Effects of the changes in the condylar long axis angle and condylar position on temporomandibular symptoms after intraoral vertical ramus osteotomy: a preliminary study.

OBJECTIVE: This study was conducted to characterize the effects of the changes in the condylar long axis and position on temporomandibular symptoms with respect proximal segment position after intraoral vertical ramus osteotomy (IVRO). STUDY DESIGN: Twenty Japanese patients with diagnosed jaw deformity underwent IVRO without internal fixation. Long-term changes in condylar long axis and position were assessed during postoperative follow-up examinations by using computed tomography, and t tests were performed for comparison. In addition, changes in temporomandibular symptoms were examined. RESULTS: The degree of axial rotation of the proximal segment changed significantly when the proximal segment was located laterally. Downward changes in condylar position significantly differed when the proximal segment was located posterolaterally. Forward changes in condylar position significantly differed when the proximal segment was located laterally; moreover, when the proximal segment was located laterally, temporomandibular symptoms disappeared. CONCLUSIONS: Lateral location of the proximal segment may be an important factor in the positive effects of IVRO, with respect to temporomandibular symptoms.

Development and evaluation of a jaw-tracking system for mice: reconstruction of three-dimensional movement trajectories on an arbitrary point on the mandible.

BACKGROUND: Mastication is one of the most fundamental functions for the conservation of life. The demand for devices for evaluating stomatognathic function, for instance, recording mandibular movements or masticatory muscle activities using animal models, has been increasing in recent years to elucidate neuromuscular control mechanisms of mastication and to investigate the etiology of oral motor disorders. To identify the fundamental characteristics of the jaw movements of mice, we developed a new device that reconstructs the three-dimensional (3D) movement trajectories on an arbitrary point on the mandible during mastication. METHODS: First, jaw movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, a 3D model of the mandible including the markers was created from micro-computed tomography images. Then, the jaw movement trajectory on the certain anatomical point was reproduced by integrating the kinematic data of the jaw movements with the geometric data of the mandible. RESULTS: The 3D movements at any points on the mandible, such as the condyle, molar, and incisor during mastication, could be calculated and visualized with an accuracy > 0.041 mm in 3D space. The masticatory cycle was found to be clearly divided into three phases, namely, the opening, closing, and occlusal phases in mice. CONCLUSIONS: The proposed system can reproduce and visualize the movements of internal anatomical points such as condylar points precisely by combining kinematic data with geometric data. The findings obtained from this system could facilitate our understanding of the pathogenesis of eating disorders or other oral motor disorders when we could compare the parameters of stomatognathic function of normal mice and those of genetically modified mice with oral behavioral dysfunctions.

Soft tissue changes after a mandibular osteotomy for symmetric skeletal class III malocclusion.

The soft tissue profile is crucial to esthetics after orthognathic surgery. The aim of this study was to assess the soft tissue changes of the subnasal and submental regions more than 1 year after a sagittal split ramus osteotomy (SSRO) in patients with skeletal class III malocclusion. A total of 22 patients with mandibular prognathism were included in this study. Patients had lateral cephalograms before and more than 1 year after they underwent an isolated SSRO. Soft and hard tissue changes were assessed using the lateral cephalograms. The lower lip, labiomenton, and soft tissue menton moved posteriorly by 85, 89, and 88% compared with the corresponding hard tissue, and the movement of the soft tissue B point and the top of the chin nearly reflected the displacement of the hard tissues, at 96 and 99%, respectively. The labiomenton, stomions, and naso-labial angles were changed after the mandibular set-back and the changes in these angles correlated with either the width of the soft tissue or skeletal displacement. The naso-labial angle could be altered even if an isolated mandibular osteotomy is performed. Changes to the stomions and naso-labial angles were affected by hard tissue movement, while changes to the labiomental angle were affected by the width of the soft tissue after the mandibular osteotomy. It is important to create an accurate preoperative prediction of the esthetic outcomes after a mandibular osteotomy by considering the interrelations between the hard and soft tissues.

IL-12 Inhibits Lipopolysaccharide Stimulated Osteoclastogenesis in Mice.

