Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jcp.30348

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>Osteocytes are believed to play a crucial role in mechanosensation and mechanotransduction which are important for maintenance of mechanical integrity of bone. Recent investigations have revealed that the preferential orientation of bone extracellular matrix (ECM) mainly composed of collagen fibers and apatite crystallites is one of the important determinants of bone mechanical integrity. However, the relationship between osteocytes and ECM orientation remains unclear. In this study, the association between ECM orientation and anisotropy in the osteocyte lacuno-canalicular system, which is thought to be optimized along with the mechanical stimuli, was investigated using male rat femur. The degree of ECM orientation along the femur longitudinal axis was significantly and positively correlated with the anisotropic features of the osteocyte lacunae and canaliculi. At the femur middiaphysis, there are the osteocytes with lacunae that highly aligned along the bone long axis (principal stress direction) and canaliculi that preferentially extended perpendicular to the bone long axis, and the highest degree of apatite <italic>c</italic>-axis orientation along the bone long axis was shown. Based on these data, we propose a model in which osteocytes can change their lacuno-canalicular architecture depending on the mechanical environment so that they can become more susceptible to mechanical stimuli via fluid flow in the canalicular channel.

DOI： 10.1007/s00223-021-00852-1

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00223-021-00901-9

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Other Link： https://link.springer.com/article/10.1007/s00223-021-00901-9/fulltext.html

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/13440241.2021.1952392

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

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<title>Abstract</title>Bone is a highly dynamic organ that undergoes remodeling equally regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. To clarify the regulation of osteoblastogenesis, primary murine osteoblasts are required for an in vitro study. Primary osteoblasts are isolated from neonatal calvariae through digestion with collagenase. However, the number of cells collected from one pup is not sufficient for further in vitro experiments, leading to an increase in the use of euthanized pups. We hypothesized that the viscosity of digested calvariae and digestion solution supplemented with collagenase results in cell clumping and reduction of isolated cells from bones. We simply added Benzonase, a genetically engineered endonuclease that shears all forms of DNAs/RNAs, in order to reduce nucleic acid-mediated viscosity. We found that addition of Benzonase increased the number of collected osteoblasts by three fold compared to that without Benzonase through reduction of viscosity. Additionally, Benzonase has no effect on cellular identity and function. The new osteoblast isolation protocol with Benzonase minimizes the number of neonatal pups required for an in vitro study and expands the concept that isolation of other populations of cells including osteocytes that are difficult to be purified could be modified by Benzonase.

DOI： 10.1038/s41598-021-87716-8

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Other Link： http://www.nature.com/articles/s41598-021-87716-8

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DOI： 10.1007/s00774-020-01135-9

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajodo.2019.10.026

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jcp.30348

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/13440241.2020.1845587

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：PeerJ  

<sec>
<title>Background</title>
In this study, we investigated the effect of the mechanical loading history on the expression of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in MLO-Y4 osteocyte-like cells.


</sec>
<sec>
<title>Methods</title>
Three hours after MLO-Y4 osteocytes were seeded, a continuous compressive force (CCF) of 31 dynes/cm² with or without additional CCF (32 dynes/cm²) was loaded onto the osteocytes. After 36 h, the additional CCF (loading history) was removed for a recovery period of 10 h. The expression of RANKL, OPG, RANKL/OPG ratio, cell numbers, viability and morphology were time-dependently examined at 0, 3, 6 and 10 h. Then, the same additional CCF was applied again for 1 h to all osteocytes with or without the gap junction inhibitor to examine the expression of RANKL, OPG, the RANKL/OPG ratio and other genes that essential to characterize the phenotype of MLO-Y4 cells. Fluorescence recovery after photobleaching technique was also applied to test the differences of gap-junctional intercellular communications (GJIC) among MLO-Y4 cells.


</sec>
<sec>
<title>Results</title>
The expression of RANKL and OPG by MLO-Y4 osteocytes without a loading history was dramatically decreased and increased, respectively, in response to the 1-h loading of additional weight. However, the expression of RANKL, OPG and the RANKL/OPG ratio were maintained at the same level as in the control group in the MLO-Y4 osteocytes with a loading history but without gap junction inhibitor treatment. Treatment of loading history significantly changed the capacity of GJIC and protein expression of connexin 43 (Cx43) but not the mRNA expression of Cx43. No significant difference was observed in the cell number or viability between the MLO-Y4 osteocyte-like cells with and without a loading history or among different time checkpoints during the recovery period. The cell morphology showed significant changes and was correlated with the expression of OPG, Gja1 and Dmp1 during the recovery period.


</sec>
<sec>
<title>Conclusion</title>
Our findings indicated that the compressive force-induced changes in the RANKL/OPG expression could be habituated within at least 11 h by 36-h CCF exposure. GJIC and cell morphology may play roles in response to loading history in MLO-Y4 osteocyte-like cells.


</sec>

DOI： 10.7717/peerj.10244

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Summary</title>
<sec>
<title>Background and objectives</title>
The masticatory force affects craniofacial development. We aimed to quantify the topological deviation of the growing craniofacial structure due to soft-food diet feeding and to map the region where the phenotypes appeared on three-dimensional (3D) images.


</sec>
<sec>
<title>Material and methods</title>
Mice were fed a powdered soft diet (SD) or conventional hard diet (HD) of regular rodent pellets at 3 weeks of age until 9 weeks of age. The heads, excluding the mandibles, were scanned by micro-computed tomography. The topographic deviation of the bony surface was quantitatively assessed by a wire mesh fitting analysis. The actual displacement and significant differences were mapped and visualized in each x-, y-, and z-axis on the 3D craniofacial image. On these reconstructed images, two-dimensional linear measurements between the landmark points confirmed the 3D skeletal displacement.


</sec>
<sec>
<title>Results</title>
In the transverse direction, the zygomatic arches and the region in which the temporal muscle attaches to the parietal and temporal bones were narrow in the SD group. The temporal muscle attachment regions significantly shifted anteriorly, and consequently, the sagittal zygomatic arch shortened. Although the cranial sagittal length was not affected, the vertical height was also reduced in the SD group compared to the HD group.


</sec>
<sec>
<title>Conclusions</title>
Our 3D surface-based analysis demonstrated that SD feeding resulted in reduced 3D bony development at the region where the chewing muscles attach to the zygomatic arches and the temporal and parietal bones. Interestingly, SD feeding induced an anterior shift in the temporal and parietal bone regions, which can affect the skeletal inter-jaw relationship.


</sec>

DOI： 10.1093/ejo/cjaa007

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INTRODUCTION: The Wnt signaling pathway acts as a key regulator of skeletal development and its homeostasis. However, the potential role of Wnt1 in the mechanotransduction machinery of orthodontic tooth movement-initiated bone remodeling is still unclear. Hence, this study focused on the regulatory dynamics of the Wnt1 expression in both the periodontal ligament (PDL) and osteocytes in vivo and in vitro. METHODS: The Wnt1 expression in the orthodontically moved maxillary first molar in mice was assessed at 0, 1, and 5 days, on both the compression and tension sides. Primary isolated human PDL (hPDL) fibroblasts, as well as murine long-bone osteocyte-Y4 (MLO-Y4) cells, were exposed to continuous compressive force and static tensile force. RESULTS: The relative quantification of immunodetection showed that orthodontic tooth movement significantly stimulated the Wnt1 expression in both the PDL and alveolar osteocytes on the tension side on day 5, whereas the expression on the compression side did not change. This increase in the Wnt1 expression, shown in vivo, was also noted after the application of 12% static tensile force in isolated hPDL fibroblasts and 20% in MLO-Y4 cells. In contrast, a compressive force led to the attenuation of the Wnt1 gene expression in both hPDL fibroblasts and MLO-Y4 cells in a force-dependent manner. In the osteocyte-PDL coculture system, recombinant sclerostin attenuated Wnt1 in PDL, whereas the antisclerostin antibody upregulated its gene expression, indicating that mechanically-driven Wnt1 signaling in PDL might be regulated by osteocytic sclerostin. CONCLUSIONS: Our findings provide that Wnt1 signaling plays a vital role in tooth movement-initiated bone remodeling via innovative mechanotransduction approaches.

DOI： 10.1016/j.ajodo.2020.08.006

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.archoralbio.2020.104841

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Pseudomonas aeruginosa (P. aeruginosa) is associated with periapical periodontitis. The lesions are characterized by a disorder in osteoblast metabolism. Quorum sensing molecular N-(3-oxododecanoyl)-homoserine lactone (AHL) is secreted by P. aeruginosa and governs the expression of numerous virulence factors. AHL can trigger intracellular calcium ([Ca2+]i) fluctuations in many host cells. However, it is unclear whether AHL can regulate osteoblast metabolism by affecting [Ca2+]i changes or its spatial correlation. We explored AHL-induced apoptosis and differentiation in pre-osteoblastic MC3T3-E1 cells and evaluated [Ca2+]i mobilization using several extraction methods. The spatial distribution pattern of [Ca2+]i among cells was investigated by Moran's I, an index of spatial autocorrelation. We found that 30 μM and 50 μM AHL triggered opposing osteoblast fates. At 50 μM, AHL inhibited osteoblast differentiation by promoting mitochondrial-dependent apoptosis and negatively regulating osteogenic marker genes, including Runx2, Osterix, bone sialoprotein (Bsp), and osteocalcin (OCN). In contrast, prolonged treatment with 30 μM AHL promoted osteoblast differentiation concomitantly with cell apoptosis. The elevation of [Ca2+]i levels in osteoblasts treated with 50 μM AHL was spatially autocorrelated, while no such phenomenon was observed in 30 μM AHL-treated osteoblasts. The blocking of cell-to-cell spatial autocorrelation in the osteoblasts provoked by 50 μM AHL significantly inhibited apoptosis and partially restored differentiation. Our observations suggest that AHL affects the fate of osteoblasts (apoptosis and differentiation) by affecting the spatial correlation of [Ca2+]i changes. Thus, AHL acts as a double-edged sword for osteoblast function.

DOI： 10.1016/j.cellsig.2020.109740

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Ameloblastoma is one of the most common benign odontogenic neoplasms. Its surgical excision has the potential to lead to postoperative malocclusion. In this case report, we describe the successful interdisciplinary orthodontic treatment of a patient with ameloblastoma who underwent marginal mandibulectomy. CASE PRESENTATION: A woman of 20-year-old was diagnosed with ameloblastoma, and underwent marginal mandibulectomy when she was 8 years of age. She had an excessive overjet (11.5 mm) and a mild open bite (- 1.5 mm) with a severely resorbed atrophic edentulous ridge in the area around the mandibular left lateral incisor, canine and first premolar. An alveolar bone defect associated with tumor resection was regenerated by vertical distraction osteogenesis (DO). Subsequently, 3 dental implants were placed into the reconstructed mandible. Orthodontic treatment using implant-anchored mechanics provided a proper facial profile with significantly improved occlusal function. The occlusion appeared stable for a 7-year retention period. CONCLUSIONS: These results suggest that surgically assisted and implant anchored-orthodontic approaches might be effective for the correction of such malocclusions.

DOI： 10.1186/s13005-020-00227-1

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：FapUNIFESP (SciELO)  

ABSTRACT Introduction: Anterior open bite is one of the most difficult malocclusions to correct in orthodontic treatment. Molar intrusion using miniscrew anchorage has been developed as a new strategy for open bite correction; however, this procedure still has an important concern about prolonged treatment duration in the patient with anteroposterior discrepancy due to the separate step-by-step movement of anterior and posterior teeth. Objective: This article illustrates a comprehensive orthodontic approach for dentoalveolar open bite correction of an adult patient, by using miniscrew. Case report: A woman 19 years and 5 months of age had chief complaints of difficulty chewing with the anterior teeth and maxillary incisor protrusion. An open bite of -2.0 mm caused by slight elongation of the maxillary molars was found. The patient was diagnosed with Angle Class II malocclusion with anterior open bite due to the vertical elongation of maxillary molars. After extraction of the maxillary first premolars, concurrent movements of molar intrusion and canine retraction were initiated with the combined use of sectional archwires, elastic chains and miniscrews. Results: At 4 months after the procedure, positive overbite was achieved subsequent to the intrusion of maxillary molars by 1.5 mm and without undesirable side effects. Class I canine relation was also achieved at the same time. The total active treatment period was 21 months. The resultant occlusion and satisfactory facial profile were maintained after 54 months of retention. Conclusion: The presented treatment shows the potential to shorten the treatment duration and to contribute to the long-term stability for open bite correction.

DOI： 10.1590/2177-6709.25.3.30.e1-12.onl

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To identify proteins that cooperate with cellular communication network factor 2 (CCN2), we carried out GAL4-based yeast two-hybrid screening using a cDNA library derived from the chondrocytic cell line HCS-2/8. Rab14 GTPase (Rab14) polypeptide was selected as a CCN2-interactive protein. The interaction between CCN2 and Rab14 in HCS-2/8 cells was confirmed using the in situ proximity ligation assay. We also found that CCN2 interacted with Rab14 through its IGFBP-like domain among the four domains in CCN2 protein. To detect the colocalization between CCN2 and Rab14 in the cells in detail, CCN2, wild-type Rab14 (Rab14WT), a constitutive active form (Rab14CA), and a dominant negative form (Rab14DN) of Rab14 were overexpressed in monkey kidney-tissue derived COS7 cells. Ectopically overexpressed Rab14 showed a diffuse cytosolic distribution in COS7 cells; however, when Rab14WT was overexpressed with CCN2, the Rab14WT distribution changed to dots that were evenly distributed within the cytosol, and both Rab14 and CCN2 showed clear colocalization. When Rab14CA was overexpressed with CCN2, Rab14CA and CCN2 also showed good localization as dots, but their distribution was more widespread within cytosol. The coexpression of Rab14DN and CCN2 also showed a dotted codistribution but was more concentrated in the perinuclear area. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that the reduction in RAB14 or CCN2 mRNA by their respective siRNA significantly enhanced the expression of ER stress markers, BIP and CHOP mRNA in HCS-2/8 chondrocytic cells, suggesting that ER and Golgi stress were induced by the inhibition of membrane vesicle transfer via the suppression of CCN2 or Rab14. Moreover, to study the effect of the interaction between CCN2 and its interactive protein Rab14 on proteoglycan synthesis, we overexpressed Rab14WT or Rab14CA or Rab14DN in HCS-2/8 cells and found that the overexpression of Rab14DN decreased the extracellular proteoglycan accumulation more than the overexpression of Rab14WT/CA did in the chondrocytic cells. These results suggest that intracellular CCN2 is associated with Rab14 on proteoglycan-containing vesicles during their transport from the Golgi apparatus to endosomes in chondrocytes and that this association may play a role in proteoglycan secretion by chondrocytes.

DOI： 10.3390/ijms21082769

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Retinoic acid (RA), an active metabolite of vitamin A, plays pivotal roles in a wide variety of biological processes, such as body patterning, organ development, and cell differentiation and proliferation. RA signaling is mediated by nuclear retinoic acid receptors, α, β, and γ (RARα, RARβ, and RARγ). RA is a well-known regulator of cartilage and skeleton formation and RARs are also essential for skeletal growth and hypertrophic chondrocyte-specific gene expression. These important roles of RA and RARs in chondrogenesis have been widely investigated using in vivo mouse models. However, few reports are available on the function of each subtype of RARs on in vitro chondrocyte differentiation. Here, we examined the effect of specific agonists of RARs on chondrogenic differentiation of ATDC5 and C3H10T1/2 cells. Subtype-specific RAR agonists as well as RA decreased the expressions of chondrogenic differentiation marker genes and inhibited chondrogenic differentiation, which was accompanied with morphological change to spindle-shaped cells. Among RAR agonists, RARα and RARγ agonists revealed a strong inhibitory effect on chondrogenic differentiation. RARα and RARγ agonists also hampered viability of ATDC5 cells. These observations suggested that RARα and RARγ are dominant receptors of RA signaling that negatively regulate chondrogenic differentiation.

DOI： 10.1007/s12565-019-00512-3

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ABSTRACT Introduction: Tooth agenesis is one of the most common dental anomalies; however, the concomitant occurrence of opposite dental numerical variation of hypohyperdontia is extremely rare. Objective: To report the successful orthodontic management of a patient with non-syndromic concomitant bilateral agenesis of mandibular canines and two midline inverted supernumerary maxillary teeth. Case report: 21-year-old female patient with a chief complaint of protrusive right maxillary central incisor. The patient was diagnosed with a mild Class II skeletal base, Angle Class III molar relationship and increased overjet associated with hypohyperdontia. Anterior open bite accompanied with tongue-thrusting habit were also observed. Two temporary anchorage devices (TADs) were implanted at the buccal side of the maxillary molar region to control vertical height. Anterior teeth retraction was done after extraction of the maxillary first premolars, to improve the excessive overjet. The treatment mechanics involved lingual brackets system for the maxillary arch and transpalatal arch for anchorage control. Results: The total active treatment period was 35 months. Acceptable occlusion with increased bite force and contact area as well as functional excursion were established without interference, following complex orthodontic treatment with premolar substitution. The resultant occlusion and a satisfactory facial profile were maintained after 29 months of retention. Conclusion: The present case report provides implications regarding the orthodontic treatment of hypohyperdontia-associated substitution for missing teeth as an effective option for improving aesthetic and functional aspects.

