Tongue pressure and maxillofacial muscle activities during swallowing in patients with mandibular prognathism.

BACKGROUND: Coordination among lip, cheek and tongue movements during swallowing in patients with mandibular prognathism remains unclear. OBJECTIVES: This study aimed to identify the temporal sequences of tongue pressure and maxillofacial muscle activities during swallowing in patients with mandibular prognathism and compared characteristics with those of healthy volunteers. METHODS: Seven patients with mandibular prognathism (mandibular prognathism group) and 25 healthy volunteers with individual normal occlusion (control group) were recruited. Tongue pressures and masseter, orbicularis oris, mentalis and supra- and infrahyoid muscle activities while swallowing gel were measured simultaneously using a sensor sheet system with five measurement points and surface electromyography, respectively. Onset time, offset time and durations of tongue pressure and muscle activities were analysed. RESULTS: In the mandibular prognathism group, tongue pressure was often produced first in more peripheral parts of the palate. Offset of tongue pressure in the posteromedian and peripheral parts of the palate and maxillofacial muscle activities except for orbicularis oris were delayed. Duration of tongue pressure in the anteromedian part of the palate was significantly shorter and durations of masseter, mentalis and suprahyoid muscle activities were significantly longer. Times to onset of orbicularis oris and suprahyoid muscle activities based on first onset of tongue pressure were significantly shorter. CONCLUSION: These results suggest that patients with mandibular prognathism may exhibit specific patterns of tongue pressure production and maxillofacial muscle activities during swallowing.

Investigation of orthognathic surgery indicators-combination with index of orthognathic functional treatment needs (IOFTN) and maxillofacial morphometric analysis.

PURPOSE: The aim of this retrospective study was to determine orthognathic surgery indicators for Japanese patients with jaw deformities using both Index of Orthognathic Functional Treatment Needs (IOFTN) and maxillofacial morphometric analysis. SUBJECTS AND METHODS: The subjects were 89 patients treated with orthognathic surgery and 92 patients treated with orthodontic treatment alone, and were classified as class I, II, or III according to the ANB angle. Based on the results for IOFTN and the results of cephalometric analysis, the indication criteria for orthognathic surgery were examined. RESULTS: In IOFTN analysis, none of patients in the orthognathic surgery group were classified as category 1 or 2, while 48% of the patients in the orthodontic treatment group were classified as category 4 or 5. The results of the cephalometric analysis of patients in classified categories 4 and 5 showed that the orthognathic surgery group had significantly greater lateral mandibular deviation in Class I cases, significantly more severe degree of mandibular retrusion in Class II cases, and significantly more severe degree of mandibular prognathism in Class III cases. The results of the logistic regression analysis showed that IOFTN was a common variable as an indication criterion for orthognathic surgery, and several different variables were also selected from the cephalometric measurements in each group. CONCLUSION: IOFTN is a highly sensitive and useful indicator as a criterion for orthognathic surgery. However, in the choice of treatment strategy, maxillofacial morphometric analyses and the patient's desired goal are important.

A three-dimensional investigation of mandibular deviation in patients with mandibular prognathism.

BACKGROUND: Craniofacial disharmony in cases of jaw deformity associated with abnormal lateral deviation of the jaw mostly involves both the maxilla and mandible. However, it has been still difficult to capture the jaw deviation aspect in a 3-dimensional and quantitative techniques. In this study, we focused on 3-dimensional mandibular morphology and position of the condylar head in relation to the base of the skull in patients with mandibular prognathism, one of the most common jaw deformities. We used cluster analysis to quantify and classify deviation and clarified its characteristics. We also investigated the degree of correlation between those findings and menton (Me) deviation measured on frontal cephalograms, which is a conventional indicator of jaw deformity. RESULTS: Findings obtained from 100 patients (35 men, 65 women) were classified into the following three groups based on mandibular morphology and condylar position relative to the skull base. Then, reclassification using these parameters enabled classification of cluster analysis findings into seven groups based on abnormal jaw deviation characteristics. Comparison among these seven groups showed that the classification criteria were ramus height, mandibular body length, distance from the gonion to the apex of the coronoid process, and the lateral and vertical positions of the mandible. Weak correlation was also found between Me deviation on frontal cephalograms and each of the above parameters measured on 3D images. CONCLUSIONS: Focusing on mandibular morphology and condylar position relative to the skull base in patients with mandibular prognathism, we used cluster analysis to quantify and classify jaw deviation. The present results showed that the 3D characteristics of the mandible based on mandibular morphology and condylar position relative to the skull base can be classified into seven groups. Further, we clarified that Me deviation on frontal cephalograms, which has been used to date, is inadequate for capturing jaw deviation characteristics.

