[Show abstract][Hide abstract] ABSTRACT: Mechanical force loading exerts important effects on the skeleton by controlling bone mass and strength. Several in vivo experimental models evaluating the effects of mechanical loading on bone metabolism have been reported. Orthodontic tooth movement is a useful model for understanding the mechanism of bone remodeling induced by mechanical loading. In a mouse model of orthodontic tooth movement, TNF- α was expressed and osteoclasts appeared on the compressed side of the periodontal ligament. In TNF-receptor-deficient mice, there was less tooth movement and osteoclast numbers were lower than in wild-type mice. These results suggest that osteoclast formation and bone resorption caused by loading forces on the periodontal ligament depend on TNF- α . Several cytokines are expressed in the periodontal ligament during orthodontic tooth movement. Studies have found that inflammatory cytokines such as IL-12 and IFN- γ strongly inhibit osteoclast formation and tooth movement. Blocking macrophage colony-stimulating factor by using anti-c-Fms antibody also inhibited osteoclast formation and tooth movement. In this review we describe and discuss the effect of cytokines in the periodontal ligament on osteoclast formation and bone resorption during mechanical force loading.
The Scientific World Journal 01/2014; 2014:617032. · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor necrosis factor- α (TNF- α ) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF- α may play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF- κ B ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF- α on bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF- α is considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon- γ (IFN- γ ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN- γ induce apoptosis in bone marrow cells treated with TNF- α in vitro, and osteoclastogenesis is inhibited by the interactions of TNF- α -induced Fas and Fas ligand induced by IL-12, IL-18, and IFN- γ . This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF- α -mediated osteoclastogenesis in vitro and in vivo.
Clinical and Developmental Immunology 01/2013; 2013:181849. · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the effects of interferon (IFN)-γ on experimental tooth movement in mice using a murine experimental tooth movement model. An Ni-Ti closed-coil spring was inserted between the upper-anterior alveolar bones and the upper-left first molars in mice. We evaluated the relationship between local Ifn-γ mRNA levels and orthodontic tooth movement. In other experiments, IFN-γ was injected adjacent to each first molar every other day during tooth movement. After 12 days, the amount of tooth movement was measured. Tartrate-resistant acid phosphatase (TRAP)-positive cells at the pressure side of each experimental tooth were counted as osteoclasts. Local Ifn-γ mRNA expression increased with orthodontic tooth movement. The number of TRAP-positive cells increased on the pressure side of the first molar. In contrast, the degree of tooth movement and the number of TRAP-positive cells on the pressure side in IFN-γ-injected mice were less than those of control mice. IFN-γ was induced in experimental tooth movement, and could inhibit mechanical force-loaded osteoclastogenesis and tooth movement. These results suggest that IFN-γ might be useful in controlling orthodontic tooth movement because of its inhibitory action on excessive osteoclastogenesis during this movement.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 09/2012; 32(9):426-31. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-12 is an important cytokine for innate and adaptive immunity. We previously reported that IL-12 inhibits tumour necrosis factor (TNF)-α-mediated osteoclast formation by inducing apoptosis. We also reported that TNF-α plays an important role in mechanical loading-induced osteoclast formation and bone resorption during orthodontic tooth movement. In this study, we investigated the effects of IL-12 on mechanical tooth movement in mice.
A Ni-Ti closed coil spring was inserted between the upper incisors and the upper left first molar in mice. IL-12 was injected locally adjacent to the first molar every other day during the experimental period, at doses varying from 0 to 1.5μg/day. After 12 days, the animals were killed and their jaws were processed for histological evaluation using tartrate-resistant acid phosphatase (TRAP) and TdT-mediated dUTP-biotin nick end-labelling (TUNEL) staining, and measurements of the root resorption area.
In the IL-12-treated mice, tooth movement and root resorption appeared to be reduced. In TUNEL-stained sections, many apoptotic cells were recognized on the pressure side in the IL-12-treated mice.
Our findings suggest that IL-12 inhibits not only mechanical tooth movement, but also root resorption during orthodontic tooth movement. These findings may arise through apoptosis induced by IL-12.