DOI： 10.1590/2177-6709.25.1.036-046.oar

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Authorship：Last author,　Corresponding author   Publishing type：Part of collection (book)   Publisher：Springer US  

DOI： 10.1007/7651_2020_322

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File： Miyazaki(ScienceAdv).pdf

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

File： EiEiHseHlaing(FASEB)2019.pdf

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This study aimed to predict the key genes and pathways that are activated when different types of mechanical loading are applied to osteocytes. mRNA expression datasets (series number of GSE62128 and GSE42874) were obtained from Gene Expression Omnibus database (GEO). High gravity-treated osteocytic MLO-Y4 cell-line samples from GSE62128 (Set1), and fluid flow-treated MLO-Y4 samples from GSE42874 (Set2) were employed. After identifying the differentially expressed genes (DEGs), functional enrichment was performed. The common DEGs between Set1 and Set2 were considered as key DEGs, then a protein-protein interaction (PPI) network was constructed using the minimal nodes from all of the DEGs in Set1 and Set2, which linked most of the key DEGs. Several open source software programs were employed to process and analyze the original data. The bioinformatic results and the biological meaning were validated by in vitro experiments. High gravity and fluid flow induced opposite expression trends in the key DEGs. The hypoxia-related biological process and signaling pathway were the common functional enrichment terms among the DEGs from Set1, Set2 and the PPI network. The expression of almost all the key DEGs (Pdk1, Ccng2, Eno2, Egln1, Higd1a, Slc5a3 and Mxi1) were mechano-sensitive. Eno2 was identified as the hub gene in the PPI network. Eno2 knockdown results in expression changes of some other key DEGs (Pdk1, Mxi1 and Higd1a). Our findings indicated that the hypoxia response might have an important role in the differential responses of osteocytes to the different types of mechanical force.

DOI： 10.1007/s00774-018-0963-7

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In vitro synthesis of bone tissue has been paid attention in recent years; however, current methods to fabricate bone tissue are still ineffective due to some remaining gaps in the understanding of real in vivo bone formation process, and application of the knowledge in bone synthesis. Therefore, the objectives of this study were first, to perform a systematic and ultrastructural investigation of the initial mineral formation during intramembranous ossification of mouse calvaria from a material scientists' viewpoint, and to develop novel mineralization methods based on the in vivo findings. First, the very initial mineral deposition was found to occur at embryonic day E14.0 in mouse calvaria. Analysis of the initial bone formation process showed that it involved the following distinct steps: collagen secretion, matrix vesicle (MV) release, MV mineralization, MV rupture, and collagen fiber mineralization. Next, we performed in vitro mineralization experiments using MVs and hydrogel scaffolds. Intact MVs embedded in collagen gel did not mineralize, whereas, interestingly, MV nanofragments obtained by ultrasonication could promote rapid mineralization. These results indicate that mechanically ruptured MV membrane can be a promising material for in vitro bone tissue synthesis. © 2019 The Authors. journal Of Biomedical Materials Research Part A Published By Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1021-1030, 2019.

DOI： 10.1002/jbm.a.36618

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This report illustrates successful nonsurgical orthodontic treatment of a hypodivergent adult patient with bilateral posterior scissors bite (Brodie bite) and excessive overjet. A 26-year-old woman primarily reported maxillary incisor protrusion. She was diagnosed with Class ll division 1 malocclusion with skeletal Class I, short face, low mandibular plane angle and bilateral posterior scissors bite. A lingual arch with anterior bite block and posterior miniscrews with preadjusted edgewise appliances were used to improve the bilateral scissors bite. After achieving molar occlusion, the maxillary first premolars were extracted, and six miniscrews were used to improve the anterior-posterior and vertical discrepancies. After active treatment for 56 months, the convex facial profile with excessively protruded lips was improved and good interdigitation with ideal incisor relationship was achieved. Additionally, the irregular movements of the incisal path and the bilateral condyles during lateral excursion were improved. At 13 months of retention, a satisfactory facial profile, occlusion, and jaw movements were maintained. The treatment results suggest that miniscrews and fixed bite blocks were effective and efficient to facilitate correction of the bilateral scissors bite, excessive overjet, and vertical relationship correction in this nonsurgical orthodontic treatment.

File： Nakamura(AngleOrthod)2019.pdf

DOI： 10.2319/111617-791.1

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Prader-Willi syndrome (PWS) is a complex disorder that affects multiple systems and may cause craniofacial and dentofacial abnormalities. However, there is still a lack of evidence in the literature regarding the progress of orthodontic treatment in patients with PWS. This case report describes the successful orthodontic treatment of a patient with PWS. A girl, 9 years 0 months of age, who had been diagnosed with PWS had protruding maxillary incisors and a convex profile. Her malocclusion was due to the posteriorly positioned mandible. Screening tests for sleep apnea syndrome showed that she had sleep-disordered breathing, including obstructive sleep apnea and bruxism. We also observed an excessive overjet of 10.0 mm, a deep overbite of 6.8 mm, and the congenital absence of the mandibular second premolars. The patient was diagnosed with an Angle Class II malocclusion and a skeletal Class II jaw-base relationship with a deep overbite. Functional appliance therapy with mandibular advancement, which can enlarge the upper airway and increase the upper airspace, was performed to prevent further deterioration of the patient's obstructive sleep apnea. An acceptable occlusion with a proper facial profile and functional excursion were achieved without interference after comprehensive 2-stage treatment that incorporated orthodontic therapy for the patient's excessive overjet and deep overbite. The resulting occlusion was stable, and the occlusal force and the contact area gradually increased over a 2-year retention period. These results suggest that orthodontic treatment offers the opportunity to greatly improve the health and quality of life of people with PWS.

DOI： 10.1016/j.ajodo.2017.05.040

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Osteocytes form a three-dimensional (3D) cellular network within the mineralized bone matrix. The cellular network has important roles in mechanosensation and mechanotransduction related to bone homeostasis. We visualized the embedded osteocyte network in chick calvariae and observed the flow-induced Ca2+ signaling in osteocytes using 3D time-lapse imaging. In response to the flow, intracellular Ca2+ ([Ca2+]i) significantly increased in developmentally mature osteocytes in comparison with young osteocytes in the bone matrix. To investigate the differences in response between young and developmentally mature osteocytes in detail, we evaluated the expression of osteocyte-related genes using the osteocyte-like cell line MLO-Y4, which was 3D-cultured within type I collagen gels. We found that the c-Fos, Cx43, Panx3, Col1a1, and OCN mRNA levels significantly increased on day 15 in comparison with day 7. These findings indicate that developmentally mature osteocytes are more responsive to mechanical stress than young osteocytes and have important functions in bone formation and remodeling.

DOI： 10.1007/s00774-017-0868-x

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A vast number of long-noncoding RNAs (lncRNA) are found expressed in human cells, which RNAs have been developed along with human evolution. However, the physiological functions of these lncRNAs remain mostly unknown. In the present study, we for the first time uncovered the fact that one of such lncRNAs plays a significant role in the differentiation of chondrocytes and, possibly, of osteoblasts differentiated from mesenchymal stem cells, which cells eventually construct the human skeleton. The urothelial cancer-associated 1 (UCA1) lncRNA is known to be associated with several human malignancies. Firstly, we confirmed that UCA1 was expressed in normal human chondrocytes, as well as in a human chondrocytic cell line; whereas it was not detected in human bone marrow mesenchymal stem cells (hBMSCs). Of note, although UCA1 expression was undetectable in hBMSCs, it was markedly induced along with the differentiation toward chondrocytes, suggesting its critical role in chondrogenesis. Consistent with this finding, silencing of the UCA1 gene significantly repressed the expression of chondrogenic genes in human chondrocytic cells. UCA1 gene silencing and hyper-expression also had a significant impact on the osteoblastic phenotype in a human cell line. Finally, forced expression of UCA1 in a murine chondrocyte precursor, which did not possess a UCA1 gene, overdrove its differentiation into chondrocytes. These results indicate a physiological and important role of this lncRNA in the skeletal development of humans, who require more sustained endochondral ossification and osteogenesis than do smaller vertebrates.

DOI： 10.1002/jcp.26285

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Language：English   Publisher：Japanese Association for Oral Biology  

Background: Bones adapt to loads by changing their structure. This biomechanical interaction and the formation/maintenance of bones are orchestrated by three major cell types residing in the bones: osteoblasts, osteocytes, and osteoclasts. Recent findings suggest that, in addition to their biomechanical interactions, bones and other organ systems may also communicate biochemically. Highlight: This brief review will discuss the interaction between the bones and the nervous system, vasculature, muscle, and fat tissues, with an emphasis on the role of the energy metabolism in these interactions. Conclusion: Studies on the connections between bones and other organ systems indicate the possible existence of a temporospatial pattern of energy metabolism through the cellular biorhythm and migration.

DOI： 10.1016/j.job.2017.11.001

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A 34-year-old female patient who had undergone surgical treatment for a cleft in the soft palate during childhood received orthodontic treatment for crowding. She had a straight type facial profile and facial asymmetry with a concave area on the left side of the philtrum and mandibular deviation to the left. The surgical scar was observed on the center of the palate. She also had a severely constricted maxillary arch and unilateral cross bite on the left side. In this report, we suggest a novel method for uneven maxillary lateral expansion using a dento-osseous-supported expansion appliance in the frontal side of the maxilla and a modified dental-supported expansion appliance in the mid-palatal area. With this method, we achieved the optimal maxillary expansion in the maxillary frontal and molar areas. As a result of the surgically-assisted orthodontic treatment, facial asymmetry, the facial midline, and severe malocclusion were corrected. Furthermore, the resulting occlusion and facial symmetry were maintained over a 2-year retention period. Although attention must be paid regarding the retention of the expanded maxillary bone, our findings in the present study suggest that differential maxillary lateral expand distraction osteogenesis, which is performed using combined expansion appliances, can be successfully performed in patients with cleft palate.

DOI： 10.1016/j.odw.2018.04.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

The collagen network acts as a scaffold for calcification and its three-dimensional structure influences bone strength. It is therefore important to observe the collagen network in detail and three-dimensionally. In this study, we observed the collagen network of chick embryonic calvariae in membranous bone three-dimensionally using orthogonally arranged FIB-SEM. A 25 × 25 μm area of chick embryonic calvaria was observed at a high resolution (25 nm per pixel). The inside of the bone (i.e. the primary calcified tissue), the bone cells (i.e. the osteoblasts and the osteocytes), the organelles, and the collagen fibrils were observed in detail. These structures were observed three-dimensionally using the Amira software program. In addition, the collagen fibrils of the bone were automatically extracted using the XTracing extension software program, and three-dimensional morphometry was performed. Almost all of the collagen fibrils ran along the longitudinal axis of the trabecular bone. We found that the regularity of the collagen fibril orientation was less remarkable in the osteoblast layer, which contained numerous osteoblasts. The collagen fibril orientation started to show regularity toward the central bone layer, which contained few bone cells.

DOI： 10.1039/c7ib00073a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Several recent prospective clinical trials have investigated the effect of supplementary vibration applied with fixed appliances in an attempt to accelerate tooth movement and shorten the duration of orthodontic treatment. Among them, some studies reported an increase in the rate of tooth movement, but others did not. This technique is still controversial, and the underlying cellular and molecular mechanisms remain unclear. In the present study, we developed a new vibration device for a tooth movement model in rats, and investigated the efficacy and safety of the device when used with fixed appliances. The most effective level of supplementary vibration to accelerate tooth movement stimulated by a continuous static force was 3 gf at 70 Hz for 3 minutes once a week. Furthermore, at this optimum-magnitude, high-frequency vibration could synergistically enhance osteoclastogenesis and osteoclast function via NF-kappa B activation, leading to alveolar bone resorption and finally, accelerated tooth movement, but only when a static force was continuously applied to the teeth. These findings contribute to a better understanding of the mechanism by which optimum-magnitude high-frequency vibration accelerates tooth movement, and may lead to novel approaches for the safe and effective treatment of malocclusion.

DOI： 10.1038/s41598-017-13541-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Craniofacial morphology varies among individuals, which is regulated by the interaction between genes and the environment. Soft-diet feeding is a widely-used experimental model for studying the association between the skeletal morphology and muscle-related loading on the bone. Traditionally, these studies have been based on linear and angular measurements provided on two-dimensional (2D) radiographs in the lateral view. However, 2D observation is based on simplification of the anatomical structures and cannot detect three-dimensional (3D) changes in detail. In this study, we newly developed a modified surface-based analysis with micro-3D computed tomography (CT) to examine and detect the 3D changes in the mandible associated with soft-diet feeding. Mice at 3 weeks of age were fed a powdered soft-diet (SD) or hard-diet (HD) of regular rodent pellets until 9 weeks of age. Micro-CT images were taken at age 9 weeks to reconstruct the anatomical architecture images. A computer-generated averaged mandible was superimposed to directly visualize the morphological phenotypes. Gross observation revealed the apparent changes at the posterior body of the mandible, the angular process and the condyle between HD and SD mice. Significant differences in the mapping indicated the regions of significant displacement in the SD mice over the averaged 3D image of the HD mice. This map revealed that vertical displacement was most evident in 3D changes. We also noted a combination of vertical, transverse and anteroposterior directions of displacement in the condylar growth, resulting in complicated shape changes in the whole condylar process in SD mice. In contrast, transverse displacement was more significant in the coronoid process. The map analysis further showed the significant outward displacement of the inner surface of the alveolar process, which consequently resulted in thinning of the alveolar process.

DOI： 10.3389/fphys.2017.00567

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Structured Abstract
ObjectivesTo test the hypothesis that the use of low-level laser therapy (LLLT) reduces elevated pain by controlling the release of neurochemicals during orthodontic tooth movement.
Setting and Sample PopulationDepartment of Orthodontics and Dentofacial Orthopedics, Okayama University. Sixty-five Sprague Dawley rats were subjected to tooth movement and LLLT.
Materials and MethodsAdult Sprague Dawley rats were used in this study. Groups included day 0 controls, irradiation only controls and with or without irradiation sacrificed at 1, 3, 5, 7 and 14days after tooth movement (n=5 each, total n=65). Tooth movement was achieved by insertion of an elastic module between molar teeth. Immunohistochemistry for CD-11b, GFAP and c-fos in the brain stem was performed. Stains were quantified by constructing a three-dimensional image using IMARIS, and counted using NEURON TRACER and WinROOF software. Two-way ANOVA followed by a Tukey's post hoc test (P&lt;.05) was used for statistical comparison between groups.
ResultsC-fos expression was significantly increased at one and three days after tooth movement. LLLT significantly diminished this increase in c-fos expression only at one day after tooth movement CD-b11 and GFAP expression also significantly increased after tooth movement. No significant change was observed for CD-11b and GFAP expression in the central nervous system upon LLLT.
ConclusionLow-level laser therapy may reduce early neurochemical markers but have no effect on delayed pain neurochemical markers after tooth movement.

DOI： 10.1111/ocr.12158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Introduction: Our objective was to elucidate the differences in treatment outcomes caused by the different mechanics of temporary anchorage devices (TADs) and Class III elastics in patients with Class III malocclusions. Methods: Records of 23 patients with Angle Class III malocclusion were selected retrospectively. All had been treated with nonextraction comprehensive orthodontic treatment; 11 were treated with TADs and 12 with Class III elastics. Pretreatment and posttreatment lateral cephalograms were used for evaluation of the treatment outcomes. A paired t test and a Student t test were used for statistical analysis. Results: In both groups, proper overjet and Class I molar relationships were achieved, and the occlusal plane was rotated counterclockwise. In the elastics group, distal tipping of the mandibular molars, extrusion of the mandibular incisors and maxillary molars, clockwise rotation of the mandibular plane angle, and increased ANB angle were observed. In the TADs group, distal tipping and intrusion of the mandibular molars, bodily movement of the mandibular incisors, and reduced mandibular plane angle were observed. Conclusions: In nonextraction treatment for Class III malocclusions, the mandibular plane angle was increased in the elastics group, whereas it was decreased in TADs group. Thus, we suggest that Class III elastics are preferred for low-angle, short-face patients, whereas TADs are preferred for high-angle, long-face patients.

