, cytokines, growth factors, and bone matrix constituents—are involved with osteoclastogenesis (Boyle et al., 2003; Kohno et al., 2003; Teitelbaum, 2007). For example, pro-inflammatory cytokines, such as TNF-, are thought to play a role in bone remodeling (Horowitz et al., 2001; Wise and Yao, 2003) and osteoclast differentiation (Azuma et al., 2000). In rats (Ogasawara et al., 2004) and in humans (Basaran et al., 2006), orthodontic tooth movement increases the levels of TNF- in the periodontal tissues. TNF- induces several biological responses via 2 cell-surface receptors, namely, TNF-receptor type 1 (p55) and TNF receptor type 2 (p75) (Peschon et al., 1998). TNF- enhances basal osteoclastogenesis, in vitro, via p55 and suppresses it via p75 (Abu-Amer et al., 2000). In addition to modifying processes directly associated with bone movement, TNF- may also induce mediators of the inflammatory process, which will then influence osteoclast recruitment and function. Recent studies from our group have shown that TNF- may modulate the expression of the chemokines Regulated upon Activaton, Normal T-cell Expressed and Secreted (RANTES/CCL5) (Garlet et al., 2007) and monocyte chemoattractant protein-1 (MCP-1/CCL2) (Barcelos et al., 2005), and, hence, influence the outcome of the inflammatory response.
Chemokines are a large family of chemotactic cytokines that provide key signals for the trafficking and homing of specific subpopulations of leukocytes and other cells in both physiological and pathological processes (Rossi and Zlotnik, 2000; Gerard and Rollins, 2001). Among the many members of the chemokine family, 2 chemokines were evaluated in the present study, CCL2 and CCL5. Both CCL2 and CCL5 may be modulated by TNF- (Barcelos et al., 2005; Garlet et al., 2007) and play a role in mechanisms underlying osteoclast recruitment and activation (Chae et al., 2002; Graves et al., 2002). CCL5 has been shown to induce osteoclast chemotaxis (Yu et al., 2004). A recent study showed that CCL2 and CCL5 are involved in human osteoclast differentiation from monocyte precursors in vitro (Kim et al., 2006).
A better understanding of cellular and molecular responses to mechanical loading is crucial for future improvements in orthodontic treatment. In the present study, we applied a tooth movement model developed in mice to investigate the role of TNF receptor signaling in osteoclast recruitment. An orthodontic device was placed, and the phenotype—osteoclast recruitment and tooth movement—of tumor necrosis factor type 1-deficient (p55–/–) and wild-type (WT) mice were compared. To gain insight into the mechanisms potentially responsible for the recruitment of osteoclasts, we also examined the expression of CCL2 and CCL5 in the mouse periodontium under mechanical loading.
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MATERIALS & METHODS
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Experimental Animals
Forty ten-week-old wild-type mice (C57BL6/J) and 40 ten-week-old TNF-RI (p55–/–)-deficient mice were used in this experiment. All animals were treated under ethical regulations for animal experiments, defined by the Ethics Committee, Federal University of Minas Gerais (UFMG). Each animal’s weight was recorded throughout the experimental period, and there was no significant loss of weight.
Experimental Protocol
The mice were anesthetized i.p. with 0.2 mL of a solution containing xylazine (0.02 mg mL–1), ketamine (50 mg mL–1), and saline in a proportion of 1:0.5:3, respectively. An orthodontic appliance consisted of a Ni-Ti 0.25 x 0.76 mm (Lancer Orthodontics, San Marcos, CA, USA) coil spring, bonded by a light-cured resin (Transbond, Unitek/3M, St. Paul, MN, USA), between the maxillary right first molar and the incisors (Fig. 1 ). The force magnitude was calibrated by a tension gauge (Shimpo Corp., Tokyo, Japan) to exert a force of 0.1 N applied in the mesial direction. The amount of force produced by the activation of the coil was based on results from our previous experiments, which were adapted from the method proposed by Pavlin et al.(2000). There was no reactivation during the experimental period. To avoid traumatic occlusal interference during tooth movement, we extracted the opposing mandibular first molar, using fine anatomical tweezers. The animals were divided into 3 groups: Control (non-operated animals), SHAM (with inactivated coil spring), and experimental group (with activated coil spring). Mice were killed with an overdose of anesthetic at the following times: 0, 12 hrs, and 3, 6, and 12 days. For every set of experiments (histological and biochemical measurements), 5 animals were used for each time-point.