Archives of oral biology 08/2011; 57(1):36-43. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TNF-α has been recognized as an important factor for osteoclastogenesis and plays an important role in bone resorption under pathological conditions. IL-12 and IL-18, which are T-cell mediators, are also important inflammatory cytokines. We have reported that IL-12 and IL-18 induce apoptosis in bone marrow cells treated with TNF-α in vitro and that osteoclastogenesis is inhibited by the interaction of TNF-α-induced Fas and the IL-12-induced Fas ligand (FasL). However, the anti-FasL antibody could not completely inhibit apoptosis. Therefore, it is possible that IL-12 and IL-18 may also trigger some other apoptotic mechanisms. Nitric oxide (NO) may act as a mediator of the apoptotic effect. In this study, we examined whether NO causes the IL-12- and IL-18-induced apoptosis of bone marrow cells in TNF-α-mediated osteoclast formation. We found that NO production was induced in bone marrow cells cultured with IL-12 and IL-18 in the presence of TNF-α. When bone marrow cells were cultured with TNF-α, osteoclasts were formed. In contrast, when bone marrow cells were cultured with both TNF-α and IL-12 or IL-18, the adherent cells were induced to undergo apoptosis. Apoptosis was partially inhibited when bone marrow cells were treated with NO synthase inhibitors. Furthermore, IL-12 and IL-18 synergistically induced cell death and upregulated NO production in the presence of TNF-α. These results indicate that the simultaneous effects of TNF-α and IL-12 or IL-18 on bone marrow cells induce apoptosis and that apoptosis is induced by the production of NO.
Calcified Tissue International 07/2011; 89(1):65-73. · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cytokines secreted by T cells play a pivotal role in inflammatory bone destruction. Tumor necrosis factor-α (TNF-α) is a major proinflammatory cytokine produced by macrophages following T cell activation, and directly promotes osteoclast differentiation resulting in accelerated bone resorption. Interferon-γ (IFN-γ) attenuates RANKL-initiated cellular signals through osteoclast formation and counterbalances aberrant bone resorption. With respect to this crosstalk during osteoclastogenesis, the direct interruption of IFN-γ in TNF-α-induced osteoclast formation still requires elucidation. We have demonstrated that IFN-γ directly inhibits osteoclastogenesis induced by TNF-α stimulation and accelerates apoptosis mediated by Fas/Fas ligand signals. There were a decreased number of osteoclasts and reduced mRNA levels encoding Nfatc1 in cultured bone marrow macrophages. Apoptotic responses of cultured cells were observed, with accelerated nuclear fragmentation in osteoclast precursor cells and increased FasL mRNA levels in bone marrow cells stimulated with TNF-α evident. IFN-γ reduced the level of osteoclastogenesis in response to TNF-α treatment in vivo. IFN-γ inhibited TNF-α-induced osteoclastogenesis in mice with T cells that had been exposed to anti-CD4 and -CD8 antibodies. These results provide evidence that IFN-γ directly inhibits osteoclastogenesis and induces cells apoptosis by Fas/FasL signals, leading to the indirect regulation of bone resorption, which is required for protective roles in bone destruction at an inflammation site.
[Show abstract][Hide abstract] ABSTRACT: It has recently been reported that tumor necrosis factor (TNF)-alpha has the ability to accelerate osteoclastogenesis. We previously reported that the proinflammatory cytokine interleukin (IL)-18 inhibits TNF-alpha-mediated osteoclastogenesis in mouse bone marrow cultures. In the present study, the effect of IL-18 on TNF-alpha-mediated osteoclastogenesis was investigated in vivo. We administered TNF-alpha with or without IL-18 into the supracalvaria of mice. The number of osteoclasts in the suture of the calvaria was increased in mice administered TNF-alpha. The number of osteoclasts in mice administered both TNF-alpha and IL-18 was lower than that in mice administered TNF-alpha alone. We previously showed that IL-12 and IL-18 synergistically inhibit TNF-alpha-mediated osteoclastogenesis in vitro. To assess the ability of these two cytokines to synergistically inhibit TNF-alpha-induced osteoclastogenesis in vivo, mice were administered the two cytokines at doses that did not inhibit osteoclast formation. The combination of IL-12 and IL-18 markedly inhibited TNF-alpha-induced osteoclastogenesis in vivo. To evaluate how IL-12 and IL-18 synergistically affect TNF-alpha-induced osteoclastogenesis, the IL-18 receptor (IL-18R) and IL-12R expression levels were analyzed by RT-PCR in bone marrow cells cultured with IL-12 or IL-18. IL-18R mRNA was increased in cells cultured with IL-12, while IL-12R mRNA was increased in cells cultured with IL-18. In addition, IL-18 inhibited TNF-alpha-induced osteoclastogenesis in mice with T-cell depletion caused by anti-CD4 and anti-CD8 antibodies. The present results suggest that IL-18 may inhibit TNF-alpha-mediated osteoclastogenesis in vivo via a T cell-independent mechanism.
Calcified Tissue International 03/2010; 86(3):242-8. · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the effect of anti-c-Fms antibody on odontoclastogenesis and root resorption in an orthodontic tooth movement mouse model.