DOI： 10.1016/j.ajodo.2016.10.040

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INTRODUCTION: In recent years, patients with orthognathic surgery in middle-aged and elderly people have come to be a more frequent occurrence. Breast cancer is the most frequently diagnosed cancer in woman worldwide, and its prevalence rate is steadily increasing. PRESENTATION OF CASE: We report a case of a 47-year-old Japanese woman in whom left-side breast cancer (Stage 1) was unexpectedly found just before orthognathic surgery in April 2012. Breast-conserving surgery was performed (estrogen receptor+, progesterone receptor+, HER2 -, surgical margin+, sentinel lymph node +) that May. From June to August docetaxel (75mg/m2) and cyclophosphamide (600mg/m2) were administrated four times every 21days and thereafter radiotherapy (total 60Gy) was completed. The cancer surgeon declared the prognosis good and the patient had a strong desire to undergo orthognathic surgery, so in November we performed a bimaxillary osteotomy, and administration of tamoxifen began 6 weeks after the osteotomy. DISCUSSION: There are breast cancer cases in which the prognosis is sufficiently good for a planned orthognathic surgery to proceed. Good communication among surgeons and the patient is important. CONCLUSION: We experienced a case in which breast cancer was found just before the orthognathic surgery; we performed a bimaxillary osteotomy, including follow-up tamoxifen administration, during breast cancer treatment.

DOI： 10.1016/j.ijscr.2016.12.014

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Language：Japanese  

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© 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group. Objectives: This study investigated the different effects of intraoral vertical ramus osteotomy (IVRO) and sagittal split ramus osteotomy (SSRO) on mandibular border movement. Methods: The participants included 22 patients receiving IVRO and 22 patients receiving SSRO who were treated at Okayama University Hospital. Their mandibular border movement was evaluated in three dimensions with 6° of freedom using an optical recording system. Results: A strong correlation between condylar and lower incisor movement was observed during maximum jaw protrusion and laterotrusion. Significant improvements in condylar and lower incisor movement were detected after orthognathic surgery during maximum jaw protrusion and laterotrusion in the IVRO group and during maximum jaw protrusion in the SSRO group. Discussion: IVRO likely achieves greater improvement in jaw movement than SSRO. Therefore, the application of IVRO could be considered in the treatment of patients with jaw deformities featuring temporomandibular joint problems.

DOI： 10.1080/08869634.2017.1317899

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Okayama University  

The rare developmental defect, Goldenhar syndrome is characterized by complex craniofacial and dentofacial anomalies. Here we describe the successful orthodontic treatment of a 5-year-old Japanese Goldenhar syndrome patient with mild facial asymmetry, right microtia, right-side hearing loss, and tongue-thrusting by a modification of dentofacial growth using a non-surgical orthopedic treatment approach. Improvement of the vertical discrepancies on the affected side and canted occlusal plane as well as mandibular deviation were achieved with a functional orthopaedic approach. Stable and acceptable occlusion were obtained over the 32-month post-retention period. A non-surgical orthodontic treatment approach offers satisfactory facial aesthetic outcomes in Goldenhar syndrome.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd  

Objectives: Platelet-rich plasma (PRP) has been widely used to enhance the regeneration of damaged joint tissues, such as osteoarthritic and rheumatoid arthritic cartilage. The aim of this study is to clarify the involvement of all of the CCN family proteins that are crucially associated with joint tissue regeneration. Methods: Cyr61-CTGF-NOV (CCN) family proteins in human platelets and megakaryocytic cells were comprehensively analyzed by Western blotting analysis. Production of CCN family proteins in megakaryocytes in vivo was confirmed by immunofluorescence analysis of mouse bone marrow cells. Effects of CCN family proteins found in platelets on chondrocytes were evaluated by using human chondrocytic HCS-2/8 cells. Results: Inclusion of CCN2, a mesenchymal tissue regenerator, was confirmed. Of note, CCN3, which counteracts CCN2, was newly found to be encapsulated in platelets. Interestingly, these two family members were not detectable in megakaryocytic cells, but their external origins were suggested. Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes. Finally, application of a CCN family cocktail mimicking platelets onto HCS-2/8 cells enhanced their chondrocytic phenotype. Conclusions: Multiple inclusion of CCN1, 2 and 3 in platelets was clarified, which supports the harmonized regenerative potential of PRP in joint therapeutics.

DOI： 10.3109/14397595.2016.1155255

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Korean Association of Orthodontists  

We report a case involving a young female patient with severe mandibular retrognathism accompanied by mandibular condylar deformity that was effectively treated with Le Fort I osteotomy and two genioplasty procedures. At 9 years and 9 months of age, she was diagnosed with Angle Class III malocclusion, a skeletal Class II jaw relationship, an anterior crossbite, congenital absence of some teeth, and a left-sided cleft lip and palate. Although the anterior crossbite and narrow maxillary arch were corrected by interceptive orthodontic treatment, severe mandibular hypogrowth resulted in unexpectedly severe mandibular retrognathism after growth completion. Moreover, bilateral condylar deformities were observed, and we suspected progressive condylar resorption (PCR). There was a high risk of further condylar resorption with mandibular advancement surgery
therefore, Le Fort I osteotomy with two genioplasty procedures was performed to achieve counterclockwise rotation of the mandible and avoid ingravescence of the condylar deformities. The total duration of active treatment was 42 months. The maxilla was impacted by 7.0 mm and 5.0 mm in the incisor and molar regions, respectively, while the pogonion was advanced by 18.0 mm. This significantly resolved both skeletal disharmony and malocclusion. Furthermore, the hyoid bone was advanced, the pharyngeal airway space was increased, and the morphology of the mandibular condyle was maintained. At the 30-month follow-up examination, the patient exhibited a satisfactory facial profile. The findings from our case suggest that severe mandibular retrognathism with condylar deformities can be effectively treated without surgical mandibular advancement, thus decreasing the risk of PCR.

DOI： 10.4041/kjod.2016.46.6.395

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INTRODUCTION: The intercellular network of cell-cell communication among osteocytes is mediated by gap junctions. Gap junctional intercellular communication (GJIC) is thought to play an important role in the integration and synchronization of bone remodeling. To further understand the mechanism of bone development it is important to quantify the difference in the GJIC capacity of young and developmentally mature osteocytes. MATERIALS AND METHODS: We first established an embryonic chick calvaria growth model to show the growth of the calvaria in embryos at 13 to 21days of age. We then applied a fluorescence recovery after photobleaching (FRAP) technique to compare the difference in the GJIC capacity of young osteocytes with that of developmentally mature osteocytes. Finally, we quantified the dye (Calcein) diffusion from the FRAP data using a mathematic model of simple diffusion which was also used to identify simple diffusion GJIC pattern cells (fitted model) and accelerated diffusion GJIC pattern cells (non-fitted model). RESULTS: The relationship between the longest medial-lateral length of the calvaria (frontal bone) and the embryonic age fit a logarithmic growth model: length=5.144×ln(day)-11.340. The morphometric data during osteocyte differentiation showed that the cellular body becomes more spindle-shaped and that the cell body volume decreased by approximately 22% with an increase in the length of the processes between the cells. However, there were no significant differences in the cellular body surface area or in the distance between the mass centres of the cells. The dye-displacement rate in young osteocytes was significantly higher than that in developmentally mature osteocytes: dye displacement only occurred in 26.88% of the developmentally mature osteocytes, while it occurred in 64.38% of the young osteocytes. Additionally, in all recovered osteocytes, 36% of the developmentally mature osteocytes comprised non-fitted model cells while 53.19% of the young osteocytes were the non-fitted model, which indicates the active transduction of dye molecules. However, there were no statistically significant differences between the young and developmentally mature osteocytes with regard to the diffusion coefficient, permeability coefficient, or permeance of the osteocyte processes, which were 3.93±3.77 (×10(-8)cm(2)/s), 5.12±4.56 (×10(-5)cm(2)/s) and 2.99±2.47 (×10(-13)cm(2)/s) (mean±SD), respectively. CONCLUSIONS: These experiments comprehensively quantified the GJIC capacity in the embryonic chick calvaria and indicated that the cell-cell communication capacity of the osteocytes in the embryonic chick calvaria was related to their development.

DOI： 10.1016/j.bone.2016.06.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

In the bone, collagen fibrils form a lamellar structure called the “twisted plywood-like model.” Because of this unique structure, bone can withstand various mechanical stresses. However, the formation of this structure has not been elucidated because of the difficulty of observing the collagen fibril production of the osteoblasts via currently available methods. This is because the formation occurs in the very limited space between the osteoblast layer and bone matrix. In this study, we used ultra-high-voltage electron microscopy (UHVEM) to observe collagen fibril production three-dimensionally. UHVEM has 3-MV acceleration voltage and enables us to use thicker sections. We observed collagen fibrils that were beneath the cell membrane of osteoblasts elongated to the outside of the cell. We also observed that osteoblasts produced collagen fibrils with polarity. By using AVIZO software, we observed collagen fibrils produced by osteoblasts along the contour of the osteoblasts toward the bone matrix area. Immediately after being released from the cell, the fibrils run randomly and sparsely. But as they recede from the osteoblast, the fibrils began to run parallel to the definite direction and became thick, and we observed a periodical stripe at that area. Furthermore, we also observed membrane structures wrapped around filamentous structures inside the osteoblasts. The filamentous structures had densities similar to the collagen fibrils and a columnar form and diameter. Our results suggested that collagen fibrils run parallel and thickly, which may be related to the lateral movement of the osteoblasts. UHVEM is a powerful tool for observing collagen fibril production.

DOI： 10.1007/s00774-015-0692-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Objectives: The purposes of this study were to investigate whether the antero-posterior and vertical facial type variations influenced the favoured lip positions and to elucidate whether the favoured lip positions differed between orthodontists and laypersons. Methods: An average profile was constructed from a Japanese female with Class I occlusion and a well-balanced profile, as assessed by several cephalometric analyses. Nine facial types were composed by morphing the chin antero-posteriorly and/or vertically. Thirteen morphed lip profiles were constructed by moving the lips antero-posteriorly in the nine facial types, respectively. Seventy-seven Japanese laypersons and 30 orthodontists were asked to choose the top three most-favoured lip positions for each facial type. Results: The protruded lip positions were significantly favoured for all the mandibular protrusive facial types. The retruded lip positions were significantly favoured for the short facial type of the antero-posteriorly average and mandibular retrusive-short facial types. Among the mandibular protrusive facial types, the protruded lip positions were significantly favoured for the long facial type. The retruded lip positions were statistically more attractive for orthodontists than laypersons on the antero-posteriorly average-short, mandibular protrusive-short, mandibular retrusive-vertically average, antero-posteriorly average-vertically average, and mandibular retrusive-long facial types. Limitations: Our data were limited by the specific ethnic groups and variety of facial types. Conclusion: The favoured antero-posterior lip position was affected by not only the antero-posterior facial disproportion but also by the vertical dimensions. The favoured lip positions differed between orthodontists and laypersons. These results might be helpful in deciding between extraction and non-extraction treatment in borderline cases.

DOI： 10.1093/ejo/cjv073

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

The orofacial muscle is an important factor in the harmony of the occlusion, and its dysfunction significantly influences a patient's occlusion after craniofacial growth and development. In this case report, we describe the successful orthodontic treatment of a patient with unilateral orofacial muscle dysfunction. A boy, 10 years 0 months of age, with a chief complaint of anterior open bite, was diagnosed with a Class III malocclusion with facial musculoskeletal asymmetry. His maxillomandibular relationships were unstable, and he was unable to lift the right corner of his mouth upon smiling because of weak right orofacial muscles. A satisfactory occlusion and a balanced smile were achieved after orthodontic treatment combined with orofacial myofunctional therapy, including muscle exercises. An acceptable occlusion and facial proportion were maintained after a 2-year retention period. These results suggest that orthodontic treatment with orofacial myofunctional therapy is an effective option for a patient with orofacial muscle dysfunction.

DOI： 10.1016/j.ajodo.2015.08.021

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Other Link： http://orcid.org/0000-0002-4419-9643

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mosby Inc.  

Introduction Orthodontic tooth movement causes pain to a patient. Glial cells are nonneuronal cells in the central nervous system and are implicated in various types of pain. In this study, we assessed glial activation responses after experimental tooth movement using immunocytochemical detection of anti-CD11b (OX42) and glial fibrillary acidic protein immunoreactivity to illustrate the microglial and astrocytes response, respectively. In addition, the effect of minocycline in reducing pain during tooth movement was also investigated. Methods Fifty-five Sprague Dawley rats with and without administration of minocycline after 1, 3, 5, 7, and 14 days (n = 5, for each) of tooth movement were used. Immunohistochemistry for microglia (OX42) and astrocyte (glial fibrillary acidic protein) were performed at the medullary dorsal horn (trigeminal subnucleus caudalis). Three-dimensional quantitative analysis was performed with a confocal fluorescence microscope and a software program. Results There was a significant increase in the OX42 and glial fibrillary acidic protein immunoreactivity in response to tooth movement in the medullary dorsal horn. Furthermore, systematic administration of minocycline, a selective inhibitor of microglial activation, significantly attenuated the nociceptive c-Fos expression in the medullary dorsal horn that was induced by experimental tooth movement. Conclusions These data indicate the possible importance of microglial activation in the development of orthodontic pain. This is also the first report on the systematic application of minocycline.

DOI： 10.1016/j.ajodo.2015.11.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Okayama University  

Although accurate bracket placement is essential for orthodontic treatment, many practitioners apply brackets indiscriminately with direct or indirect bonding techniques. Nonetheless, there have been few prospective clinical comparisons of the 2 techniques. We will therefore conduct a single-center, randomized control trial in 100 patients aged ≥2 years and diagnosed with malocclusion. All patients will receive orthodontic treatment using brackets with direct or indirect bonding techniques. The primary endpoints will be the total treatment time, occlusal index, discomfort at bonding, and oral hygiene after bonding. This study will clarify whether indirect bonding can improve the efficiency of orthodontic treatment.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Okayama University  

Permanent canines are thought to play a pivotal role in obtaining an ideal occlusion. Dentists occasionally encounter patients who lack canines and are therefore missing a key to harmonious guidance during functional mandibular excursions. This case report describes the substitution of maxillary first premolars for congenitally missing canines in the context of an orthodontic treatment plan. A boy, age 10 years and 11 months, with a chief complaint of crooked teeth was diagnosed with Class II division 2 malocclusion associated with a high mandibular plane angle and deep overbite. A stable occlusion with a satisfactory facial profile and functional excursions without interference were achieved after a comprehensive two-stage orthodontic treatment process. The resulting occlusion and satisfactory facial profile were maintained for 12 months. These results indicate that substituting the first premolars for the canines is an effective option in treating patients with missing canines while maintaining functional goals.

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：Japanese   Publisher：中・四国矯正歯科学会  

患者は20歳6ヵ月の女性で、上顎前歯部の叢生および前歯部開咬を主訴に岡山大学病院矯正歯科を受診した。側貌は凸型、オトガイの後退感、口唇閉鎖不全が認められた。両側アングルI級、前歯部開咬を呈し、上下顎前歯はやや唇側傾斜していた。さらに、予後不良な下顎左側第一大臼歯、上下顎歯列の叢生、軽度の咬合平面の二面性が認められた。分析の結果、上下顎前歯部叢生を伴う骨格性II級、ハイアングル、ロングフェイス、前歯部開咬症例と診断された。予後不良歯である下顎左側第一大臼歯に加え下顎右側第一大臼歯及び上顎両側第一小臼歯の抜歯を伴うカモフラージュ治療を行うこととなった。下顎両側第二・第三大臼歯の近心移動およびスピー彎曲の改善に伴い下顎臼歯の挺出が生じ、下顎骨の時計回り回転が危惧されたため、下顎骨回転に伴う側貌の悪化を防ぐことを目的に上顎両側大臼歯の圧下を行うこととした。動的治療期間は4年5ヵ月であった。オトガイの後退感は残るものの口元の突出感は改善し良好な側貌を獲得した。治療前後の重ね合わせでは、上下顎前歯歯軸および臼歯移動量は治療目標設定値と近似しており、下顎下縁平面角は維持されていた。保定2年が経過したが、咬合は安定している。長期予後不良な第一大臼歯を認める場合、下顎第一大臼歯抜歯による下顎第二・第三大臼歯の近心移動は有用な治療法であるが、ハイアングル・ロングフェイス症例においては、下顎大臼歯の挺出による顔貌の悪化を防ぐため上顎大臼歯の圧下を行うことが望ましいと考える。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Aggressive periodontitis is a great challenge to clinicians when providing orthodontic treatment because of the potential for progression of periodontal disease. In this article, we report the successful comprehensive orthodontic treatment of bimaxillary protrusion and severe crowding in an adult with generalized aggressive periodontitis. A woman, aged 22 years 7 months, with a chief complaint of incisal crowding was diagnosed with a skeletal Class I malocclusion associated with severe anterior crowding, possibly worsened by generalized aggressive periodontitis. In addition to a periodontal examination, a blood IgG antibody titer analysis and microbiologic examination for periodontal pathogens were used to diagnose the type of periodontal disease and determine the proper timing to initiate orthodontic treatment. The total active treatment period was 28 months, followed by periodontal prostheses and regeneration therapy. Consequently, satisfactory facial profile, occlusion, and periodontal health were maintained for at least 36 months. These results indicate that efficient screening is important for providing successful orthodontic treatment in patients with advanced periodontal disease. This report also demonstrates the diagnostic importance of blood IgG antibody titer assays and microbiologic examinations to detect periodontal pathogens.