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Figure 1. Occlusal view of a Ni-Ti open coil spring placed between the upper right first molar and the upper incisors. The orthodontic appliance applied a force of 0.1 N.
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Measurement of Cytokine Levels
Using a stereomicroscope, we extracted periodontal ligament and surrounding alveolar bone samples from the areas adjacent to the upper first molars. The samples were weighed and homogenized in PBS (0.4 mM NaCl and 10 mM NaPO4) containing protease inhibitors (0.1 mM PMSF, 0.1 mM benzethonium chloride, 10 mM EDTA, and 0.01 mg/mL aprotinin A) and 0.05% Tween-20 at 1 mg/mL. The mixture was placed on ice and centrifuged (10.000 g) for 10 min. The supernatant was then collected and stored at –70°C until further analysis. The levels of TNF-, CCL2, and CCL5 were evaluated by a double-ligand enzyme-linked immunosorbent assay (ELISA), according to the manufacturer’s protocol (R&D Systems, Minneapolis, MN, USA). The results were expressed as picograms of cytokine/mg tissue. In preliminary experiments, the inter-experimental variability was below 5%.
Histology
The right and left halves of the maxillae, including first, second, and third molars, were dissected, fixed in 4% paraformaldehyde, and rinsed in distilled water. After fixation, the hemimaxillae were decalcified in 14% EDTA (pH 7.4) for 14 days and embedded in paraffin. Paraffin-embedded samples were cut into vertical sections of 4-µm thickness. The selection was based on morphological criteria, such as the position of the distal root, where it appeared to be as long as possible. The sections were stained for tartrate-resistant acid phosphatase (TRAP; Sigma-Aldrich, St. Louis, MO, USA), counterstained with hematoxylin, and used for histological examination. The distal-buccal root, on its coronal two-thirds of the mesial periodontal site, was used for the osteoclast counts, on 5 sections per animal. Osteoclasts were identified as TRAP-positive, multinucleated cells located on the bone surface. To validate the consistency of the measurement, two examiners measured 20 successive slides until an r2 of at least 0.85 was repeatedly obtained.
Measurement of Tooth Movement
We evaluated the amount of tooth movement morphometrically by measuring the distance between the cementum-enamel junctions (CEJs) from the first molar and the second molar (1st and 2nd molar distances) in 5 vertical sections per animal under an Axioskop 40 microscope (Carl Zeiss, Göttingen, Germany), linked to a digital camera (PowerShot A620, Canon, Tokyo, Japan), adapted from a previous study (Mavragani et al., 2005). We used National Institutes of Health Image J software. A single examiner (I.A.) conducted observations blinded to the group status. Three measurements were conducted for each evaluation, and the variability was below 5% in all cases.
Statistical Analysis
The evaluation of each group was expressed as the mean ± SEM. Comparison among the groups was statistically analyzed by one-way analysis of variance (ANOVA), followed by the Newman-Keuls’ multiple comparison test. P < 0.05 was considered statistically significant.
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RESULTS
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CCL5 Levels in the Periodontal Tissue were Diminished in p55–/– Mice
There was no significant difference in cytokine levels between control and SHAM-operated groups. In WT mice, there was a significant increase in periodontal tissue levels of TNF-, CCL2, and CCL5 at 12 hrs after mechanical loading (p < 0.05). Levels of mediators returned to baseline at 72 hrs (Figs. 2A, 2B, 2C). In p55–/– mice, there was an increase in TNF- and CCL2, similar to that found in WT mice (Figs. 2A, 2B). However, there was no significant increase in levels of CCL5 after mechanical loading (Fig. 2C).
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Figure 2. Mean concentrations of TNF- (A), CCL2 (B), and CCL5 (C) in the mouse periodontium (WT and p55–/–) after 12 hrs and 72 hrs of mechanical loading, respectively. There were 5 animals in each group on each day. The data were expressed as the mean ± SEM. *P < 0.05 compared with control and 72 hrs of orthodontic force (in the same animal strain). #P < 0.05 compared with WT groups at the same moment, by one-way ANOVA and Newman-Keuls’ multiple-comparison test.