Lipopolysaccharide (LPS) is related to osteoclastogenesis in osteolytic diseases. Interleukin- (IL-) 12 is an inflammatory cytokine that plays a critical role in host defense. In this study, we investigated the effects of IL-12 on LPS-induced osteoclastogenesis. LPS was administered with or without IL-12 into the supracalvariae of mice, and alterations in the calvarial suture were evaluated histochemically. The number of osteoclasts in the calvarial suture and the mRNA level of tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, were lower in mice administered LPS with IL-12 than in mice administered LPS alone. The serum level of tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker, was also lower in mice administered LPS with IL-12 than in mice administered LPS alone. These results revealed that IL-12 might inhibit LPS-induced osteoclastogenesis and bone resorption. In TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assays, apoptotic changes in cells were recognized in the calvarial suture in mice administered LPS with IL-12. Furthermore, the mRNA levels of both Fas and FasL were increased in mice administered LPS with IL-12. Taken together, the findings demonstrate that LPS-induced osteoclastogenesis is inhibited by IL-12 and that this might arise through apoptotic changes in osteoclastogenesis-related cells induced by Fas/FasL interactions.

The skeletal stability after maxillo-mandibular osteotomy with a "physiological positioning strategy".

The aim of this study was to estimate skeletal and dental stability after maxillomandibular osteotomy with physiological positioning. Ten patients (7 men and 3 women) with skeletal mandibular prognathism were treated by conventional Le Fort I osteotomy for the maxilla and unfixed short lingual osteotomy for the mandible together with physiological positioning. We used cephalometric analysis to evaluate the skeletal and dental stability preoperatively, immediately after maxillomandibular osteotomy, and more than 1 year later. The immediately postoperative measurements for the SNA and the SN-palatal planes were 0.15° (p=0.67) and 1.0° (p=0.17), respectively. The positions of the anterior nasal spine, posterior nasal spine, and A point showed minimal changes 1 year postoperatively. The postoperative difference for SNB was 0.76° (p=0.04). Dental stability was apparent postoperatively. We conclude that reliable stability of both the maxilla and the mandible was achieved after maxillomandibular osteotomy with physiological positioning in patients with mandibular prognathism.

Effect of cytokines on osteoclast formation and bone resorption during mechanical force loading of the periodontal membrane.

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.

Short lingual osteotomy without fixation: a new strategy for mandibular osteotomy known as "physiological positioning".

We describe the strategy of physiological positioning, which we regard as a new alternative treatment to conventional orthognathic operations, and treated 18 patients with skeletal mandibular prognathism using it. The positions of SNB, FMA, and Me were measured postoperatively to assess skeletal stability, changes in the angle and perpendicular length of the upper and lower central incisors were measured to assess dental stability, and we confirmed that both skeletal and dental stability were excellent. The width to which the jaw could be opened recovered early, and we saw only one case of disorder of the temporomandibular joint. Short lingual osteotomy with physiological positioning is an effective new approach to the treatment of deformities of the mandible.

A patient with severe maxillary gingival exposure treated with combined compression osteogenesis of the anterior alveolar bone and conventional Le Fort I osteotomy.

Excessive gingival exposure at the maxillary anterior region during not only smiling (a gummy face) but also at rest creates both functional and aesthetic problems for patients. We herein introduce a unique treatment procedure for mandibular retrognathia with a gummy face. This procedure combines conventional Le Fort I osteotomy and following corticotomy at the anterior region of the maxilla. Subsequently, the anterior segment is continuously compressed (compression osteogenesis) in a posterior-superior direction until it reaches an ideal position. This procedure appears to safely and adequately resolve both the aesthetic and functional complaints associated with patients with a gummy face.

Immunological reaction in TNF-α-mediated osteoclast formation and bone resorption in vitro and in vivo.

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.

Inhibitory effect of interferon-γ on experimental tooth movement in mice.

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.

Inhibitory effects of IL-12 on experimental tooth movement and root resorption in mice.

OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-α-mediated osteoclastogenesis of bone marrow cells.

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.

IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions.

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.

IL-18 inhibits TNF-alpha-induced osteoclastogenesis possibly via a T cell-independent mechanism in synergy with IL-12 in vivo.

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.

Influence of bisphosphonates on orthodontic tooth movement in mice.

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.

An M-CSF receptor c-Fms antibody inhibits mechanical stress-induced root resorption during orthodontic tooth movement in mice.

OBJECTIVE: To examine the effect of anti-c-Fms antibody on odontoclastogenesis and root resorption in an orthodontic tooth movement mouse model. MATERIALS AND METHODS: 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. RESULTS: The anti-c-Fms antibody significantly inhibited odontoclastogenesis and root resorption during orthodontic tooth movement. CONCLUSION: 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.

IL-12 inhibits TNF-alpha induced osteoclastogenesis via a T cell-independent mechanism in vivo.

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.