DOI： 10.1016/j.ajodo.2014.09.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

This article reports the case of a 44-year-old male with skeletal Class III, Angle Class III malocclusion and unilateral crossbite with concerns about obstructive sleep apnea syndrome (OSAS), esthetics and functional problems. To correct the skeletal deformities, the maxilla was anteriorly repositioned by employing LeFort I osteotomy following pre-surgical orthodontic treatment, because a mandibular setback might induce disordered breathing and cause OSAS. After active treatment for 13 months, satisfactory occlusion was achieved and an acceptable facial and oral profile was obtained. In addition, the apnea hypopnea index (AHI) decreased from 18.8 preoperatively to 10.6 postoperatively. Furthermore, after a follow-up period of 7 months, the AHI again significantly decreased from 10.6 to 6.2. In conclusion, surgical advancement of the maxilla using LeFort I osteotomy has proven to be useful in patients with this kind of skeletal malocclusion, while preventing a worsening of the OSAS.

DOI： 10.18926/AMO/53525

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Association for Oral Biology  

Background Newly developed visualization methods often lead to breakthroughs in the bioscience field. In particular, the ability to reveal temporal-spatial responses in cells, while visualizing molecular events through bioimaging techniques is very important. One such event is the regulation of bone remodeling by osteocytes. It is thought that osteocyte processes sense the flow of interstitial fluid that is driven through the osteocyte canaliculi by mechanical stimuli caused in the bone. However, the precise mechanism by which the flow elicits a cellular response is still unknown. Highlight It is critical to obtain precise morphological and/or morphometrical data from osteocytes and their surrounding microenvironment. In this review, we describe our application of confocal laser scanning microscopy to visualize osteocyte morphology in the bone and the combination of ultra-high voltage electron microscopy (UHVEM) and computer simulation of fluid flow to reveal the mechanosensitivity of osteocytes in the bone. Conclusion The osteocyte network in the bone as well as the microstructure of osteocyte cell processes and the surrounding bone matrix were visualized. We found fluorescence to be useful for studying the osteocyte network morphology. Additionally, the combination of UHVEM and computer simulation is a powerful tool to study the fluid flow in osteocyte canaliculi.

DOI： 10.1016/j.job.2015.02.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

We herein describe a novel procedure for dentin regeneration that mimics the biological processes of tooth development in nature. The canonical Wnt signaling pathway is an important regulator of the Dentin sialophosphoprotein (Dspp) expression. Our approach mimics the biological processes underlying tooth development in nature and focuses on the activation of canonical Wnt signaling to trigger the natural process of dentinogenesis. The coronal portion of the dentin and the underlying pulp was removed from the first molars. We applied lithium chloride (LiCl), an activator of canonical Wnt signaling, on the amputated pulp surface to achieve transdifferentiation toward odontoblasts from the surrounding pulpal cells. MicroCT and microscopic analyses demonstrated that the topical application of LiCl induced dentin repair, including the formation of a complete dentin bridge. LiCl-induced dentin is a tubular dentin in which the pulp cells are not embedded within the matrix, as in primary dentin. In contrast, a dentin bridge was not induced in the control group treated with pulp capping with material carriers alone, although osteodentin without tubular formation was induced at a comparatively deeper position from the pulp exposure site. We also evaluated the influence of LiCl on differentiation toward odontoblasts in vitro. In the mDP odontoblast cell line, LiCl activated the mRNA expression of Dspp, Axin2 and Kallikrein 4 (Klk4) and downregulated the Osteopontin (Osp) expression. These results provide a scientific basis for the biomimetic regeneration of dentin using LiCl as a new capping material to activate dentine regeneration.

DOI： 10.1371/journal.pone.0121938

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BACKGROUND: The rodent salivary gland is not fully developed at birth and the cellular definitive differentiation takes place postnatally. However, little is known about its molecular mechanism. RESULTS: Here we provide the loss-of-function genetic evidence that Runx signaling affects postnatal development of the submandibular gland (SMG). Core binding factor β (Cbfb) is a cotranscription factor which forms a heterodimer with Runx proteins. Cbfb was specifically expressed in the duct epithelium, specifically in the SMG. Epithelial Cbfb deficiency resulted in decrease in the size of the SMG and in the saliva secretion on postnatal day 35. The Cbfb mutant SMG specifically exhibited involution of the granular convoluted tubules (GCT), with a down-regulated expression of its marker genes, such as Klk1, Ngf, and Egf. The induction of GCT is under the control of androgens, and the Cbfb mutant SMG demonstrated down-regulated expression of Crisp3, an androgen-dependent transcript. Because the circulating testosterone or tissue dihydrotestosterone levels were not affected in the Cbfb mutants, it appears that Runx/Cbfb signaling regulate androgen receptor pathway, but does not affect the circulating testosterone levels or the enzymatic conversion to DHT. CONCLUSIONS: Runx signaling is important in the postnatal development of androgen-dependent GCT in the SMG.

DOI： 10.1002/dvdy.24231

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Language：Japanese   Publisher：中・四国矯正歯科学会  

患者は初診時年齢37歳9ヵ月の女性で、口唇の突出感を主訴に岡山大学病院矯正歯科を受診した。側貌はConvex typeで、下顎の後退感、上下口唇の突出、口唇閉鎖時のオトガイ部の筋緊張および口唇閉鎖不全を認めた。口腔内はAngle II級であり、オーバージェットが大きかった。また、下顎前歯が挺出しており、過大なSpee彎曲を認め、過蓋咬合を呈していた。さらに、上顎前歯は舌側傾斜し、下顎歯列に叢生を認めた。骨格的には骨格性II級、high mandibular plane angleであった。分析の結果、上顎前歯の舌側傾斜を伴う下顎骨の後退による骨格性II級、Angle II級、high mandibular plane angle、過蓋咬合症例と診断した。上下顎両側第一小臼歯の抜歯を伴うカモフラージュ治療を行うことになったが、過蓋咬合を治療する従来のメカニクスでは、小臼歯の挺出に伴う下顎下縁平面のさらなる開大が危惧された。そのため、下顎前歯圧下のための固定源として、下顎両側側切歯・犬歯間頬側歯槽部の歯科矯正用アンカースクリューを利用した。また、上顎前歯を舌側へ歯体移動させるための固定源として、上顎両側第一大臼歯・第二大臼歯間および上顎両側側切歯・犬歯間頬側歯槽部の歯科矯正用アンカースクリューを利用した。治療の結果、下顎の時計回りの回転を起こさずに下顎前歯は圧下、上顎前歯はほぼ舌側へ歯体移動し、良好な咬合関係を確立できた。(著者抄録)

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Language：Japanese   Publisher：中・四国矯正歯科学会  

【目的】好ましい側貌の基準を具体的・客観的に明らかにすることは、実際の矯正歯科治療における治療ゴールを設定する上で必要不可欠である。本研究は、一般人を対象にアンケートを行い、上唇、下唇およびオトガイの前後的位置関係が与える側貌の審美的認識への影響について検討を行った。【資料および方法】標準的な日本人女性の側貌を元に、専用ソフトウェアを用いて下顎骨を前後に10mmずつ移動させ、上顎前突、標準および下顎前突の3パターンの側貌シルエットを作成した。次に、その上唇と下唇をそれぞれ3mmずつ前後に移動させ、17通りの口唇位を作成した。一般人178名を対象に、3パターンの側貌それぞれに17通りの口唇位を組み合わせたシルエットを提示し、好ましい側貌に関するアンケートを実施した。【結果および考察】標準的な側貌では、上唇-下唇の前後的距離の差が+3mmの側貌が最も好まれた。口唇とオトガイとの前後的距離の差が大きい上顎前突の側貌では、上唇-下唇の前後的距離が比較的大きい+6mmの側貌が最も好まれた。口唇とオトガイとの前後的距離の差が小さい下顎前突の側貌では、上唇-下唇の前後的距離の差により好まれ方に違いは認められなかった。【結論】骨格の違いにより、審美的に好ましい上唇-下唇の前後的距離には差異が存在することが明らかになった。審美的に好ましい上下口唇およびオトガイの前後的位置は、上唇-下唇-オトガイの前後的距離の比により規定される可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：日本骨形態計測学会  

細胞内カルシウム(Ca2+)は多様な細胞機能を仲介する重要な情報伝達物質であり、Ca2+オシレーションと呼ばれる周期的なCa2+濃度の上昇様式は、骨代謝調節を含む広範な生理機構に関与すると考えられている。しかし、3次元的な骨芽細胞-骨細胞ネットワークから成り立つ骨組織中でのCa2+オシレーションの動態は、周囲の骨基質が障壁となるためこれまで不明であった。近年我々は、骨組織をまるごと生きた状態のままCa2+イメージングする事に成功し、骨芽細胞と骨細胞の自律性細胞内Ca2+オシレーションの存在と、それらの現象に対するメカニカルストレスの影響およびギャップ結合の関与について報告した。本論文では、蛍光ライブイメージングを用いた骨組織中のCa2+オシレーションについて最新の研究成果を交えて解説する。(著者抄録)

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Language：English   Publisher：Japanese Association for Oral Biology  

Intracellular calcium (Ca2+) is an important secondary messenger that modulates many cellular processes. Its oscillatory signaling is considered to participate in the regulation of many different cell functions, including bone metabolism. However, it is not entirely clear whether Ca2+ oscillations occur between osteoblasts and osteocytes in integrated bone tissues because of the complex mineralized matrices surrounding bone cells. To address this issue, we have recently developed a novel ex vivo realtime imaging system, which made it possible to observe repetitive and autonomous oscillations in the intracellular Ca2+ concentration ([Ca2+]i) in intact chick calvarial explants. This system revealed that Ca2+ release from intracellular stores plays a key role in Ca2+ oscillations in bone cells. Additionally, gap junctions are important for the maintenance of these oscillations in osteocytes but not in osteoblasts. In this review, we describe the dynamic oscillatory elevations of Ca2+ levels that occur in osteoblasts and osteocytes in living bone. © 2014 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.job.2014.03.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Periodontal tissue homeostasis depends on a complex cellular network that conveys cell-cell communication. Gap junctions (GJs), one of the intercellular communication systems, are found between adjacent human periodontal ligament (hPDL) cells; however, the functional GJ coupling between hPDL cells has not yet been elucidated. In this study, we investigated functional gap-junction-mediated intercellular communication in isolated primary hPDL cells. SEM images indicated that the cells were in contact with each other via dendritic processes, and also showed high anti-connexin43 (Cx43) immunoreactivity on these processes. Gap-junctional intercellular communication (GJIC) among hPDL cells was assessed by fluorescence recovery after a photobleaching (FRAP) analysis, which exhibited dye coupling between hPDL cells, and was remarkably down-regulated when the cells were treated with a GJ blocker. Additionally, we examined GJs under hypoxic stress. The fluorescence recovery and expression levels of Cx43 decreased time-dependently under the hypoxic condition. Exposure to GJ inhibitor or hypoxia increased RANKL expression, and decreased OPG expression. This study shows that GJIC is responsible for hPDL cells and that its activity is reduced under hypoxia. This is consistent with the possible role of hPDL cells in regulating the biochemical reactions in response to changes in the hypoxic environment.

DOI： 10.1177/0022034513489992

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：E H ANGLE EDUCATION RESEARCH FOUNDATION, INC  

Objective: To investigate dental appearance and cephalometric features, using a sample of orthognathic and/or orthodontic patients. A special interest was to identify the relationship of the Dental Aesthetic Index (DAI) with anteroposterior basal bone discrepancy (APBBD) and cephalometric indicators.
Materials and Methods: A full sample of 159 patients in two Japanese hospitals was used. Each patient was assessed with a preorthodontic dental cast and cephalometric radiography.
Results: Malocclusion with APBBD was more prevalent among high DAI subjects (P = .034, OR = 1.04, 95% CI: 1.00-1.08), Class III malocclusion patients (P = .048, OR = 2.32, 95% CI: 1.01-5.34) and male patients (P = .008, OR = 2.96, 95% CI: 1.33-6.61). Participants scoring 88 points (the highest score in this sample) of the DAI had 16.84 times the risk of APBBD of those who scored 17 points (the lowest score in this sample). Patients with APBBD presented with a greater adjusted ANB angle (t = -8.10, P &lt; .001) and a larger adjusted A-B/NF appraisal (t = -9.65, P &lt; .001). The SNA angle (P &lt; .001), the SNB angle (P = .002), the adjusted ANB angle (P = .001), and the adjusted A-B/NF appraisal (P = .035) were associated with DAI scores in cubic regression models.
Conclusion: This study has demonstrated a relationship between the DAI and APBBD. Feasibility of using the adjusted ANB angle and the adjusted A-B/NF appraisal to assess severity of APBBD has been confirmed. The DAI may provide a supportive method to evaluate orthognathic needs. Future investigations are indicated.

DOI： 10.2319/050312-369.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

This case report illustrates the use of miniscrews to treat a patient with an open bite caused by mandibular condylar fractures. The patient was 36 years old when she visited our hospital with a chief complaint of difficulty with chewing. She had suffered condylar and maxillary bone fractures in a traffic accident 6 months before her visit. She had an anterior open bite and Angle Class II molar relationships. Her mandibular midline was deviated to the right relative to the maxilla. The cephalometric analysis showed a skeletal Class II relationship. Titanium miniscrews were implanted in the bilateral maxillary buccal areas. The maxillary dentition was retracted and intruded by using elastomeric chains and miniscrews. After this treatment, an Angle Class I molar relationship was achieved, her overjet and overbite became ideal, and a good facial appearance was obtained. The total active orthodontic treatment period was 33 months. Treating an open bite with molar intrusion often leads to counter-clockwise rotation of the mandible; however, in this patient, the mandible was moved anteriorly and upward. We believe that this movement was caused by the patient's condylar fractures and the subsequent remodeling. Although there was some relapse, our results suggest that implant anchorage is useful for correcting anterior open bites originating from condylar fractures. (Am J Orthod Dentofacial Orthop 2013;143:S137-47)

DOI： 10.1016/j.ajodo.2012.04.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Bone cells respond to mechanical stimuli by producing a variety of biological signals, and one of the earliest events is intracellular calcium ([Ca(2+)](i)) mobilization. Our recently developed ex vivo live [Ca(2+)](i) imaging system revealed that bone cells in intact bone explants showed autonomous [Ca(2+)](i) oscillations, and osteocytes specifically modulated these oscillations through gap junctions. However, the behavior and connectivity of the [Ca(2+)](i) signaling networks in mechanotransduction have not been investigated in intact bone. We herein introduce a novel fluid-flow platform for probing cellular signaling networks in live intact bone, which allows the application of capillary-driven flow just on the bone explant surface while performing real-time fluorogenic monitoring of the [Ca(2+)](i) changes. In response to the flow, the percentage of responsive cells was increased in both osteoblasts and osteocytes, together with upregulation of c-fos expression in the explants. However, enhancement of the peak relative fluorescence intensity was not evident. Treatment with 18 α-GA, a reversible inhibitor of gap junction, significantly blocked the [Ca(2+)](i) responsiveness in osteocytes without exerting any major effect in osteoblasts. On the contrary, such treatment significantly decreased the flow-activated oscillatory response frequency in both osteoblasts and osteocytes. The stretch-activated membrane channel, when blocked by Gd(3+), is less affected in the flow-induced [Ca(2+)](i) response. These findings indicated that flow-induced mechanical stimuli accompanied the activation of the autonomous [Ca(2+)](i) oscillations in both osteoblasts and osteocytes via gap junction-mediated cell-cell communication and hemichannel. Although how the bone sense the mechanical stimuli in vivo still needs to be elucidated, the present study suggests that cell-cell signaling via augmented gap junction and hemichannel-mediated [Ca(2+)](i) mobilization could be involved as an early signaling event in mechanotransduction.