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TRAP Activity and the Number of TRAP-positive Cells in the Periodontal Tissue was Diminished in p55–/– Mice
In the control and SHAM-operated animals, TRAP activity was found on the distal side of the alveolar bone surface, and no activity was observed in the mesial region of the periodontium (Figs. 3A, 3B). On day 6, TRAP activity appeared to increase on the mesial periodontium of the distobuccal root, the side of pressure after mechanical loading, and to decrease on the distal side of this root in WT mice (Fig. 3C). In p55–/– mice, there appeared to be a similar decrease in the distal side, but a smaller increase of TRAP activity on the mesial side (Fig. 3D). On day 12, TRAP activity appeared to increase more extensively in WT mice, which presented a greater alveolar bone resorption area than did p55–/– mice (Figs. 3E, 3F). Overall, there was a good correlation between the intensity of TRAP activity, as evaluated qualitatively, and the number of TRAP-positive osteoclasts. Indeed, the quantification of TRAP-positive osteoclasts had a steady increase from days 3 to 12 in WT mice subjected to orthodontic force (Fig. 4A). The increased number of TRAP-positive osteoclasts was greater in WT than in p55–/– mice (Fig. 4A).
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Figure 3. Histological changes related to orthodontic tooth movement in WT (A,C,E,G) and p55–/– mice (B,D,F,H). Vertical sections (4-µm thickness) of the periodontium around the distobuccal root of the first molar stained with TRAP. (A-B) Controls (before mechanical loading). TRAP activity was found on the distal alveolar bone, demonstrating physiological distal tooth movement. (C-D) Experimental group (6 days after the application of orthodontic force). TRAP activity increased on the mesial alveolar bone and decreased on the distal alveolar bone. In p55–/– mice, there was a smaller increase of TRAP activity on the mesial alveolar bone. (E-F) Experimental group (12 days after mechanical loading). TRAP activity was less in p55–/– mice, which showed a smaller mesial alveolar bone resorption area. (G-H) Close-up view of the detached area in E and F. TRAP-positive osteoclasts are shown in blue arrows. MB, mesial alveolar bone; DB, distal alveolar bone; PL, periodontal ligament; R, root. The black arrows indicate the orthodontic tooth movement. Bar = 100 µm.
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Figure 4. Number of TRAP-positive osteoclasts (A) and amount of tooth movement (B). (A) The number of TRAP-positive cells on the pressure side of the distobuccal root of the first molar during orthodontic tooth movement in the WT mice (dotted bars) and p55-/- mice (black and white square bars). The total number of positive cells in the distobucal root was determined in 5 consecutive microscopic fields (x 40), and each field had an area of 0.12 mm2. The results represent the mean of 5 sections per animal. (B) Time-course of changes in the amount of tooth movement between WT mice and p55–/– mice. We evaluated it morphometrically by measuring the distance between the cementum-enamel junctions (CEJs) from the first molar and second molars. These mice were killed before and 3, 6, and 12 days after the experiment was initiated. WT mice (filled squares); p55–/– mice (filled triangles). There were 5 animals in each group on each day. The data are expressed as the mean ± SEM. *P < 0.05 compared with 0 and 3 days of orthodontic force (in the same animal strain). **P < 0.05 compared with 0, 3, and 6 days of orthodontic force (in the same animal strain). #P < 0.05 compared with WT groups at the same moment, by one-way ANOVA and Newman-Keuls’ multiple-comparison test.
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The Amount of Tooth Movement was Reduced in p55–/– Mice
Analysis of the above data demonstrates that production of CCL5 and recruitment of TRAP-positive osteoclasts in response to orthodontic force are diminished in p55–/– mice. Next, we evaluated whether the latter changes were reflected in changes of tooth movement. After an initial displacement phase that peaked on day 3, appreciable tooth movement was not observed between days 3 and 6 in both groups. From days 6 to 12, there was another phase of tooth movement (Fig. 4B ). Overall, tooth movement in p55–/– mice followed a similar pattern, but the movement was significantly smaller than that observed in WT mice (Fig. 4B).
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DISCUSSION
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The recruitment of osteoclasts to a site of periodontal ligament compression is essential for bone remodeling and consequent tooth movement. Several studies have attempted to elucidate the role of mediators of the inflammatory process on the mechanisms controlling the appearance of osteoclasts at compression sites and consequent osteoclast-dependent tooth movement (Brezniak and Wasserstein, 2002; Kohno et al., 2003; Jager et al., 2005). Previous studies showed that TNF-, a pro-inflammatory cytokine, might be associated with osteoclast differentiation (Abu-Amer et al., 2000; Azuma et al., 2000) and bone remodeling (Horowitz et al., 2001; Wise and Yao, 2003). The present study aimed to investigate the role of the TNFRI in controlling the production of chemokines and osteoclast and tooth movement after the application of orthodontic force in mice.
