担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Royal Society of Chemistry (RSC)  

<p>Bone formation<italic>in vivo</italic>occurs in alkaline environment, which determines the optimal p<italic>K</italic>_aof phosphatases, the optimal amount of calcium for mineral precipitation, and the spherical shape of initial minerals. Manipulation of environmental pH for<italic>in vitro</italic>synthesis of bone-like tissue, showed a markedly rapid mineralization with nanofragments and alkaline milieu.</p>

DOI： 10.1039/c8tb01544a

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

Biomineralization involves complex processes and interactions between organic and inorganic matters, which are controlled in part by the cells. The objectives of this study were, first, to perform a systematic and ultrastructural investigation of the initial mineral formation during secondary ossification center of mouse femur based on material science and biology viewpoint, and then develop novel biomaterials for mineralization based on the in vivo findings. First, we identified the very initial mineral deposition at postnatal day 5 (P5) at the medial side of femur epiphysis by nanocomputed tomography. Initial minerals were found in the surroundings of hypertrophic chondrocytes. Interestingly, histological and immunohistochemical analyses showed that initial mineralization until P6 was based on chondrocyte activity only, i.e., it occurred in the absence of osteoblasts. Moreover, electron microscopy-based ultrastructural analysis showed that cell-secreted matrix vesicles were absent in the early steps of osteoblast-independent endochondral ossification. Instead, chondrocyte membrane nanofragments were found in the fibrous matrix surrounding the hypertrophic chondrocytes. EDS analysis and electron diffraction study indicated that cell membrane nanofragments were not mineralized material, and could be the nucleation site for the newly formed calcospherites. The phospholipids in the cell membrane nanofragments could be a source of phosphate for subsequent calcium phosphate formation, which initially was amorphous, and later transformed into apatite crystals. Finally, artificial cell nanofragments were synthesized from ATDC5 chondrogenic cells, and in vitro assays showed that these nanofragments could promote mineral formation. Taken together, these results indicated that cell membrane nanofragments were the nucleation site for mineral formation, and could potentially be used as material for manipulation of biomineralization.

DOI： 10.1021/acsbiomaterials.7b00962

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.actbio.2017.05.014

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-3-associated chondrogenesis, and suggest that the FA/TGF-3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells. (c) 2015 American Society for Bone and Mineral Research.

DOI： 10.1002/jbmr.2502

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbmr.2502

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

A significant number of natural compounds have been shown to regulate the behavior of the cells, in collaboration with cellular proteins. CCN2/connective tissue growth factor (CTGF) has been reported to have essential roles in cartilage development, chondrocyte proliferation and differentiation as well as regulation of the extracellular matrix metabolism. Previous studies demonstrated the capability of CCN2 to regenerate surgical defects in articular cartilage of rat knee. Also, transgenic mice over-expressing cartilage-specific CCN2 were shown to be more resistant to aging-related cartilage degradation. We hypothesized that small molecules that induce CCN2 in chondrocytes could be novel candidates to increase the resistance to aging-related cartilage degradation, or even to correct cartilage degenerative changes incurred in OA. Therefore, this study screened a compound library and identified the beta-carboline alkaloid harmine as a novel inducer of CCN2 in human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes. Harmine increased the expression of the cartilage markers aggrecan and COL2 alpha 1, as well as that of the master regulator of chondrogenesis, SOX-9. Moreover, harmine notably induced chondrogenesis of prechondrocytic ATDC5 cells in micromass cultures. The chondroprotective effect of harmine was investigated under inflammatory condition by stimulation with TNF alpha, and harmine was shown to ameliorate TNF alpha-induced decrease in expression of CCN2 and cartilage markers. These findings uncover novel chondrogenic effects of harmine and indicate harmine as a potential drug for prevention and/or repair of cartilage degradation. (C) 2012 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.biochi.2012.10.016

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/β-Tricalcium phosphate (E-rhBMP-2/β-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/β-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/β-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/β-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.

DOI： 10.3390/ijms25126648

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Controlling stem cell behavior at the material interface is crucial for the development of novel technologies in stem cell biology and regenerative medicine. The composition and presentation of bio-factors on a surface strongly influence the activity of stem cells. Herein, we designed an electroactive surface that mimics the initial process of trabecular bone formation, by immobilizing chondrocyte-derived plasma membrane nanofragments (PMNFs) on its surface for rapid mineralization within 2 days. Moreover, the electroactive surface was based on the conducting polymer polypyrrole (PPy), which enabled dynamic control of the presentation of PMNFs on the surface via electrochemical redox switching, further resulting in the formation of bone minerals with different morphologies. Furthermore, bone minerals with contrasting surface morphologies had differential effects on the differentiation of human bone marrow-derived stem cells (hBMSCs) cultured on the surface. Together, this electroactive surface showed multifunctional characteristics, not only allowing dynamic control of PMNF presentation but also promoting the formation of bone minerals with different morphologies within 2 days. This electroactive substrate could be valuable for more precise control of stem cell growth and differentiation, and further development of more suitable microenvironments containing bone apatite for housing a bone marrow stem cell niche, such as biochips/bone-on-chips.