DOI： 10.1016/j.bone.2012.12.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Osteocytes are considered to act as mechanosensory cells in bone. They form a functional synctia in which their processes become interconnected to constitute a three-dimensional (3D) network. Previous studies reported that in mice, the two-dimensional osteocyte network becomes progressively more regular as they grow, although the key factors governing the arrangement of the osteocyte network during bone growth remain unknown. In this study, we characterized the 3D formation of the osteocyte network during bone growth. Morphological skeletal changes have been reported to occur in response to mechanical loading and unloading. In order to evaluate the effect of mechanical unloading on osteocyte network formation, we subjected newborn mice to sciatic neurectomy in order to immobilize their left hind limb as an unloading model. The osteocyte network was visualized by staining osteocyte cell bodies and processes with fluorescently labeled phalloidin. First, we compared the osteocyte network in the femora of embryonic and 6-week-old mice in order to understand the morphological changes that occur with normal growth and mechanical loading. In embryonic mice, the osteocyte network in the femur cortical bone displayed a random cell body distribution, non-directional orientation of cell processes, and irregularly shaped cells. In 6-week-old mice, the 3D network contained spindle-shaped osteocytes, which were arranged parallel to the longitudinal axis of the femur. In addition, more and longer cell processes radiated from each osteocyte. Second, we compared the cortical osteocyte networks of 6-week-old mice that had or had not undergone sciatic neurectomy in order to evaluate the effect of unloading on osteocyte network formation. The osteocyte network formation in both cortical bone and cancellous bone was affected by mechanical loading. However, there were differences in the extent of network formation between cortical bone and cancellous bone in response to mechanical loading with regard to the orientation, nuclear shape and branch formation.

DOI： 10.1016/j.bone.2012.09.033

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Other Link： http://orcid.org/0000-0002-4419-9643

Language：Japanese   Publisher：岡山歯学会  

2008〜2012年に岡山大学大学院歯科矯正学分野医局を訪れた岡山大学学生128名と職員11名の計139名(男性40名、女性99名)を対象に、矯正相談の実態について調査した。その結果、相談の契機は掲示されたポスターによる者が最も多く75名54%であった。学年別では1年生48名、2年生21名、3年生15名、4年生18名で、学部別では医学部保健学科と歯学部が最も多く各18名であった。主訴の最多は上顎前突34名(24.5%)で、次いで上顎の叢生27名(19.4%)であった。相談後に矯正を開始したのは学年別で最多は1年生で相談者のうち35名72.9%、全治療開始者の40.7%を占めた。以上より、矯正相談は、歯並びのコンプレックス等の解決や福利厚生として有効であることが示唆された。

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The aims of this study were to investigate how the Peer Assessment Rating (PAR index) predicts the perceived need for orthodontic treatment of mandibular protrusion in Japanese subjects, and to elucidate whether the perceived need for treatment was affected by the raters' orthodontic expertise. The subjects were 110 dental students and 32 orthodontists. We showed them casts of 10 untreated mandibular protrusion cases and gave them a questionnaire in which they had to describe their perceptions of the orthodontic treatment needs using a 10-point visual analog scale (VAS). The PAR index was used for cast evaluation. The PAR index scores showed significant correlations with the VAS scores. In casts with a low PAR score, there were no differences in the VAS scores between orthodontists and students. In casts with a PAR score greater than 23, the orthodontists perceived a significantly greater treatment need than did the students
for scores of 22, 28, and 29, students who had received orthodontic treatment themselves were more likely to perceive the treatment need. The PAR index is a good clinical predictor for assessing the perceived treatment needs for mandibular protrusion. Perception of the need for orthodontic treatment for mandibular protrusion depended on the degree of orthodontic expertise in Japanese subjects. © 2013 by Okayama University Medical School.

DOI： 10.18926/AMO/51863

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Other Link： http://orcid.org/0000-0002-4419-9643

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Fluid flow stress (FSS) is a major mechanical stress that induces bone remodeling upon orthodontic tooth movement, whereas CCN family protein 2 (CCN2) is a potent regenerator of bone defects. In this study, we initially evaluated the effect of laminar FSS on Ccn2 expression and investigated its mechanism in osteoblastic MC3T3-E1 cells. The Ccn2 expression was drastically induced by uniform FSS in an intensity dependent manner. Of note, the observed effect was inhibited by a Rho kinase inhibitor Y27632. Moreover, the inhibition of actin polymerization blocked the FSS-induced activation of Ccn2, whereas inducing F-actin formation using cytochalasin D and jasplakinolide enhanced Ccn2 expression in the same cells. Finally, F-actin formation was found to induce osteoblastic differentiation. In addition, activation of cyclic AMP-dependent kinase, which inhibits Rho signaling, abolished the effect of FSS. Collectively, these findings indicate the critical role of actin polymerization and Rho signaling in CCN2 induction and bone remodeling provoked by FSS.

DOI： 10.1007/s12079-012-0177-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Osteocytes play a pivotal role in the regulation of skeletal mass. Osteocyte processes are thought to sense the flow of interstitial fluid that is driven through the osteocyte canaliculi by mechanical stimuli placed upon bone, but how this flow elicits a cellular response is virtually unknown. Modern theoretical models assume that osteocyte canaliculi contain ultrastructural features that amplify the fluid flow-derived mechanical signal. Unfortunately the calcified bone matrix has considerably hampered studies on the osteocyte process within its canaliculus. Using one of the few ultra high voltage electron microscopes (UHVEM) available worldwide, we applied UHVEM tomography at 2 MeV to reconstruct unique three-dimensional images of osteocyte canaliculi in 1 μm sections of human bone. A realistic three-dimensional image-based model of a single canaliculus was constructed, and the fluid dynamics of a Newtonian fluid flow within the canaliculus was analyzed. We created virtual 2.2 nm thick sections through a canaliculus and found that traditional TEM techniques create a false impression that osteocyte processes are directly attached to the canalicular wall. The canalicular wall had a highly irregular surface and contained protruding axisymmetric structures similar in size and shape to collagen fibrils. We also found that the microscopic surface roughness of the canalicular wall strongly influenced the fluid flow profiles, whereby highly inhomogeneous flow patterns emerged. These inhomogeneous flow patterns may induce deformation of cytoskeletal elements in the osteocyte process, thereby amplifying mechanical signals. Based on these observations, new and realistic models can be developed that will significantly enhance our understanding of the process of mechanotransduction in bone.

DOI： 10.1039/c2ib20092a

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Other Link： http://orcid.org/0000-0002-4419-9643

Language：English   Publishing type：Research paper (scientific journal)  

Confocal immunofluorescence tiling imaging revealed the spatio-temporal distributions of osterix and sclerostin in femurs from 3-day-old, 2-week-old and 4-week-old rats to be reciprocally exclusive at the tissue level. Further quantitative three-dimensional immuno fluorescence morphometry demonstrated the increasing distribution of sclerostin in the osteocytic lacuno-canalicular system specifically in diaphysis, which paralleled the cooperative participation and depletion of osterix and β-catenin in adjacent periosteum cells. Treating MC3T3-E1 cells with BIO (a GSK3 inhibitor) induced the stabilization of β-catenin and nuclear translocation of osterix, and negatively regulated osteocalcin/BGLAP and Dmp1. These results collectively demonstrate that the increasing distribution of sclerostin in diaphyseal cortical bone appears to be involved in the attenuation of osterix and β-catenin in adjacent periosteum cells, thus possibly contributing to osteoblast maturation and reducing the osteoblast formation at this bone site. Our confocal microscopy-based imaging analyses provide a comprehensive and detailed view of the spatio-temporal distribution of sclerostin, β-catenin and osterix at the tissue to subcellular level in a coherent manner, and uncovered their spatio-temporal cooperation in postnatal bone development, thus providing evidence that they link skeletogenic growth and functional bone development.

DOI： 10.1016/j.bone.2012.06.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Bone cells form a complex three-dimensional network consisting of osteoblasts and osteocytes embedded in a mineralized extracellular matrix. Ca(2+) acts as a ubiquitous secondary messenger in various physiological cellular processes and transduces numerous signals to the cell interior and between cells. However, the intracellular Ca(2+) dynamics of bone cells have not been evaluated in living bone. In the present study, we developed a novel ex-vivo live Ca(2+) imaging system that allows the dynamic intracellular Ca(2+) concentration ([Ca(2+)](i)) responses of intact chick calvaria explants to be observed without damaging the bone network. Our live imaging analysis revealed for the first time that both osteoblasts and osteocytes display repetitive and autonomic [Ca(2+)](i) oscillations ex vivo. Thapsigargin, an inhibitor of the endoplasmic reticulum that induces the emptying of intracellular Ca(2+) stores, abolished these [Ca(2+)](i) responses in both osteoblasts and osteocytes, indicating that Ca(2+) release from intracellular stores plays a key role in the [Ca(2+)](i) oscillations of these bone cells in intact bone explants. Another possible [Ca(2+)](i) transient system to be considered is gap junctional communication through which Ca(2+) and other messenger molecules move, at least in part, across cell-cell junctions; therefore, we also investigated the role of gap junctions in the maintenance of the autonomic [Ca(2+)](i) oscillations observed in the intact bone. Treatment with three distinct gap junction inhibitors, 18α-glycyrrhetinic acid, oleamide, and octanol, significantly reduced the proportion of responsive osteocytes, indicating that gap junctions are important for the maintenance of [Ca(2+)](i) oscillations in osteocytes, but less in osteoblasts. Taken together, we found that the bone cells in intact bone explants showed autonomous [Ca(2+)](i) oscillations that required the release of intracellular Ca(2+) stores. In addition, osteocytes specifically modulated these oscillations via cell-cell communication through gap junctions, which maintains the observed [Ca(2+)](i) oscillations of bone cells.

DOI： 10.1016/j.bone.2012.01.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Cell surface heparan sulfate (HS) is an essential regulator of cell signaling and development. HS traps signaling molecules, like Wnt in the glycosaminoglycan side chains of HS proteoglycans (HSPGs), and regulates their functions. Endosulfatases Sulf1 and Sulf2 are secreted at the cell surface to selectively remove 6-O-sulfate groups from HSPGs, thereby modifying the affinity of cell surface HSPGs for its ligands. This study provides molecular evidence for the functional roles of HSPG sulfation and desulfation in dentinogenesis. We show that odontogenic cells are highly sulfated on the cell surface and become desulfated during their differentiation to odontoblasts, which produce tooth dentin. Sulf1/Sulf2 double null mutant mice exhibit a thin dentin matrix and short roots combined with reduced expression of dentin sialophosphoprotein (Dspp) mRNA, encoding a dentin-specific extracellular matrix precursor protein, whereas single Sulf mutants do not show such defective phenotypes. In odontoblast cell lines, Dspp mRNA expression is potentiated by the activation of the Wnt canonical signaling pathway. In addition, pharmacological interference with HS sulfation promotes Dspp mRNA expression through activation of Wnt signaling. On the contrary, the silencing of Sulf suppresses the Wnt signaling pathway and subsequently Dspp mRNA expression. We also show that Wnt10a protein binds to cell surface HSPGs in odontoblasts, and interference with HS sulfation decreases the binding affinity of Wnt10a for HSPGs, which facilitates the binding of Wnt10a to its receptor and potentiates the Wnt signaling pathway, thereby up-regulating Dspp mRNA expression. These results demonstrate that Sulf-mediated desulfation of cellular HSPGs is an important modification that is critical for the activation of the Wnt signaling in odontoblasts and for production of the dentin matrix.

DOI： 10.1074/jbc.M111.332924

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER INC  

Embryonic stem cell-associated antigens are expressed in a variety of adult stem cells as well as embryonic stem cells. In the present study, we investigated whether stage-specific embryonic antigen (SSEA)-4 can be used to isolate dental pulp (DP) stem cells. DP cells showed plastic adherence, specific surface antigen expression, and multipotent differentiation potential, similar to mesenchymal stem cells (MSC). SSEA-4+ cells were found in cultured DP cells in vitro as well as in DP tissue in vivo. Flow cytometric analysis demonstrated that 45.5% of the DP cells were SSEA-4+. When the DP cells were cultured in the presence of all-trans-retinoic acid, marked downregulation of SSEA-3 and SSEA-4 and the upregulation of SSEA-1 were observed. SSEA-4+ DP cells showed a greater telomere length and a higher growth rate compared to ungated and SSEA-4 - cells. A clonal assay demonstrated that 65.5% of the SSEA-4+ DP cells had osteogenic potential, and the SSEA-4+ clonal DP cells showed multilineage differentiation potential toward osteoblasts, chondrocytes, and neurons in vitro. In addition, the SSEA-4+ DP cells had the capacity to form ectopic bone in vivo. Thus, our results suggest that SSEA-4 is a specific cell surface antigen that can be used to identify DP stem cells. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2012.01.008

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Language：English   Publisher：WILEY-BLACKWELL  

Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rats desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 degrees C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P &lt; 0.05). Complete reversal of thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 degrees C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.

DOI： 10.1111/j.1365-2842.2011.02236.x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：中・四国矯正歯科学会  

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The study of osteocytes has progressed in chicks. We examined whether chick osteocyte data can be applied to other species. We used mice for comparison because they are common clinical tools in biomedical research and useful for future study. We analyzed the three-dimensional (3D) osteocyte network and gap junctional intercellular communication (GJIC) in living embryonic calvaria for the anatomical features. Embryonic parietal bones were stained with fluorescently labeled phalloidin and observed using confocal laser scanning microscopy. GJIC between osteocytes in chick and mouse parietal bone was assessed using fluorescence recovery after photobleaching (FRAP). The values for one chick and mouse osteocyte, respectively, were calculated as follows: cell processes 1,131 ± 139 μm, 2,668 ± 596 μm; surface area 1,128 ± 358 μm(2), 2,654 ± 659 μm(2); and cell volume 455 ± 90 μm(3), 1,328 ± 210 μm(3). The density of 3D osteocyte processes in the bone matrix was not significantly different. FRAP analysis showed dye coupling among osteocytes in chick and mouse bone. The fluorescence intensity recovered to 49.0 ± 2.4% in chicks and 39.9 ± 2.4% in mice after 5 minutes. Fluorescence recovery was similar within 4 minutes. The difference in osteocyte size between the two species might have affected their functions. Osteocyte processes in the two species may sense similarly changes in the exterior environment. We successfully conducted morphological and functional analyses of the osteocyte network in chicks and mice. The size of the osteocytes in bone differed between the two species.

DOI： 10.1007/s00223-011-9471-7

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The molecular and cellular mechanisms involved in bone development provide an insight into the nature of bone regeneration. Sox9 is a key transcription factor for chondrogenesis and is also expressed in osteochondroprogenitors during embryonic bone development. However, it has not been determined whether Sox9-expressing cells appear during fracture repair other than in the cartilaginous callus. On the other hand, the difference between bone development and repair is that the motion of the fractured segments is associated with the subsequent fate decision of osteochondrogenic precursors between osteogenesis or chondrogenesis, but the underlying mechanism of this still has to be elucidated. We herein evaluate whether Sox9 expressing cells appear during osseous regeneration in the initial stages of fracture healing in vivo. We also investigated the association between Sox9 induction and mechanical stress and the role of Runx1 expression. As a result, Sox9- and Runx1-expressing cells were detected in the periosteal callus together with Runx2 expression. Their expression levels were significantly downregulated during its ossification, as observed in embryonic bone development. The application of cyclic tension to isolated and cultured stromal cells resulted in the upregulation and maintenance of Sox9 mRNA expression in vitro. These results showed that as in early skeletal development, Sox9- and Runx1-expressing precursor cells first appear in the periosteal callus as an early fracture repair response. Our findings also suggested that the mechanical environment modulates Sox9 expression levels in osteochondrogenic precursors and consequently influences their fate decision between osteogenic and chondrogenic lineage commitment. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000322557

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In a variety of scientific fields, it is helpful to visualize natural phenomena. Newly developed methods of visualization often lead to breakthroughs in scientific fields. Especially, in the bioscience field, it is significant to reveal temporal-spatial responses in cells while visualizing molecular phenomena. Such visualization may provide information to help understand cellular behavior in response to an extracellular stimulus. Although osteocytes are the most abundant cells in bone, it has been difficult to study their biological nature because they are embedded in hard bone tissue. So, the real 3D structure of osteocytes was not clarified until recently. On the other hand, a newly developed technique of visualization was recently introduced into bone cell biology. In this review, we introduce and review our application of a bioimaging technique to reveal the morphology of osteocytes as well as part of their biological nature. © Springer Science+Business Media, LLC 2010.