Ift88 regulates enamel formation via involving Shh signaling.

OBJECTIVES: The ciliopathies are a wide spectrum of human diseases, which are caused by perturbations in the function of primary cilia. Tooth enamel anomalies are often seen in ciliopathy patients; however, the role of primary cilia in enamel formation remains unclear. MATERIALS AND METHODS: We examined mice with epithelial conditional deletion of the ciliary protein, Ift88, (Ift88fl / fl ;K14Cre). RESULTS: Ift88fl / fl ;K14Cre mice showed premature abrasion in molars. A pattern of enamel rods which is determined at secretory stage, was disorganized in Ift88 mutant molars. Many amelogenesis-related molecules expressing at the secretory stage, including amelogenin and ameloblastin, enamelin, showed significant downregulation in Ift88 mutant molar tooth germs. Shh signaling is essential for amelogenesis, which was found to be downregulated in Ift88 mutant molar at the secretory stage. Application of Shh signaling agonist at the secretory stage partially rescued enamel anomalies in Ift88 mutant mice. CONCLUSION: Findings in the present study indicate that the function of the primary cilia via Ift88 is critical for the secretory stage of amelogenesis through involving Shh signaling.

Occlusal Evaluation Using Modified Huddart and Bodenham Scoring System Following 2-Stage Palatoplasty With Hotz Plate: A Comparison Among 3 Different Surgical Protocols.

OBJECTIVE: This study aimed to determine if the change in technique of soft palate closure or timing of hard palatal repair induced occlusal changes in patients with complete unilateral cleft lip and palate (CUCLP). DESIGN: Retrospective study. SETTINGS: A medical and dental hospital in Japan. SUBJECTS: A total of 96 patients with CUCLP treated with 2-stage palatoplasty were included in the study and categorized into 3 groups (G1, G2, and G3) according to the protocol used. INTERVENTIONS: G1 underwent soft palate repair using Perko method at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. Furlow method was used for soft palate repair in G2 at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. The Furlow method was used to repair the soft palate in G3 at 1.5 years of age and vomer flap procedure was used to repair the hard palate at 4 years of age. MAIN OUTCOME MEASURES: Two evaluators assessed the dental arch relationship using the modified Huddart/Bodenham (mHB) index on 2 separate occasions. RESULTS: Intra- (intraclass correlation coefficient [ICC]: 0.962) and inter-examiner (ICC: 0.950) reliability showed very good agreement. The frequency of crossbite present in the major and minor segments gradually decreased with each change in protocol. Mean segmental scores showed no significant difference between 3 protocols (P > .05). Good inter-arch alignment occurred with all 3 surgical protocols (G1:82.6%, G2:89.8%, and G3:91.7%). CONCLUSIONS: There was no significant difference in the dental arch relationship outcomes between the 3 surgical protocols. The dentition status was comparable with all surgical protocols, even after the changes.

Perivascular Hedgehog responsive cells play a critical role in peripheral nerve regeneration via controlling angiogenesis.

Hh signaling has been shown to be activated in intact and injured peripheral nerve. However, the role of Hh signaling in peripheral nerve is not fully understood. In the present study, we observed that Hh signaling responsive cells [Gli1(+) cells] in both the perineurium and endoneurium. In the endoneurium, Gli1(+) cells were classified as blood vessel associated or non-associated. After injury, Gli1(+) cells around blood vessels mainly proliferated to then accumulate into the injury site along with endothelial cells. Hh signaling activity was retained in Gli1(+) cells during nerve regeneration. To understand the role of Hedgehog signaling in Gli1(+) cells during nerve regeneration, we examined mice with Gli1(+) cells-specific inactivation of Hh signaling (Smo cKO). After injury, Smo cKO mice showed significantly reduced numbers of accumulated Gli1(+) cells along with disorganized vascularization at an early stage of nerve regeneration, which subsequently led to an abnormal extension of the axon. Thus, Hh signaling in Gli1(+) cells appears to be involved in nerve regeneration through controlling new blood vessel formation at an early stage.