Initial studies investigated the expression of cytokines in the periodontium of WT mice during tooth movement and related histological changes. The results demonstrated that expression of TNF- was detectable at 12 hrs after mechanical loading. After 3 days, TNF- returned to basal levels. Levels of the chemokines CCL2 and CCL5 followed a pattern similar to that of TNF-. One limitation of this approach is that it evaluates levels of mediators in both the compression and the tension sites after mechanical loading. Nevertheless, it is clear that the local enhancement of TNF- and chemokine activity preceded the enhancement in TRAP activity and the number of TRAP-positive cells in the mesial alveolar bone. We measured the distance between the CEJs to evaluate the effect of the orthodontic device on tooth movement. The results demonstrated that, under the applied experimental conditions, the tooth movement had an initial displacement, followed by a plateau phase between days 3 and 6. In agreement with this finding, recent studies demonstrated that tooth movement may be delayed by the development of hyalinized areas and protracted osteoclast recruitment (van Leeuwen et al., 1999; Rody et al., 2001; von Böhl et al., 2004a,b; Krishnan and Davidovitch, 2006). After day 6, the tooth movement was re-initiated and increased steadily until day 12. This tooth movement was preceded and paralleled by a significant increase in the number of TRAP-positive osteoclasts, TRAP activity, and histological changes associated with osteoclast function.
To evaluate the role of TNFRI on orthodontic tooth movement, we used p55–/– mice, in which there were levels of both TNF- and CCL2 similar to those found in WT mice. However, the local production of CCL5 was reduced. We also found less TRAP activity, significantly fewer osteoclasts, and diminished tooth movement on days 6 and 12 after the application of orthodontic force than in WT mice. TNF- and its TNFRI are well-known for their ability to enhance tissue expression of cell adhesion molecules (Zhou et al., 2007) and to facilitate leukocyte influx (Barcelos et al, 2005). TNF- may also enhance osteoclast differentiation and basal osteoclastogenesis, in vitro, via p55 (Azuma et al., 2000; Abu-Amer et al., 2000). A recent study has shown that pre-osteoblast migration could be induced by CCL5 secreted from osteoclasts in a paracrine mode of action, and indicated CCL5 as being an important molecule for communication between osteoclasts and osteoblasts (Yano et al., 2005). Moreover, CCL5 has been shown to induce osteoclast chemotaxis (Yu et al., 2004), and may be involved in human osteoclast differentiation in vitro (Kim et al., 2006). Together, the actions of TNF-, via its TNFRI receptor, and CCL5 could facilitate osteoclast chemotaxis, differentiation, and activity. In the absence of the TNFRI and the consequent diminished production of CCL5, the latter parameters would be deficient, as would tooth movement. In accordance with this hypothesis, a previous study demonstrated decreased levels of CCL5 and its receptor in p55–/– mice with periodontal disease (Garlet et al., 2007).
Our results are not in agreement with those of a previous study (Yoshimatsu et al., 2006) that showed a similar number of TRAP-positive cells in tissues from WT and p55–/– mice under orthodontic force, without a significant difference between the amounts of tooth movement in both groups. The reasons for the discrepancy between findings are not known. However, it is possible that the different methodologies used to quantify TRAP-positive osteoclasts and to measure tooth movement in both studies could be an underlying reason. In our study, the use of careful morphometric analysis to quantify osteoclast numbers and tooth movement clearly showed an inhibition in mice lacking the TNFRI.
In conclusion, our study suggests that TNF signaling via p55 plays a significant role in osteoclast recruitment induced by mechanical loading, and this mechanism is related (and possibly secondary) to decreased CCL5 production. Further studies are now required for a better understanding of the role of chemokines, such as CCL2 and CCL5, their receptors, and other cytokines on tooth movement induced by an orthodontic appliance.
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ACKNOWLEDGMENTS
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We are grateful to Fundação de Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG, Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasil) for financial support.
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.
Received for publication February 20, 2007.
Revision received July 11, 2007.
Accepted for publication August 2, 2007.
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Journal of Dental Research, Vol. 86, No. 11,
1089-1094 (2007)
DOI: 10.1177/154405910708601113
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ABSTRACT
INTRODUCTION