DOI： 10.1007/s12018-010-9077-z

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The periodontal ligament (PDL) comprises adult stem cells, which are responsible for periodontal tissue regeneration. In the present study, we investigated the specific profile of the stem cells in the human PDL. Microscopic analysis demonstrated that PDL cells showed a fibroblastic appearance, forming flat and loose aggregates. PDL cells expressed embryonic stem cell-associated antigens (SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, OCT4, NANOG, SOX2, and REX1, and alkaline phosphatase activity), as well as conventional mesenchymal stem cell markers. When PDL cells were cultured in the presence of all-trans-retinoic acid, the numbers of SSEA-3+ and SSEA-4+ PDL cells were significantly decreased, while that of SSEA-1+ was increased. SSEA-4+ PDL cells showed a greater telomere length and growth rate. SSEA-4+ PDL cells exhibited the potential to generate specialized cells derived from three embryonic germ layers: mesodermal (adipocytes, osteoblasts, and chondrocytes), ectodermal (neurons), and endodermal (hepatocytes) lineages. Our findings demonstrated that SSEA-4, a major antigen to distinguish human embryonic stem cells, could also be used to identify multipotent stem cells in the PDL. Hence, SSEA-4+ human PDL cells appear to be a promising source of stem cells for regenerative medicine. (C) 2009 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.diff.2009.10.005

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Language：Japanese   Publisher：岡山歯学会  

岡山大学病院矯正歯科では2000年度から術前の顎機能検査とMRI検査を取り入れ、より精度の高い診断の基に個々の患者の様々な主訴に応じた治療を行っており、患者数も2001年度の184名から2008年度には209名に増加傾向を示した。2009年4月の1ヵ月間に来院した患者を対象に診療体制に関するアンケート調査を実施、回収された269名について分析した。その結果、対象の性別は女性が男性の1.5倍多く、年齢は成人患者が過半数を占め、矯正治療開始時の主訴は歯ならびの外観63.7%、顔や顎の形9.9%、噛み難い6.9%、発音し難い2.7%、顎関節疾患3.1%、虫歯や歯周病予防3.4%であった。来院のきっかけはかかりつけ医の紹介が35.1%と最も多く、来院動機は高度な専門医療が受けられると思うからが27.9%であった。以上より、岡山大学病院矯正歯科の特色であるインプラントアンカー治療や舌側矯正装置による治療を、地域との連携を深めながらより一層周知すること、さらなる技術の向上に努める必要性が示唆された。

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This is a case report of a female patient (10 years 3 months) whose chief complaint was edge-to-edge bite. At the initial examination, the diagnosis was severe skeletal Class III. In first-phase treatment, growth modification was planned. Although forward and downward maxillary growth was observed, skeletal Class III still remained. In the second-phase treatment, implant anchorage was applied for distal movement of the mandibular teeth. A favorable occlusal relationship was achieved, and acceptable stomatognathic function was maintained after 2 years of retention. © 2009 Elsevier Ltd and the Japanese Orthodontic Society.

DOI： 10.1016/j.odw.2009.05.001

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Bone functional adaptation by remodeling is achieved by harmonized activities of bone cells in which osteocytes in the bone matrix are believed to play critical roles in sensing mechanical stimuli and transmitting signals to osteoclasts/osteoblasts on the bone surface in order to regulate their bone remodeling activities through the lacuno-canalicular network with many slender osteocytic processes. In this study, we investigated the intercellular communication between bone cells, particularly focusing on its directionality, through in vitro observations of the calcium signaling response to mechanical stimulus and its propagation to neighboring cells (NCs). Direct mechanical stimulus was applied to isolated bone cells from chick calvariae, osteocytes (Ocys) and bone surface cells (BSCs) mainly containing osteoblasts, and the percentage of calcium signaling propagation from the stimulated cell to NCs was analyzed. The results revealed that, regardless of the type of stimulated cell, the signaling propagated to BSCs with a significantly higher percentage, implying that calcium signaling propagation between bone cells strongly depends on the type of receiver cell and not the transmitter cell. In addition, in terms of mutual communication between Ocys and BSCs, the percentage of propagation from Ocys to BSCs is significantly higher than that in the opposite direction, suggesting that the calcium signaling mainly propagates asymmetrically with a bias from Ocys in bone matrix to BSCs on bone surfaces. This asymmetric communication between Ocys and BSCs suggests that osteocytic mechanosensing and cellular communications, which significantly affect bone surface remodeling activities to achieve functional adaptation, seem to be well coordinated and active at the location of biologically suitable and mechanically sensitive regions close to the bone surfaces.

DOI： 10.1016/j.bbrc.2009.09.010

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Osteocytes embedded in calcified bone matrix have been widely believed to play important roles in mechanosensing to achieve adaptive bone remodeling in a changing mechanical environment. In vitro studies have clarified several types of mechanical stimuli such as hydrostatic pressure, fluid shear stress, and direct deformation influence osteocyte functions. However, osteocyte response to mechanical stimuli in the bone matrix has not been clearly understood. In this study, we observed the osteocyte calcium signaling response to the quantitatively applied deformation in the bone matrix. A novel experimental system was developed to apply deformation to cultured bone tissue with osteocytes on a microscope stage. As a mechanical stimulus to the osteocytes in bone matrix, in-plane shear deformation was applied using a pair of glass microneedles to bone fragments, obtained from 13-day-old embryonic chick calvariae. Deformation of bone matrix and cells was quantitatively evaluated using an image correlation method by applying for differential interference contrast images of the matrix and fluorescent images of immunolabeled osteocytes, together with imaging of the cellular calcium transient using a ratiometric method. As a result, it was confirmed that the newly developed system enables us to apply deformation to bone matrix and osteocytes successfully under the microscope without significant focal plane shift or deviation from the observation view field. The system could be a basis for further development to investigate the mechanosensing mechanism of osteocytes in bone matrix through examination of various types of rapid biochemical signaling responses and intercellular communication induced by matrix deformation.

DOI： 10.1016/j.jbiomech.2009.07.006

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Osteocytes are surrounded by hard bone matrix, and it has not been possible previously to directly observe the in situ architecture of osteocyte morphology in bone. Electron microscope tomography, however, is a technique that has the unique potential to provide three-dimensional (3D) visualization of cellular ultrastructure. This approach is based on reconstruction of 3D volumes from a tilt series of electron micrographs of cells, and resolution at the nanometer level has been achieved. We applied electron microscope tomography to thick sections of silver-stained osteocytes in bone using a Hitachi H-3000 ultra-high voltage electron microscope equipped with a 360 degrees tilt specimen holder, at an accelerating voltage of 2 MeV. Osteocytes with numerous processes and branches were clearly seen in the serial tilt series acquired from 3-microm-thick sections. Reconstruction of young osteocytes showed the 3D topographic morphology of the cell body and processes at high resolution. This morphological data on osteocytes should provide useful information to those who study osteocyte physiology and the several models used to explain their mechanosensory properties.

DOI： 10.1017/S1431927609990420

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DOI： 10.1016/j.neuroscience.2009.04.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

This case report describes the treatment of a patient with bimaxillary protrusion and masseter muscle hypertrophy. At age 21 years 7 months, this woman had temporomandibular disorder (TMD) symptoms, severe bimaxillary protrusion, and a prominent mandibular angle with facial asymmetry. After an attempt to alleviate the TMD symptoms with occlusal splint stabilization, portions of the masseter muscle and the mandible were surgically removed. Titanium screws were placed bilaterally in both arches, and a retraction force was applied. After active treatment for 38 months, the convexity of the facial profile with lip protrusion was improved remarkably, and good occlusion was achieved. The prominent mandibular angle with facial asymmetry was improved as a result of the surgical reduction of the masseter muscle and the modeling ostectomy near the masseteric tuberosity. The TMD symptoms disappeared, and the jaw movement pattern became normal. Therefore, our results suggest that this combination treatment would be useful for masseter muscle hypertrophy for morphologic and functional problems. (Am J Orthod Dentofacial Orthop 2009; 135:536-48)

DOI： 10.1016/j.ajodo.2006.10.043

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A number of fascinating studies suggest that osteocytes play an important role in bone metabolism, especially in its regulation by mechanical stimuli. However, it has been still discussed how the osteocytes were activated by mechanical stimuli. For example, direct mechanical load applied to cells at levels measured to occur in humans in vivo do not affect bone cells in vitro . In order to solve the contradiction, theories based on fluid flow-induced shear stress stimulation around osteocytes in bone have appeared with the most prominence. In addition, I would like to introduce recent hypothesis to mechanically stimulate osteocyte, such as strain amplification by radial hoop strains, flow induced integrin mediated signaling, and osteocyte lacuna strain. To validate the availability of these hypothesis, it is important to observe 3-dimensional osteocyte morphology as well as its interaction with pericellular matrix.

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

骨は機械的刺激を受けマクロな変化を遂げる。その結果は、骨に存在する細胞群が引き起こすミクロな変化の集積である。このような変化を生じるためには、骨の細胞は何らかの方法で機械的刺激を感知しなければならない。実際に、骨の形態を変化させるのは骨芽細胞および破骨細胞であるが、機械的刺激を感知し、これらの細胞の役割を調節しているのが骨細胞であると考えられている。骨細胞は骨基質に囲まれている特異な環境のために、実際にどのようにして機械的刺激を感知しているのかは明らかではない。しかしながら、近年、生体工学的な試みにより、さまざまな骨細胞の機械的刺激の受容機構が提案されてきた。そこで、本稿ではこれらの説を紹介するとともに、骨細胞およびその周囲骨基質の三次元構造を求めることの重要性について解説していきたい。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Osteocytes acquire their stellate shape during the process of changing from osteoblasts in bone. Throughout this process, dynamic cytoskeletal changes occur. In general, changes of the cytoskeleton affect cellular mechanical properties. Mechanical properties of living cells are connected with their biological functions and physiological processes. In this study, we for the first time analyzed elastic modulus, a mechanical property of bone cells. Bone cells in embryonic chick calvariae and in isolated culture were identified using fluorescently labeled phalloidin and OB7.3, a chick osteocyte-specific monoclonal antibody, and then observed by confocal laser scanning microscopy. The elastic modulus of living cells was analyzed with atomic force microscopy. To examine the consequences of focal adhesion formation on the elastic modulus, cells were pretreated with GRGDS and GRGES, and then the elastic modulus of the cells was analyzed. Focal adhesions in the cells were visualized by immunofluorescence of vinculin. From fluorescence images, we could distinguish osteoblasts, osteoid osteocytes and mature osteocytes both in vivo and in vitro. The elastic modulus of peripheral regions of cells in all three populations was significantly higher than in their nuclear regions. The elastic modulus of the peripheral region of osteoblasts was 12053+/-934 Pa, that of osteoid osteocytes was 7971+/-422 Pa and that of mature osteocytes was 4471+/-198 Pa. These results suggest that the level of elastic modulus of bone cells was proportional to the stage of changing from osteoblasts to osteocytes. The focal adhesion area of osteoblasts was significantly higher than that of osteocytes. The focal adhesion area of osteoblasts was decreased after treatment with GRGDS, however, that of osteocytes was not. The elastic modulus of osteoblasts and osteoid osteocytes were decreased after treatment with GRGDS. However, that of mature osteocytes was not changed. There were dynamic changes in the mechanical property of elastic modulus and in focal adhesions of bone cells.

DOI： 10.1016/j.bone.2008.02.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Introduction: Recently, miniscrews have been used to provide anchorage during orthodontic treatment, especially for incisor intrusion. Miniscrews during incisor intrusion are commonly used in implant orthodontics. Traditionally, effective incisor intrusion has been accomplished with J-hook headgear. In this study, we compared the effect of incisor intrusion, force vector, and amount of root resorption between implant orthodontics and J-hook headgear. Methods: Lateral cephalometric radiographs from 8 patients in the implant group and 10 patients in the J-hook headgear group were analyzed for incisor retraction. The estimated force vector was analyzed in the horizontal and vertical directions in both groups. Root resorption was also measured on periapical radiographs. Results: In the implant group, significant reductions in overjet, overbite, maxillary incisor to palatal plane, and maxillary incisor to upper lip were observed after intrusion of the incisors. In the J-hook headgear group, significant reductions in overjet, overbite, maxillary incisor to upper lip, and maxillary incisor to SN plane were observed after intrusion of the incisors. There were significantly greater reductions in overbite, maxillary incisor to palatal plane, and maxillary incisor to upper lip in the implant group than in the J-hook headgear group. Estimated force analysis resulted in significantly more force in the vertical direction and less in the horizontal direction in the implant group. Furthermore, significantly less root resorption was observed in the implant group compared with the J-hook headgear group. Conclusions: The maxillary incisors were effectively intruded by using miniscrews as orthodontic anchorage without patient cooperation. The amount of root resorption was not affected by activating the ligature wire from the miniscrew during incisor intrusion.

DOI： 10.1016/j.ajodo.2006.04.047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BONE & MINERAL RES  

UNLABELLED: Gap junctional intercellular communication among osteocytes in chick calvaria, their natural 3D environment, was examined using FRAP analysis. Cell-cell communication among osteocytes in chick calvaria was mediated by Cx43 and was regulated by extracellular pH, extracellular calcium ion concentration, and PTH. INTRODUCTION: The intercellular network of communication among osteocytes is mediated by gap junctions. Gap junctional intercellular communication (GJIC) is thought to play an important role in integration and synchronization of bone remodeling. We hypothesized that extracellular pH (pH(o)) and extracellular calcium ion concentration ([Ca2+](e)), both of which are dynamically altered by osteoclasts during bone remodeling, affect GJIC among osteocytes. Using fluorescence replacement after photobleaching (FRAP) analysis, we examined the effect of changes in pH(o) and [Ca2+](e) and addition of PTH on GJIC in osteocytes in chick calvaria. Additionally, we examined the role of intracellular calcium on the regulation of GJIC among osteocytes. MATERIALS AND METHODS: Anti-Connexin43 (Cx43) immunolabeling was used to localize gap junctions in chick calvaria. GJIC among osteocytes in chick calvariae was assessed using FRAP. RESULTS: Cx43 immunoreactivity was detected in most of the osteocyte processes. FRAP analysis showed dye-coupling among osteocytes in chick calvariae. In untreated osteocytes, fluorescence intensity recovered 43.7 +/- 2.2% within 5 min after photobleaching. Pretreatment of osteocytes with 18 alpha-GA, a reversible inhibitor of GJIC, significantly decreased fluorescence recovery to 10.7 +/- 2.2%. When pH(o) was decreased from 7.4 to 6.9, fluorescence recovery significantly decreased from 43.3 +/- 2.9% to 19.7 +/- 2.3%. Conversely, when pH(o) was increased from 7.4 to 8.0, fluorescence recovery was significantly increased to 61.9 +/- 4.5%. When [Ca2+](e) was increased from 1 to 25 mM, fluorescence recovery was significantly decreased from 47.0 +/- 6.1% to 16.1 +/- 2.1%. In bone fragments exposed to 1.0-10 nM rPTH for 3 h, replacement of fluorescence was significantly increased to 60.7 +/- 7.2%. Chelating intracellular calcium ions affected GJIC regulation by [Ca2+](e) and PTH. CONCLUSIONS: Our study of cell-cell communication between osteocytes in chick calvaria showed for the first time that GJIC among osteocytes is regulated by the extracellular environment and by hormonal stimulation during bone remodeling. This method may be more biologically relevant to living bone than current methods.

DOI： 10.1359/JBMR.071102

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17歳女性。斜頸による舌骨上筋群および下筋群の高度緊張を認めた著しいオトガイ後退を伴う顎顔面の変形をきたした症例で、オトガイ部の後退に対する形態改善の目的で受診となった。顔貌所見にて正貌で眼瞼下垂、側貌でconvex type、口腔内所見にて両側Angel class II、overjet 3.7mm、overbite -2.5mm、前歯部は開咬を示していた。セファロ分析ではオトガイの劣成長を認め、舌骨が下方へ位置していた。CTデータをOsiriX Medical Imaging Softwareを用いた3Dおよび再構築CT画像においては、両側下顎犬歯から両側第二大臼歯部にかけて舌側皮質骨に溝状の凹みと同部の骨の非薄を認めた。骨非薄部の厚みは最も薄いところで約3mmであった。下顎後退症の臨床診断で、オトガイ形成術とベニアグラフトを併用して治療を行った。術後の側貌においてはlabiomental foldが明瞭化し、オトガイから頸部にかけての審美的改善が認められた。術後経過は良好で、骨片のずれや吸収等は認められない。

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The patient was a 12-year-old female who presented with unilateral cleft lip and palate, facial asymmetry, mandibular protrusion, resorption of condyle heads, and transverse maxillary deficiency. At the age of 13 years 10 months, maxillary expansion and autogenous bone graft were performed to improve the maxillary collapsed arch. Aged 14 years 10 months, she described symptoms of temporomandibular joint pain and dysfunction. Segmental Le Fort I osteotomy and intraoral vertical ramus osteotomy (IVRO) were performed at the age of 15 years 11 months. Segmental Le Fort I osteotomy resulted in improved sagittal and transverse discrepancy of the maxilla. After IVRO, facial symmetry, a good facial profile, and disappearance of TMD symptoms were achieved. The occlusion and esthetics were stable after 5 years of retention. © 2007 Elsevier Ltd and the Japanese Orthodontic Society.

DOI： 10.1016/j.odw.2007.06.002

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DOI： 10.1007/s00774-007-0772-x

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At the age of 10 years and 10 months, a patient was brought to our office with a chief complaint of dental crowding and narrow maxilla. She had been diagnosed as having Pierre-Robin sequence at birth. She showed a convex profile with Class II molar relationship. The dental relationship was corrected with headgear and functional appliance in phase I orthodontic treatment. Optimal intercuspation of the teeth achieved after edgewise treatment and good facial profile with Class I relationship were obtained. When she started retention at the age of 17 years, she was diagnosed as having Stickler syndrome. Although slight reduction of the mandible was observed after a retention period of 5 years, optimal intercuspation of teeth was maintained. © 2007 Elsevier Ltd and the Japanese Orthodontic Society.