We used orthodontic tooth movement in which an Ni-Ti coil spring was inserted between the upper incisors and the upper first molar. Root resorption occurred in this model. Anti-c-Fms antibody was injected daily into a local site for 12 days during mechanical loading. Odontoclastogenesis and root resorption were assessed by histology and scanning electron microscopy.
The anti-c-Fms antibody significantly inhibited odontoclastogenesis and root resorption during orthodontic tooth movement.
M-CSF and/or its receptor is a potential therapeutic target in mechanical stress- induced odontoclastogenesis, and injection of an anti-c-Fms antibody might be useful for inhibition of mechanical stress-induced root resorption during orthodontic tooth movement.
The Angle Orthodontist 10/2009; 79(5):835-41. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanical stress such as orthodontic tooth movement induces osteoclastogenesis. Sometimes, excessive mechanical stress results in root resorption during orthodontic tooth movement. It has been reported that bisphosphonate inhibits osteoclastogenesis. Recently, there have been concerns for orthodontic patients receiving bisphosphonates. Thus, the aim of this study was to investigate the effect of bisphosphonates on orthodontic tooth movement and root resorption in mice. A nickel-titanium (Ni-Ti) closed coil spring delivering a force of 10 g was inserted between the upper anterior alveolar bone and the first molar in 8-week-old male C57BL/6 mice. Bisphosphonate (2 microg/20 microl) was injected daily into a local site adjacent to the upper molar. After 12 days, the distance the tooth had moved was measured. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells was counted as osteoclasts in histological sections. Root resorption was assessed by scanning electron microscopy. The data were analysed with a Student's t-test. The orthodontic appliance increased the number of osteoclasts on the pressure side and mesial movement of the first molar. Bisphosphonates reduced the amount of tooth movement and the number of osteoclasts. In addition, they also reduced root resorption on the pressure side. Bisphosphonates inhibit orthodontic tooth movement and prevent root resorption during orthodontic tooth movement in mice. These results suggest that bisphosphonates might have an inhibiting effect on root resorption during orthodontic tooth movement in humans and that they may interrupt tooth movement in orthodontic patients undergoing treatment, thus altering the outcome of treatment.
The European Journal of Orthodontics 10/2009; 31(6):572-7. · 1.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been reported that TNF-alpha plays an important role in bone resorption in pathological conditions. IL-12, which is a T cell mediator, is also an important inflammatory cytokine. We previously reported that IL-12 induces apoptosis in bone marrow cells treated with TNF-alpha in vitro via an interaction between TNF-alpha-induced Fas and IL-12-induced Fas ligand (FasL), and that, as a result, osteoclastogenesis is inhibited. The purpose of this study was to investigate the effects of IL-12 on TNF-alpha-mediated osteoclastogenesis in vivo. We administered TNF-alpha with and without IL-12 into the supracalvaria in mice. The numbers of osteoclasts in the sutures in the calvaria were higher in mice administered TNF-alpha than in control mice not administered TNF-alpha. The numbers of osteoclasts in mice administered both TNF-alpha and IL-12 were lower than those in mice administered only TNF-alpha. Next, we determined the levels of mRNAs for cathepsin K and tartrate-resistant acid phosphatase (TRAP). mRNA levels were increased in mice administered TNF-alpha compared with control mice, but not in mice administered both TNF-alpha and IL-12. We also evaluated the amounts of tartrate-resistant acid phosphatase 5b (TRACP 5b) in mouse sera. The levels of TRACP 5b in mice administered TNF-alpha were higher than those in control mice. On the other hand, in mice administered both TNF-alpha and IL-12, the levels were lower than those in mice administered TNF-alpha alone. Fas and FasL expression levels were analyzed by real-time RT-PCR. The levels of Fas mRNA were increased in the calvaria of mice administered TNF-alpha compared with control mice, while those of FasL mRNAs were increased in the calvaria of mice administered IL-12. In TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assays, many apoptotic cells were found in the sutures in the calvaria of mice administered both TNF-alpha and IL-12. IL-12 also inhibited TNF-alpha-induced osteoclastogenesis in mice whose T cells were blocked by anti-CD4 and anti-CD8 antibodies. These results suggest that IL-12 inhibits TNF-alpha-mediated osteoclastogenesis and induces apoptotic changes through an interaction between TNF-alpha-induced Fas and IL-12-induced FasL, in vivo, via a T cell-independent mechanism.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the kinetics of heat shock protein 47 (HSP47) and proliferating cell nuclear antigen (PCNA) immunohistochemistry in periodontal ligament (PDL) cells during orthodontic tooth movement in a mouse model. An orthodontic appliance was set between the upper incisors and the upper left first molar. The mice were killed 2, 6 and 10 days after initiation of orthodontic tooth movement. Computer-assisted image analysis was used to compare the quantitative expression of HSP47 in the PDL. HSP47 expression was significantly higher on the tension side 2 days after application of the appliance, whereas no significant change was observed on the pressure side at any time point. Furthermore, the PCNA labelling indices of PDL cells were increased significantly on the tension side 6 and 10 days after application of the appliance, and on the pressure side 2, 6 and 10 days after application of the appliance. These data suggest that collagen is metabolised predominantly on the tension side, and that PDL cells actively proliferate on both the tension and pressure sides during orthodontic tooth movement.