DOI： 10.1080/14686996.2023.2183710

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担当区分：最終著者,　責任著者  

DOI： 10.1109/biosensors58001.2023.10281047

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/admt.202201651

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/admt.202201651

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1039/d2tb02351b

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rb/rbac088

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担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/adbi.202200076

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/adbi.202200076

掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1109/marss55884.2022.9870251

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/adbi.202101315

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/adbi.202101315

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.colsurfb.2021.112283

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms222312823

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1039/d1tb00919b

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1039/d1ma00273b

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2186/jpr.jpr_d_20_00226

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ma14010208

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ma13225099

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms21218103

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms21217967

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms21197028

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掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Current stem cell-based techniques for bone-like tissue synthesis require at least two to three weeks. Therefore, novel techniques to promote rapid 3D bone-like tissue synthesis in vitro are still required. In this study, we explored the concept of using cell nanofragments as a substrate material to promote rapid bone formation in vitro. The methods for cell nanofragment fabrication were ultrasonication (30 s and 3 min), non-ionic detergent (triton 0.1% and 1%), or freeze-dried powder. The results showed that ultrasonication for 3 min allowed the fabrication of homogeneous nanofragments of less than 150 nm in length, which mineralized surprisingly in just one day, faster than the fragments obtained from all other methods. Further optimization of culture conditions indicated that a concentration of 10 mM or 100 mM of β-glycerophosphate enhanced, whereas fetal bovine serum (FBS) inhibited in a concentration-dependent manner, the mineralization of the cell nanofragments. Finally, a 3D collagen-cell nanofragment-mineral complex mimicking a bone-like structure was generated in just two days by combining the cell nanofragments in collagen gel. In conclusion, sonication for three min could be applied as a novel method to fabricate cell nanofragments of less than 150 nm in length, which can be used as a material for in vitro bone tissue engineering.

DOI： 10.3390/ijms21155327

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/admi.201902089

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/admi.201902089

掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/joor.12913

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/08869634.2018.1488652

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Stem cells have essential applications in in vitro tissue engineering or regenerative medicine. However, there is still a need to understand more deeply the mechanisms of stem cell differentiation and to optimize the methods to control stem cell function. In this study, we first investigated the activity of DNA methyltransferases (DNMTs) during chondrogenic differentiation of human bone marrow-derived mesenchymal stem/progenitor cells (hBMSCs) and found that DNMT3A and DNMT3B were markedly upregulated during hBMSC chondrogenic differentiation. In an attempt to understand the effect of DNMT3A and DNMT3B on the chondrogenic differentiation of hBMSCs, we transiently transfected the cells with expression vectors for the two enzymes. Interestingly, DNMT3A overexpression strongly enhanced the chondrogenesis of hBMSCs, by increasing the gene expression of the mature chondrocyte marker, collagen type II, more than 200-fold. Analysis of the methylation condition in the cells revealed that DNMT3A and DNMT3B methylated the promoter sequence of early stem cell markers, NANOG and POU5F1(OCT-4). Conversely, the suppression of chondrogenic differentiation and the increase in stem cell markers of hBMSCs were obtained by chemical stimulation with the demethylating agent, 5-azacitidine. Loss-of-function assays with siRNAs targeting DNMT3A also significantly suppressed the chondrogenic differentiation of hBMSCs. Together, these results not only show the critical roles of DNMTs in regulating the chondrogenic differentiation of hBMSCs, but also suggest that manipulation of DNMT activity can be important tools to enhance the differentiation of hBMSCs towards chondrogenesis for potential application in cartilage tissue engineering or cartilage regeneration.