DOI： 10.1016/j.odw.2007.03.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

The inaccessibility of osteocytes due to their embedment in the calcified bone matrix in vivo has precluded direct demonstration that osteocytes use gap junctions as a means of intercellular communication. In this article, we report successfully isolating primary cultures of osteocytes from chick calvaria, and, using anti-connexin 43 immunocytochemistry, demonstrate gap junction distribution to be comparable to that found in vivo. Next, we demonstrate the functionality of the gap junctions by (1) dye coupling studies that showed the spread of microinjected Lucifer Yellow from osteoblast to osteocyte and between adjacent osteocytes and (2) analysis of fluorescence replacement after photobleaching (FRAP), in which photobleaching of cells loaded with a membrane-permeable dye resulted in rapid recovery of fluorescence into the photobleached osteocyte, within 5 min postbleaching. This FRAP effect did not occur when cells were treated with a gap junction blocker (18 alpha-glycyrrhetinic acid), but replacement of fluorescence into the photobleached cell resumed when it was removed. These studies demonstrate that gap junctions are responsible for intercellular communication between adjacent osteocytes and between osteoblasts and osteocytes. This role is consistent with the ability of osteocytes to respond to and transmit signals over long distances while embedded in a calcified matrix.

DOI： 10.1017/S143192760707016X

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Cell shape is the most critical determinant of cell function and is potentially influenced by the organization of a cell's cytoskeletal components. It has been reported that three-dimensionally cultured osteoblasts have a morphology that closely resembles that of osteocytes, most notably including formation of processes. We have previously shown the critical differences between cytoskeletal components in osteoblasts and osteocytes in two-dimensional culture. We have now extended that investigation to the cytoskeletal components of 3D-cultured osteoblasts and osteocytes using 3D cultures of the osteoblast cell line, MC3T3-E1, and primary osteocytes grown in collagen gel. Three-dimensional fluorescent image reconstructions for actin, fimbrin, alpha-actinin, myosin, tropomyosin, and microtubules were made using IMARIS software. Actin, fimbrin, alpha-actinin, myosin, and tropomyosin all appeared in the processes of both cell types, but fimbrin and myosin showed differences in their distribution patterns between cell types. Microtubules were limited in distribution to the proximal region of osteocyte processes but extended the entire length of MC3T3-E1 cell processes. Microtubules were essential for the integrity and formation of MC3T3-E1 cell processes, but osteocyte processes were dependent on actin. These results showed that there are significant differences between the actin and microtubule cytoskeletons in the processes of 3D-cultured MC3T3-E1 cells and in the processes of 3D-cultured primary osteocytes. These differences in the cytoskeleton of the processes of 3D-cultured osteoblasts and of osteocyte dendrites suggest that osteoblast processes may have a different functional role than the osteocyte dendritic network.

DOI： 10.1007/s00774-006-0745-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

We propose that specific osteocyte-matrix interactions regulate the volume-sensitive calcium influx pathway, which we have shown is mediated by stretch-activated cation channels (SA-Cat) and is essential for the stretch-activated anabolic response in bone. The current study measured the hypotonic swelling-induced increase in cytosolic calcium concentration, [Ca2+](i), in rat osteocytes, and found that cells adherent to different matrices behave differently. Osteopontin and vitronectin, matrix molecules that bind the alpha(V)beta(3) integrin, induced larger responses to the hypotonic swelling than other matrix molecules that bind other integrins. Addition of echistatin, which is a soluble alpha(V)beta(3) ligand, significantly enhanced the hypotonic [Ca2+](i) increase in addition to inducing an immediate increase in [Ca2+](i) by itself. These results strongly support the contention that alpha(V)beta(3) integrin signaling in osteocytes interacts with that in mechanotransduction, which is downstream of SA-Cat.

DOI： 10.1007/s00774-006-0716-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Introduction: To explore the immediate response to mechanical stress in a bone cell population, we examined flow-induced calcium transients. In addition, the involvement of focal adhesion-related calcium transients in response to fluid flow in the cells was studied.
Materials and Methods: Bone cells were isolated from 16-day-old embryonic chicken calvaria by serial treatment with EDTA and collagenase. Single cells on glass without intercellular connections were subjected to fluid flow, and intracellular calcium concentration was measured using imaging with fluo-3. The identification of cell populations in the same field was performed with a chick osteocyte-specific antibody, OB7.3, and an alkaline phosphatase substrate, ELF-97, for osteoblast identification afterward. Immunofluorescence staining of vinculin was performed to visualize focal adhesions.
Results: The percentage of cells responding to fluid shear stress at 1.2 Pa was 5.5% in osteocytes, 32.4% in osteoblasts, and 45.6% in OB7.3/ELF-97-negative cells. Furthermore, osteoblasts and OB7.3/ELF-97-negative cells were more responsive to 2.4 Pa than 1.2 Pa, whereas osteocytes were less responsive. The elevation of calcium transients over baseline did not show any significant differences in the populations. To elucidate the mechanism accounting for the fact that single osteocytes are less sensitive to fluid shear stress of up to 2.4 Pa than osteoblasts, we studied focal adhesion-related calcium transients. First, we compared focal adhesion formation between osteocytes and osteoblasts and found a larger number of focal adhesions in osteoblasts than in osteocytes. Next, when the cells were pretreated with GRGDS (0.5 mM) before flow treatment, a significant reduction of calcium transients in osteoblasts (18%) was observed, whereas calcium transients in osteocytes were not changed by GRGDS. Control peptide GRGES did not reduce the calcium transients in either cell type. Furthermore, we confirmed that osteoblasts in calvaria showed a marked formation of vinculin plaques in the periphery of the cells. However, osteocytes in calvaria showed faint vinculin plaques only at the base of the processes.
Conclusions: On glass, single osteocytes are less sensitive to fluid shear stress up to 2.4 Pa than osteoblasts. The difference in calcium transients might be related to differences in focal adhesion formation. Shear stress of a higher magnitude or direct deformation may be responsible for the mechanical response of osteocytes in bone.

DOI： 10.1359/JBMR.060408

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Introduction: The purpose of this study was to quantitatively evaluate cortical bone thickness in various locations in the maxilla and the mandible. In addition, the distances from intercortical bone surface to root surface, and distances between the roots of premolars and molars were also measured to determine the acceptable length and diameter of the miniscrew for anchorage during orthodontic treatment. Methods: Three-dimensional computed tomographic images were reconstructed for 10 patients. Cortical bone thicknesses were measured in the buccal and lingual regions mesial and distal to the first molar, distal to the second molar, and in the premaxillary region at 2 different levels. Differences in cortical bone thickness at 3 angles (30°, 45°, and 90°) were also assessed. Distances of the intercortical bone surface to the root surface and the root proximity were also measured at the above areas. Results: Significantly less cortical bone thickness was observed at the buccal region distal to the second molar compared with other areas in the maxilla. Significantly more cortical bone was observed on the lingual side of the second molar compared with the buccal side. In the mandible, mesial and distal to the second molar, significantly more cortical bone was observed compared with the maxilla. Furthermore, significantly more cortical bone was observed at the anterior nasal spine level than at Point A in the premaxillary region. Cortical bone thickness resulted in approximately 1.5 times as much at 30° compared with 90° Significantly more distance from the intercortical bone surface to the root surface was observed at the lingual region than at the buccal region mesial to the first molar. At the distal of the first mandibular molar, significantly more distance was observed compared to that in the mesial, and also compared with both distal and mesial in the maxillary first molar. There was significantly more distance in root proximity in the mesial area than in distal area at the first molar, and significantly more distance was observed at the occlusal level than at the apical level. Conclusions: These data show that the safest location for placing miniscrews might be mesial or distal to the first molar, and an acceptable size of the miniscrew is less than approximately 1.5 mm in diameter and approximately 6 to 8 mm in length. © 2006 American Association of Orthodontists.

DOI： 10.1016/j.ajodo.2006.02.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Immunohistochemistry for brain-derived neurotrophic factor (BDNF) was performed on the rat trigeminal ganglion (TG). The immunoreactivity (IR) was detected in 46% of TG neurons. These neurons were mostly small- or medium-sized (range, 149.7-1246.3 mu m(2); mean +/- SD = 373.4 +/- 151.6 mu m(2)). A double immunofluorescence method also revealed that 54% of BDNF-immunoreactive (IR) neurons were immunoreactive for calcitonin-gene related peptide. in addition, 93% of BDNF-IR TG neurons contained vanilloid receptor subtype 1. However, the co-expression of BDNF and vanilloid receptor 1-like receptor was very rare (less than 1%). In the trigeminal sensory nuclei, laminae II of the medullary dorsal horn was abundant in presumed BDNF-IR axon terminals. Such profiles were also detected in the dorsolateral part of the subnucleus oralis. The retrograde tracing and immunohistochemical methods demonstrated that BDNF-IR was common among cutaneous TG neurons (47%) but not tooth pulp TG neurons (13%). The present study indicates that BDNF-IR TG neurons have unmyelinated axons and project to the superficial medullary dorsal horn. It is likely that BDNF-containing neurons in both the trigeminal and spinal sensory systems have similarities in morphology and function. However, the content of BDNF in TG neurons probably depends on their peripheral targets. BDNF seems to convey nociceptive cutaneous input to the trigeminal sensory nuclei. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2006.01.027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Osteocytes are surrounded by hard bone matrix. Therefore, it has not previously been possible to demonstrate the real architecture of the osteocyte network in bone. We previously reported that it is possible to observe osteocytes in bone by labeling the cells with fluorescence and using confocal laser scanning (CLS) microscopy. In this study, we for the first time conducted an extensive analysis of the morphology and morphometry of the three-dimensional (3D) osteocyte structure using three-dimensionally reconstructed fluorescent images. Sixteen-day-old embryonic chick calvariae were stained with fluorescently labeled phalloidin and observed using a confocal laser scanning microscope. Morphometry of osteocytes in the calvaria was analyzed using extensive three-dimensional reconstructing software IMARIS, process length measuring software NEURON TRACER and cell surface area-/cell volume-analyzing software SURPASS. From the IMARIS-derived images, we found that the average of 10 osteocytes is 52.7 &PLUSMN; 5.7 processes, and the point-to-point distance between centers of the osteocytes was 24.1 &PLUSMN; 2.8 &mu; m. In addition, we could calculate that each osteocyte spans an average of 4180 &PLUSMN; 673 &mu; m(3) of bone volume. NEURON TRACER showed that the length of osteocyte processes was 0.26 &PLUSMN; 0.02 &mu; m per 1 &mu; m(3) bone compartment. In addition, SURPASS indicated that the surface area of osteocytes was 0.36 &PLUSMN; 0.03 &mu; m(2) per 1 &mu; m(3) bone compartment and that the volume ratio of osteocyte cell body to bone compartment was 9.42% &PLUSMN; 1.18%. Together, the average total length of the processes, the average surface area, and the average volume of one osteocyte were 1070 &PLUSMN; 145 &mu; m, 1509 &PLUSMN; 113 &mu; m(2), and 394 &PLUSMN; 49 &mu; m(3), respectively. It is possible to reconstruct the real architecture of the osteocyte network and obtain morphometric data from fluorescently labeled osteocytes in chick calvaria. &COPY; 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2004.10.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BONE & MINERAL RES  

We evaluated the detailed expression patterns of Runx1 and Sox9 in various types of bone formation, and determined whether Runx1 expression was affected by Runx2 deficiency and Runx2 expression by Runx1 deficiency. Our results indicate that both Runx1 and Sox9 are intensely expressed in the future osteogenic cell compartment and in cartilage. The pattern of Runx1 and Sox9 expression suggests that both genes could potentially be involved in incipient intramembranous bone formation during craniofacial development.

DOI： 10.1359/JBMR.04081

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BONE & MINERAL RES  

Immunofluorescence staining of actin-binding proteins in osteoblasts and osteocytes was performed. alpha-Actinin, myosin, and tropomyosin showed similar organization in both osteoblastic stress fibers and osteocyte processes. However, fimbrin, villin, filamin, and spectrin showed dramatic differences in distribution between osteoblasts and osteocytes. This study suggested that terminal differentiation of osteoblasts to osteocytes is accompanied by highly dramatic changes in the distribution of actin-binding proteins.
Introduction: We previously reported that osteocyte shape is dependent on actin filaments. To analyze the terminal differentiation from osteoblasts to osteocytes, we investigated the actin-binding proteins, which are the control elements in the dynamic organization of the actin cytoskeleton.
Materials and Methods: We used primary chick osteocytes and osteoblasts, the phenotypes of which were confirmed by use of OB7.3, a chick osteocyte-specific monoclonal antibody and by detection of alkaline phosphatase activity, respectively, Immunofluorescence staining was performed for visualizing actin-binding proteins. Furthermore, we applied shear stress at 12 dyns/cm(2) to the cells and compared the changes in fimbrin distribution.
Results: Immunofluorescence staining of fimbrin and alpha-actinin showed their presence in the processes of osteocytes, with especially strong signals of fimbrin at the sites of divarication of the processes. Anti-villin was reactive with the osteocyte cytoplasm but not with the processes. Interestingly, anti-villin immunoreactivity was much stronger in osteocytes than in osteoblasts. Filamin was localized along the stress fibers of osteoblasts but was seen only in those in the proximal base of osteocyte processes. Myosin and tropomyosin were found to have a similar pattern in both stress fibers of osteoblasts and osteocyte processes. The difference in the distribution of anti-spectrin staining was highly dramatic. Osteoblasts immunostained with anti-spectrin showed punctate signals on their cytoplasmic membranes, whereas anti-spectrin in osteocytes detected a filamentous organization; and the spectrin was totally colocalized with actin from the distal portion of the cytoplasmic processes to the cell center. In osteoblasts, shear stress induced recruitment of fimbrin to the end of stress fibers. However, fimbrin in the osteocyte processes did not change its localization.
Conclusion: We found that terminal differentiation of osteoblasts to osteocytes was accompanied by highly dramatic changes in the distribution of actin-binding proteins, changes of which may affect cellular function.

DOI： 10.1359/JBMR.040128

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Language：Japanese   Publisher：岡山歯学会  

平成14年2月より,矯正科において毎週水曜日の診療時間を2時間延長した.診療時間延長開始以降1年間の矯正科新患数は316名で,平成13年度は12年度とほぼ同数であったが,14年度は13年度に比較して11%増加した.14年度の矯正治療開始患者数は201名で,平成12年度は160名,13年度は177名であり,前年度に比較して14%増加した.診療時間延長は患者サービスに多大な貢献をしたことが示された

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications Inc.  

Connective tissue growth factor (CTGF), which is encoded by an immediate early gene and a member of the CCN family, has been shown to be expressed in osteoblasts, fibroblasts, and chondrocytes. Although CTGF is expressed in bone and cartilage tissues, we tested the hypothesis that CTGF is regulated in mechanotransduction. In the alveolar bone during experimental tooth movement, CTGF mRNA was expressed in osteoblasts and in osteocytes localized around the periodontal ligament under control conditions. Interestingly, 12 hrs after the start of experimental tooth movement, the expression of CTGF mRNA in osteocytes and osteoblasts became more intense around the periodontal ligament, and the intense expression of CTGF extended to osteocytes situated deep in alveolar bone matrix apart from periodontal ligament in both tension and compression sides. Our present findings indicate that CTGF could play a role in regulation of osteocyte function during the mechanical stimulation of bone.

DOI： 10.1177/00220345010800021201

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Osteocytes are the most numerous cells in bone, embedded within the mineralized bone matrix. Their slender cytoplasmic processes form a complex intercellular network. In addition, these processes are thought to be important structures in the response to mechanical stress. This study provides an extensive analysis of the three-dimensional structure of the osteocyte and its processes in 16-day-old embryonic chick calvariae, based on nondestructive subsurface histotomography using both confocal laser scanning (CLS) microscopy and differential interference contrast (DIC) microscopy. OB7.3, a chicken osteocyte-specific monoclonal antibody, and Texas Red-X-conjugated phalloidin were used to confirm the osteocyte phenotype and to identify whole cells in the calvariae, respectively. Serial CLS images revealed morphological changes in bone cells up to 20 μm in depth. Osteocytes had widely spread their processes into the osteoblast layer, and we found for the first time that some of these processes had elongated to the vascular-facing surface of the osteoblast layer. Furthermore, stereotype images reconstructed from CLS images could show the three-dimensional distribution of these processes. Using the stereopair image, we could evaluate the frequency of processes between osteocytes and osteoblasts. Complementation of DIC microscopy revealed canaliculi and lacunae with high contrast. The distributional pattern of canaliculi generally coincided with that of the osteocyte processes. We consider that the combination method of CLS microscopy and DIC microscopy using a laser scanning microscope is a very useful new technical approach for investigating osteocytes in bone. Copyright © 2001 Elsevier Science Inc.