Expression of R-spondins/Lgrs in development of movable craniofacial organs.

Wnt signaling plays a critical role in the development of many organs, including the major movable craniofacial organs tongue, lip, and eyelid. Four members of the R-spondin family (Rspo1-4) bind to Lgr4/5/6 to regulate the activation of Wnt signaling. However, it is not fully understood how Rspos/Lgrs regulate Wnt signaling during the development of movable craniofacial organs. To address this question, we examined the expression of Rspos, Lgrs, and Axin2 (major mediator of canonical Wnt signaling) during tongue, lip, and eyelid development. The expression of Axin2, Rspos and Lgrs was observed in many similar regions, suggesting that Rspos likely activate canonical Wnt signaling through the Lgr-dependent pathway in these regions. Lgr expression was not detected in regions where Axin2 and Rspos were expressed, suggesting that Rspos might activate canonical Wnt signaling through the Lgr-independent pathway in these regions. In addition, the expression of Rspos and Lgrs were observed in some other regions where Axin2 was not expressed, suggesting the possibility that Rspos and/or Lgrs are involved in non-canonical Wnt signaling or the Wnt-independent pathway. Thus, we identified a dynamic spatiotemporal expression pattern of Rspos and Lgrs during the development of the eyelid, tongue, and lip.

MicroRNAs regulate distal region of mandibular development through Hh signaling.

Mandibular anomalies are often seen in various congenital diseases, indicating that mandibular development is under strict molecular control. Therefore, it is crucial to understand the molecular mechanisms involved in mandibular development. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating the level of gene expression. We found that the mesenchymal conditional deletion of miRNAs arising from a lack of Dicer (an essential molecule for miRNA processing, Dicerfl/fl ;Wnt1Cre), led to an abnormal groove formation at the distal end of developing mandibles. At E10.5, when the region forms, inhibitors of Hh signaling, Ptch1 and Hhip1 showed increased expression at the region in Dicer mutant mandibles, while Gli1 (a major mediator of Hh signaling) was significantly downregulated in mutant mandibles. These suggest that Hh signaling was downregulated at the distal end of Dicer mutant mandibles by increased inhibitors. To understand whether the abnormal groove formation inDicer mutant mandibles was caused by the downregulation of Hh signaling, mice with a mesenchymal deletion of Hh signaling activity arising from a lack of Smo (an essential molecule for Hh signaling activation, Smofl/fl ;Wnt1Cre) were examined. Smofl/fl ;Wnt1Cre mice showed a similar phenotype in the distal region of their mandibles to those in Dicerfl/fl ;Wnt1Cre mice. We also found that approximately 400 miRNAs were expressed in wild-type mandibular mesenchymes at E10.5, and six microRNAs were identified as miRNAs with binding potential against both Ptch1 and Hhip1. Their expressions at the distal end of the mandible were confirmed by in situ hybridization. This indicates that microRNAs regulate the distal part of mandibular formation at an early stage of development by involving Hh signaling activity through controlling its inhibitor expression level.

Overactivation of the NF-κB pathway impairs molar enamel formation.

OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm-derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF-κB pathway is known to be responsible for HED, it remains unclear whether this pathway is involved in the process of enamel formation. EXPERIMENTAL SUBJECTS AND METHODS: To address this question, we examined the mice overexpressing Ikkß (an essential component required for the activation of NF-κB pathway) under the keratin 5 promoter (K5-Ikkß). RESULTS: Upregulation of the NF-κB pathway was confirmed in the ameloblasts of K5-Ikkß mice. Premature abrasion was observed in the molars of K5-Ikkß mice, which was accompanied by less mineralized enamel. However, no significant changes were observed in the enamel thickness and the pattern of enamel rods in K5-Ikkß mice. Klk4 expression was significantly upregulated in the ameloblasts of K5-Ikkß mice at the maturation stage, and the expression of its substrate, amelogenin, was remarkably reduced. This suggests that abnormal enamel observed in K5-Ikkß mice was likely due to the compromised degradation of enamel protein at the maturation stage. CONCLUSION: Therefore, we could conclude that the overactivation of the NF-κB pathway impairs the process of amelogenesis.

ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation.

Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chemical compounds that enhance turnover of bone metabolism for promoting bone healing. First, we screen a chemical library which includes 378 compounds by using murine pre-osteoclastic RAW264.7 cells to identify compounds that promote osteoclastic differentiation. We find that two ROCK (Rho-associated coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compounds also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo experiment shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.

Gli3 is a Key Factor in the Schwann Cells from Both Intact and Injured Peripheral Nerves.

Hedgehog (Hh) signaling has been shown to be involved in regulating both intact and injured peripheral nerves. Therefore, it is critical to understand how Hh signaling is regulated in the peripheral nerve. One of the transcription factors of the Hh signaling pathway, Gli3, functions as both a repressor and an activator of Hh signaling activity. However, it remains unclear whether Gli3 is involved in controlling the intact and/or injured peripheral nerves. We found that Gli3 act as a repressor in the Schwann cells (SCs) of intact sciatic nerves. Although Dhh and Ptch1 expression were present, Hh signaling was not activated in these SCs. Moreover, heterozygous Gli3 mutation (Gli3-/+) induced ectopic Hh signaling activity in SCs. Hh signaling was thus suppressed by Gli3 in the SCs of intact sciatic nerves. Minor morphological changes were observed in the intact nerves from Gli3-/+ mice. Gli3 expression was significantly decreased following injury and ligand expression switched from Dhh to Shh, which activated Hh signaling in SCs from wild-type mice. Changes of these ligands was found to be important for nerve regeneration in which the downregulation of Gli3 was also involved. In fact, Gli3-/+ mice exhibited accelerated ligand switching and subsequent nerve regeneration. Both suppression of Hh signaling with Gli3 in the intact nerves and activation of Hh signaling without Gli3 in the injured nerve were observed in the SCs in an autocrine manner. Thus, Gli3 is a key factor in the control of intact peripheral nerve homeostasis and nerve regeneration.

Molecular mechanisms in palatal rugae development.

BACKGROUND: Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structures helps to elucidate the genetic commonality of developmental processes, as organs with these structures are believed to share the same molecular mechanisms and fundamental processes. Palatal rugae are periodic corrugated structures on the hard palate and are conserved in all mammals. Although the numbers and patterns of the palatal rugae are species specific, they are consistent in each mammalian species, except humans. HIGHLIGHT: Palatal rugae development is thus under strict genetic control in most mammals and is an excellent model to investigate the genetic commonality of developmental processes to form periodic patterning. CONCLUSION: This review highlights the current understanding of the molecular mechanisms of palatal rugae development.

The inhibitors of cyclin-dependent kinases and GSK-3ß enhance osteoclastogenesis.

Osteoclasts are multinucleated cells with bone resorption activity that is crucial for bone remodeling. RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling has been shown as a main signal pathway for osteoclast differentiation. However, the molecular mechanism and the factors regulating osteoclastogenesis remain to be fully understood. In this study, we performed a chemical genetic screen, and identified a Cdks/GSK-3ß (cyclin-dependent kinases/glycogen synthase kinase 3ß) inhibitor, kenpaullone, and two Cdks inhibitors, olomoucine and roscovitine, all of which significantly enhance osteoclastogenesis of RAW264.7 cells by upregulating NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) levels. We also determined that the all three compounds increase the number of osteoclast differentiated from murine bone marrow cells. Furthermore, the three inhibitors, especially kenpaullone, promoted maturation of cathepsin K, suggesting that the resorption activity of the resultant osteoclasts is also activated. Our findings indicate that inhibition of GSK-3ß and/or Cdks enhance osteoclastogenesis by modulating the RANK-RANKL signaling pathway.

Finite element analysis of mandibular molar protraction mechanics using miniscrews.