Archives of Oral Biology 10/2008; 53(9):890-5. · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To test the hypothesis that there is no difference in the effect of different continuous moderate to very heavy forces on root resorption or amount of tooth movement.
In the study, 10, 25, 50 and 100 g mesial force were applied to the maxillary first molars of rat using nickel titanium closed-coil springs for 3 days, 14 days, and 28 days. The molars were extracted and the surface areas of the root resorption craters were measured using scanning electron microscope. The depths of the root resorption craters were measured using a three-dimensional laser scanning microscope. Tooth movement of the maxillary first molar was measured in relation to the maxillary second molar on digitized lateral cephalometric radiographs.
Three days after force application, the tooth movement was not proportionally related to force magnitude. However, 14 days of force application resulted in significantly more tooth movement in the 10, 25, and 50 g force groups than in the 100 g force group. A force application of 10 g produced significantly more tooth movement at 28 days than all the other three force applications. The largest and deepest resorption craters were observed in the disto-buccal root followed by disto-palatal, middle-buccal, middle-palatal, and mesial root. Root resorption and tooth movement increased over time from 3 to 28 days. As heavier forces were applied, greater root resorption occurred.
The hypothesis is rejected. The light mesially oriented forces, as applied in this study, produced more tooth movement and less root resorption compared with heavier forces.
The Angle Orthodontist 06/2008; 78(3):502-9. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Orthodontic force induces osteoclastogenesis in vivo. It has recently been reported that administration of an antibody against the macrophage-colony-stimulating factor (M-CSF) receptor c-Fms blocks osteoclastogenesis and bone erosion induced by tumor necrosis factor-alpha (TNF-alpha) administration. This study aimed to examine the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and osteolysis in an orthodontic tooth movement model in mice. Using TNF receptor 1- and 2-deficient mice, we showed that orthodontic tooth movement was mediated by TNF-alpha. We injected anti-c-Fms antibody daily into a local site, for 12 days, during mechanical loading. The anti-c-Fms antibody significantly inhibited orthodontic tooth movement, markedly reduced the number of osteoclasts in vivo, and inhibited TNF-alpha-induced osteoclastogenesis in vitro. These findings suggest that M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement mediated by TNF-alpha.
Journal of Dental Research 05/2008; 87(4):396-400. · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activating receptor activator of NF-kappaB (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-alpha promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.
Journal of Clinical Investigation 07/2006; 116(6):1525-34. · 12.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Orthodontic tooth movement is achieved by mechanical loading; however, the biological mechanism involved in this process is not clearly understood owing to the lack of a suitable experimental model. In the present study, we established an orthodontic tooth movement model in mice using a Ni-Ti closed coil spring that was inserted between the upper incisors and the upper first molar. Histological examination demonstrated that the orthodontic force moved the first upper molar mesially without necrosis of the periodontium during tooth movement. The number of TRAP-positive osteoclasts on the pressure side significantly increased in a time-dependent manner. Quantitative real time-based reverse transcription-polymerase chain reaction analysis demonstrated increased levels of mRNA for cathepsin K. Immunohistochemical staining revealed the expression of tumor necrosis factor-alpha (TNFalpha) in periodontium on the pressure side of the first molar during orthodontic tooth movement. When this tooth movement system was applied to TNF type 1 receptor-deficient mice and TNF type 2 receptor-deficient mice, tooth movement observed in TNF type 2 receptor-deficient mice was smaller than that in the wild-type mice and TNF type 1 receptor-deficient mice. The number of TRAP-positive osteoclasts on the pressure side was significantly small in TNF type 2 receptor-deficient mice compared with that in TNF type 1 receptor-deficient mice on day 6 after application of the appliance. The present study indicates that TNFalpha signaling plays some important roles in orthodontic tooth movement.
Journal of Bone and Mineral Metabolism 02/2006; 24(1):20-7. · 2.22 Impact Factor