DOI： 10.1016/S8756-3282(00)00421-X

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1359/jbmr.1998.13.10.1555

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We have recently demonstrated that a rise in the extracellular divalent cation concentration induces a rapid elevation of cytosolic calcium in chick osteocytes. Here, we demonstrate that cytosolic calcium elevation that occurs in osteocytes on exposure to elevated extracellular calcium is independent of membrane voltage and is insensitive to modulation by organic calcium channel modulators, namely, BAY K 8644, nicardipine, and nifedipine. However, the calcium elevation was sensitive to modulation by an intracellular calcium antagonist, TMB-8, suggesting that the cytosolic calcium elevation was due to mobilization of this cation from an intracellular store. © 1995 Academic Press, Inc.

DOI： 10.1006/bbrc.1995.2024

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag  

Transforming growth factor-β1 (TGF-β1) has biological functions in various types of cells. However, its roles in the regulation of osteoclast formation and function are unclear. To examine them, we employed a culture system in which unfractionated cells obtained from long bones of 13-day-old mice were cultured on a dentine slice. We found that TGF-β1 has a potent inhibitory effect on osteoclastic bone resorption at a dose of 0.2-5 ng/ml. By electron microscopy the osteoclasts appeared to have fewer mitochondria and ruffled borders than those in control cultures. But in the presence of 1,25-dihydroxyvitamin D3, [1,25-(OH)2D3], TGF-β1 at a dose of 0.2-1 ng/ml stimulated the formation of osteoclasts from unfractionated bone cell cultures in which preexistent osteoclasts had degenerated. Thus, using stromal cell-free he-mopoietic blast cells, we examined the direct action of TGF-β1 on osteoclast precursors. Although TGF-β1 inhibited tartrate-resistant acid phosphatase-positive (TRAP) multinucleate cell (MNC) formation induced by 1,25-(OH)2D3, the conditioned medium (CM) of TGF-β1-treated MC3T3-E1 cells stimulated such formation. These results suggest that TGF-β1 inhibits osteoclastic bone resorption but stimulates osteoclast formation via the action of factor(s) produced by TGF-β1-treated osteoblasts in the presence of 1,25-(OH)2D3. © 1995 Springer-Verlag.

DOI： 10.1007/BF01771798

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Though it is proposed that osteocytes have several functions in bone metabolism, only limited definite information including results of calcium regulation has been forthcoming. We demonstrate here for the first time that the concentration of divalent cations, such as calcium, nickel and cadmium, directly regulates the cytosolic calcium concentration in osteocytes. © 1994 Academic Press. All rights reserved.

DOI： 10.1006/bbrc.1994.2490

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The secretion mechanisms of cathepsin L from osteoclasts in the process of bone resorption were investigated. The increases in bone pit numbers formed take place by PTH addition in parallel with the increases of cathepsin L and/or L-like proteinase activities in the culture medium of bone cells, and these were suppressed by the addition ofcalcitonin. The Z-Phe-Arg-MCA hydrolysing activity increased in the medium through the effect of PTH is considered to be a kind of procathepsin L by Western blotting analysis, and was suppressed by calcitonin addition. Furthermore, monensin inhibited not only the PTH-induced pit formation, but also cysteine proteinase activity in osteoclasts. Therefore, the procathepsin L excreted might be transferred from endothelial reticulum via Golgi and/or via lysosomes. © 1994.

DOI： 10.1016/0014-5793(94)80522-9

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Osteoclasts are multinucleate giant cells playing key roles in bone resorption. These cells solubilize mineralized bone matrix by means of acid and protease action
however, the precise mechanism of this process is not well known. Recently, we succeeded in the isolation of pure osteoclasts from rabbit bones and constructed a cDNA library. Using a differential screening procedure, two genes expressed predominantly in osteoclasts compared with spleen cells were isolated (Tezuka, K., Sato, T., Kamioka, H., Nijweide, P. J., Tanaka, K., Matsuo, T., Ohta, M., Kurihara, N., Hakeda, Y., and Kumegawa, M. (1992) Biochem. Biophys. Res. Commun. 186, 911-917). One of them, OC-2, was found to encode a possible cysteine proteinase structurally related to cathepsins L and S. By in situ hybridization, OC-2 was confirmed to be expressed in osteoclasts in vivo. By Northern blot analysis, OC-2 was highly and preferentially expressed in osteoclasts compared with other tissues such as kidney, liver, spleen, and lung. The predominant expression of OC-2 in osteoclasts may suggest that OC-2 encodes a protein, possibly a cysteine proteinase, that plays an important role in osteoclastic bone resorption.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

The proteinase responsible for bone collagen degradation in osteo-resorption was examined. The bone pit formation induced by parathyroid hormone (PTH) was markedly suppressed by leupeptin, E-64 and cystatin A, while no inhibition was observed by CA-074, a specific inhibitor of cathepsin B. Pig leucocyte cysteine proteinase inhibitor (PLCPI), a specific inhibitor of cathepsin L, and chymostatin, a selective inhibitor of cathepsin L, completely inhibited the pit formation. Cathepsin L activity in osteoclasts was much higher than the other cathepsin activities. Serum calcium in rats placed on a low calcium diet was decreased by treatment of E-64 or cystatin A, but not by CA-074. These findings suggest that cathepsin L is the main proteinase responsible for bone collagen degradation. © 1993.

DOI： 10.1016/0014-5793(93)80118-E

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Bone remodeling is a complex process coupling bone formation and resorption. Osteoblasts, the bone-forming cells, are known to produce various bone matrix proteins and cytokines
however, little is known about protein factors produced by osteoclasts or bone-resorbing cells. A method utilizing the high affinity of osteoclasts for tissue culture dishes was developed to isolate a large number of pure osteoclasts from rabbit long bones. A cDNA library was then constructed from these isolated osteoclasts, and differential cDNA screening was performed between osteoclasts and spleen cells. Two clones representing osteoclast-specific clones, named OC-1 and OC-2, were isolated. By Northern blot analysis, OC-1 was expressed in osteoclasts and in kidneys, whereas OC-2 was specific for osteoclasts. OC-1 was found to encode osteopontin from its nucleotide sequence, and therefore, osteopontin may have other functions for osteoclastic bone resorption besides osteoclast attachment to bone. © 1992.

DOI： 10.1016/0006-291X(92)90832-6

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J-GLOBAL

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Authorship：Lead author   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：(NPO)日本顎変形症学会  

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Authorship：Lead author   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Authorship：Lead author   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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Language：Japanese   Publisher：中・四国矯正歯科学会  

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Language：Japanese   Publisher：中・四国矯正歯科学会  

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Language：Japanese   Publisher：中・四国矯正歯科学会  

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Most bones are anisotropically loaded and seem to be adapted to the anisotropic stress or strain field by changing the anisotropy in their microstructure. Osteocyte (OCY) is believed to play an important role as a mechanosensor and regulator of modeling and/or remodeling orchestrating osteoblast and osteoclast activity to make bone suitable to resist the mechanical environment. In general, osteocytes sense magnitude of stress (strain) applied upon the bone and then work as a trigger to change bone mass to adjust bone&#039;s mechanical function to the stress field. This structural optimization is an important aspect of the bone functional adaptation; another inevitable optimization might be achieved through the change in intrinsic material anisotropy including the preferential c-axis orientation of biological apatite (BAp) crystal. To achieve this adaptation through material anisotropy, osteocyte needs to be a mechanosensor which can detect anisotropic stress field. In the present study, osteocyte lacunae and canaliculi in the mid-diaphysis and the distal part of the rat femur were stained by a fluorescein dye for visualization and analysis. The mid-diaphysis shows greater degree of the preferential c-axis orientation of BAp crystal than the distal part in relation to the magnitude of uni-axial stress field. It was found that the osteocytes in long bone preferentially align along the bone long axis and the degree of alignment is greater in the mid-diaphysis than in the distal region, which seems to be effective for the sensation of the site-dependent specific stress field applied on the long bone. © (2014) Trans Tech Publications, Switzerland.

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

Osteocytes play a significant role in the regulation of bone mass.Osteocyte processes are thought to sense the flow of interstitial fluid that is driven through the osteocyte canaliculi by mechanical stimuli forced on the bone,but how this flow elicits a cellular response is unknown.Recent theoretical models assume that osteocyte canaliculi contain ultrastructural features that amplify the fluid flow-derived mechanical signal.However,the calcified bone matrix has considerably hampered studies on the osteocyte process within its canaliculus.Therefore,we applied UHVEM tomography at 2 MeV to reconstruct unique three-dimensional images of osteocyte canaliculi in 1 μm sections of human bone.A realistic 3-dimensional image-based model of a single canaliculus was constructed,and the fluid dynamics of a Newtonian fluid flow within the canaliculus was analyzed.We created virtual 2.2 nm-thickness sections through a osteocyte canaliculus.The canalicular wall had a highly irregular surface,and contained protruding structures similar in size and shape to collagen fibrils.We also found that the microscopic surface roughness of the canalicular wall strongly influenced the fluid flow profiles,whereby highly inhomogeneous flow patterns emerged.Based on these observations,new and realistic models can be developed that will significantly enhance our understanding of the process of mechanotransduction in bone.

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

It is believed osteocytes embedded in mineralized bone matrix play an important role as a mechanosensor cell in bone remodeling. Osteocyte processes are thought to be stimulated by the interstitial fluid flow in canaliculi. In order to understand the mechanical behavior of the osteocyte process in the interstitial fluid, a mathematical model of osteocyte cell membrane was developed. Together with the lattice Boltzmann method to calculate the fluid velocity field, we simulated the deformation of a single osteocyte process due to interstitial fluid flow. The fluid flow induced the tensile strain at the upstream region and the compressive strain at the downstream region of the osteocyte cell membrane. In addition, inhomogeneous flow patterns produced by the projection on the wall of flow channel deformed the osteocyte process in the direction perpendicular to its longitudinal direction. These results show the importance of the effect of geometric complexity of the canaliculus on the flow profiles that drive cellular mechanotransduction.

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Language：Japanese  

It is suggested that osteocytes play an important role in bone metabolism, especially in their regulation by mechanical stimuli. However, it has been still discussed how the osteocytes were activated by mechanical stimuli. Recently, theories based on fluid flow-induced shear stress stimulation around osteocytes in bone have appeared with the most prominence. In addition, we would like to introduce several theories to mechanically stimulate osteocyte, such as deformation, strain amplification by radial hoop strains, flow induced integrin mediated signaling, and primary cilia mediated signaling. To validate the availability of these theories, it is important to obtain 3-dimensional morphometrical data of osteocytes as well as their interaction with pericellular matrix.

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Other Link： http://orcid.org/0000-0002-4419-9643

Language：Japanese   Publisher：(株)医薬ジャーナル社  

多くの器官、組織、細胞は少なからずの影響を機械的刺激によって受ける。一見、静的にみえる骨も機械的刺激に応答して経時的にマクロな変化を遂げる。その結果は、骨に存在する細胞群が引き起こすミクロな変化の集積である。このような変化を生じるための機械的刺激センサーとして、骨細胞が注目されている。しかしながら、骨細胞は骨基質に囲まれている特異な環境のために、実際にどのようにして機械的刺激を感知しているのかは明らかではない。そこで、近年、生体工学的な試みにより、さまざまな骨細胞の機械的刺激の受容機構が提案されてきた。この総説では、これらの説が生まれた経緯を簡単に紹介するとともに、骨細胞およびその周囲骨基質の3次元構造をナノレベルで追求することの重要性について解説していきたい。(著者抄録)

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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CiNii Article

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It is proposed that osteocytes embedded in the bone matrix have the ability to sense deformation and/or damage to the matrix and to feed these mechanical signals back to the adaptive bone remodeling process. When osteoblasts differentiate into osteocytes during the bone formation process, they change their morphology to a stellate form with many slender processes. This characteristic cell shape may underlie the differences in mechanosensitivity between the cell processes and cell body. To elucidate the mechanism of cellular response to mechanical stimulus in osteocytes, we investigated the site-dependent response to quantitatively controlled local mechanical stimulus in single osteocytes isolated from chick embryos, using the technique of calcium imaging. A mechanical stimulus was applied to a single osteocyte using a glass microneedle targeting a microparticle adhered to the cell membrane by modification with a monoclonal antibody OB7.3. Application of the local deformation induced calcium transients in the vicinity of the stimulated point and caused diffusive wave propagation of the calcium transient to the entire intracellular region. The rate of cell response to the stimulus was higher when applied to the cell processes than when applied to the cell body. In addition, a large deformation was necessary at the cell body to induce calcium transients, whereas a relatively small deformation was sufficient at the cell processes, suggesting that the mechanosensitivity of the cell processes was higher than that of the cell body. These results suggest that the cell shape with slender processes contributes to the site-dependent mechanosensitivity in osteocytes.

DOI： 10.1016/j.jbiomech.2009.04.034

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Language：English   Publisher：SPRINGER  

It is proposed that osteocytes embedded in mineralized bone matrix play a role in mechanosensory system during bone remodeling for mechanical adaptation. Various experimental and computer simulation approaches have revealed that the osteocytes sense the mechanical stimulus such as deformation/force and microdamages in bone matrix generated by mechanical loading, and also still have continued discussion. In this study, for interest to morphological character of osteocytes, we investigated site-dependence of mechanosensitivity in the osteocytes through observation of calcium response to applied local deformation. We developed a quantitative method using a microneedle and microparticles to apply local deformation to an isolated chick osteocyte, and analyzed intracellular calcium dynamics to the applied deformation. As the results, the applied local deformation induced calcium response at the vicinity of the stimulated point and caused its diffusive wave propagation to whole intracellular region in a single osteocyte. Furthermore, the large deformation was necessary at the cell body to induce calcium response, while a relatively small deformation was sufficient at the cell process, suggesting that the mechanosensitivity at the cell process was higher than that at the cell body. These results suggest that the cell shape with processes contributes to the mechanism of cellular response to mechanical stimulus in osteocytes, and that the site-dependent mechanosensitivity depends on cell shape in a single osteocyte.

DOI： 10.1007/978-3-540-92841-6_498

Web of Science

Scopus

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Publisher：医歯薬出版  

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Authorship：Lead author  

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DOI： 10.11239/jsmbe.44.484

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Event date： 2021.9.10 - 2021.9.11

Language：Japanese  

Event date： 2021.9.4

Language：Japanese  

Venue：岡山市   Country：Japan  

Event date： 2021.7.1 - 2021.7.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2021.6.26

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：サン・ピーチOKAYAMA   Country：Japan  

Event date： 2021.3.26 - 2021.3.27

Language：Japanese  

Country：Japan  

Event date： 2020.10.9 - 2020.10.11

Language：Japanese  

Country：Japan  

Event date： 2020.10.4 - 2020.10.7

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2020.10.4 - 2020.10.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.5.23 - 2020.5.24

Language：Japanese  

Country：Japan  

Event date： 2020.5

Language：Japanese  

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Event date： 2020.5

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Event date： 2020.5

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Event date： 2019.12

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Event date： 2019.11

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Event date： 2019.11

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Event date： 2019.5

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Event date： 2019.5

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Event date： 2019.5

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Event date： 2018.10

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Event date： 2018.10

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Event date： 2018.10

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Event date： 2017.7

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Event date： 2017

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INTRODUCTION: In recent years, patients with orthognathic surgery in middle-aged and elderly people have come to be a more frequent occurrence. Breast cancer is the most frequently diagnosed cancer in woman worldwide, and its prevalence rate is steadily increasing. PRESENTATION OF CASE: We report a case of a 47-year-old Japanese woman in whom left-side breast cancer (Stage 1) was unexpectedly found just before orthognathic surgery in April 2012. Breast-conserving surgery was performed (estrogen receptor+, progesterone receptor+, HER2 -, surgical margin+, sentinel lymph node +) that May. From June to August docetaxel (75mg/m2) and cyclophosphamide (600mg/m2) were administrated four times every 21days and thereafter radiotherapy (total 60Gy) was completed. The cancer surgeon declared the prognosis good and the patient had a strong desire to undergo orthognathic surgery, so in November we performed a bimaxillary osteotomy, and administration of tamoxifen began 6 weeks after the osteotomy. DISCUSSION: There are breast cancer cases in which the prognosis is sufficiently good for a planned orthognathic surgery to proceed. Good communication among surgeons and the patient is important. CONCLUSION: We experienced a case in which breast cancer was found just before the orthognathic surgery; we performed a bimaxillary osteotomy, including follow-up tamoxifen administration, during breast cancer treatment.

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Event date： 2010.9

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Event date： 2010.1

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Event date： 2006.6.30

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Event date： 2000.10.25

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Event date： 2000.8

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Event date： 1992.8

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Presentation type：Poster presentation  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

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