BACKGROUND/OBJECTIVES: The aim of this study was to determine the most desirable force system to achieve molar protraction from an interdental miniscrew minimizing side-effects. Several iterations of force delivery were simulated through variations in the height of a miniscrew, length of a molar extension arm, and incorporation of a lingual force. MATERIALS/METHODS: A three-dimensional mesh model of the right posterior segment of the mandible was developed from cone beam computed tomography data from a patient missing a first molar. Protraction appliances were constructed using computer-aided design software and integrated with finite element software. After mesh generation, a total of 80 loading conditions were simulated by altering the extension arm length (2-10mm), miniscrew height (0-8mm), and magnitude of protraction force from the lingual side (0-1.5 N). A constant labial force of 1 N was used in all models. RESULTS: As the length of the extension arm increased, mesial tipping decreased, rotation decreased, and buccolingual inclination remained the same without lingual traction force. Lingual traction reduced rotation but increased tipping. Similar trends were observed in all situations despite of the height of the miniscrew. CONCLUSIONS: The height of the miniscrew is not as critical in affecting tooth movement during mandibular second molar protraction as the length of the extension arm. The most ideal force system in the model appeared to be the longest extension arm (10mm) with the addition of a lingual force of half or equal magnitude of the labial force.

Osteocyte death during orthodontic tooth movement in mice.

OBJECTIVE: To investigate the time course of osteocyte death in a mouse model of orthodontic tooth movement (OTM) and its association to the caspase-3 activation pathway and osteoclast formation. MATERIALS AND METHODS: Twenty-five male wild type CD-1 mice (8-12 weeks old) were loaded with an orthodontic appliance. A spring delivering 10-12 g of force was placed between the right first molar and the incisor to displace the first molar mesially. The contralateral unloaded sides served as the control. The animals were equally divided into five different time points: 6, 12, 24, and 72 hours and 7 days of orthodontic loading. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, caspase-3 immunostaining, and tartrate-resistant acid phosphatase (TRAP) staining was performed on histologic sections of the first molars. The labeling was quantified in osteocytes on the compression side of the alveolar bone at each time point. RESULTS: TUNEL labeling significantly increased at 12, 24, and 72 hours after orthodontic loading; the peak was observed at 24 hours. Elevated caspase-3 labeling was noted at 12, 24, and 72 hours and 7 days after loading, although the increase was not significant. Significant osteoclast formation was initially evident after 72 hours and progressively increased up to 7 days. CONCLUSIONS: Osteocyte death during OTM peaks at 24 hours, earlier than initial osteoclast activation. However, only a slight trend for increased caspase-3 activity suggests that other mechanisms might be involved in osteocyte death during OTM.

Effect of cyclical forces on the periodontal ligament and alveolar bone remodeling during orthodontic tooth movement.

OBJECTIVE: To investigate the effect of externally applied cyclical (vibratory) forces on the rate of tooth movement, the structural integrity of the periodontal ligament, and alveolar bone remodeling. METHODS: Twenty-six female Sprague-Dawley rats (7 weeks old) were divided into four groups: CTRL (unloaded), VBO (molars receiving a vibratory stimulus only), TMO (molars receiving an orthodontic spring only), and TMO+VB (molars receiving an orthodontic spring and the additional vibratory stimulus). In TMO and TMO+VB groups, the rat first molars were moved mesially for 2 weeks using Nickel-Titanium coil spring delivering 25 g of force. In VBO and TMO+VB groups, cyclical forces at 0.4 N and 30 Hz were applied occlusally twice a week for 10 minutes. Microfocus X-ray computed tomography analysis and tooth movement measurements were performed on the dissected rat maxillae. Tartrate-resistant acid phosphatase staining and collagen fiber assessment were performed on histological sections. RESULTS: Cyclical forces significantly inhibited the amount of tooth movement. Histological analysis showed marked disorganization of the collagen fibril structure of the periodontal ligament during tooth movement. Tooth movement caused a significant increase in osteoclast parameters on the compression side of alveolar bone and a significant decrease in bone volume fraction in the molar region compared to controls. CONCLUSIONS: Tooth movement was significantly inhibited by application of cyclical forces.