DOI： 10.1159/000502885

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掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

DOI： 10.3390/ijms20194739

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background Recent advances in tissue regeneration approaches including 3D organoids, were based on various 3D organogenesis models. However, 3D models are generally technique-sensitive and time-consuming. Thus, we utilized an existing model of submandibular salivary gland (SMG) to modify a simple and highly reproducible in vitro 3D culture model of primary SMG cells self-organization into a well-developed cell spheroid inside Matrigel substrate. We used this model to observe the collective multicellular behavior during spheroid formation. Further, we applied various quantitative approaches including real-time live imaging and immune histochemical image analysis to dissect the cellular dynamics during tissue patterning. Results On a time-scale of hours, we observed marked size and shape transformations in the developed 3D spheroid which resulted in a spatially-controlled growth differential from the canter to the periphery of the formed aggregates. Moreover, we investigated the effect of fibronectin (FN) on SMG cells self-organization using our simplified culture model. Interestingly, we discovered a novel role of FN in inducing duct-like elongation during initial stages of SMG bud formation. Conclusion This in vitro model provides an excellent tool for analyzing the intercellular dynamics during early SMG tissue development as well as revealing a novel role of FN in SMG ductal expansion.

DOI： 10.1002/dvdy.78

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

OBJECTIVE: To assess whether a thermal annealing with a monoclinic zirconia (mZrO2) nanoparticle coating can improve the reliability of sandblasted yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and maintain its mechanical strength. METHODS: Commercially available Y-TZP (Lava Frame, 3M Dental Products) disks were sintered and surface-treated as follows: AS (as sintered, with no treatment); SB (sandblasting); SB-TA (sandblasting followed by thermal annealing at 1000 °C); and SB-mZr-TA (sandblasting followed by thermal annealing at 1000 °C with the mZrO2 nanoparticle coating). The mZrO2 nanoparticles of 21 nm in size were prepared by a hydrothermal method, and coated onto Y-TZP sintered disks as a 5 g/L ethanol dispersion. Biaxial flexural strength (S) was measured using the piston-on-three-ball test, and reliability was evaluated by the Weibull modulus (m). RESULTS: Biaxial flexural tests showed a significant increase in the strength of Group SB (SSB = 1445 ± 191 MPa) compared with Group AS (SAS = 1071 ± 112 MPa). The thermal annealing improved the reliabilities of the sandblasted Y-TZP (mSB-TA = 20.14 and mSB-mZr-TA = 21.33), as compared with Group SB (mSB = 7.77). However, the conventional thermal annealing without the mZrO2 coating caused a significant decrease in the strength of sandblasted Y-TZP (SSB-TA = 1273 ± 65 MPa). Importantly, the mZrO2 coating prevented the decrease in the strength caused by conventional thermal annealing (SSB-mZr-TA = 1379 ± 65 MPa). SIGNIFICANCE: The thermal annealing with the mZrO2 nanoparticle coating can improve the reliability of sandblasted Y-TZP and maintain its mechanical strength, which would otherwise be decreased by the conventional annealing process.

DOI： 10.1016/j.dental.2019.04.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

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. (c) 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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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbm.a.36618

掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society ({ACS})  

DOI： 10.1021/acsabm.9b00014

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

A deeper understanding of the detailed mechanism of in vivo tissue healing is necessary for the development of novel regenerative therapies. Among several external factors, environmental pH is one of the crucial parameters that greatly affects enzyme activity and cellular biochemical reactions involving tissue repair and homeostasis. In this study, in order to analyze the microenvironmental conditions during bone healing, we first measured the pH in vivo at the bone healing site using a high-resolution fiber optic pH microsensor directly in femur defects and tooth extraction sockets. The pH was shown to decrease from physiological 7.4 to 6.8 during the initial two days of healing (inflammatory phase). In the same initial stages of the inflammatory phase of the bone healing process, mesenchymal stem cells (MSCs) are known to migrate to the healing site to contribute to tissue repair. Therefore, we investigated the effect of a short-term acidic (pH 6.8) pre-treatment on the stemness of bone marrow-derived MSCs (BMSCs). Interestingly, the results showed that pre-treatment of BMSCs with acidic pH enhances the expression of stem cell markers (OCT-4, NANOG, SSEA-4), as well as cell viability and proliferation. On the other hand, acidic pH decreased BMSC migration ability. These results indicate that acidic pH during the initial stages of bone healing is important to enhance the stem cell properties of BMSCs. These findings may enable the development of novel methods for optimization of stem cell function towards tissue engineering or regenerative medicine.

DOI： 10.3390/ijms20051097

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Anti-inflammatory agents have been widely used to ameliorate severe inflammatory symptoms of a number of diseases, and such therapeutics are particularly useful for diseases with intolerable pain without significant mortality. A typical example of this is a disease known as stomatitis; although stomatitis itself is not a life-threatening disease, it severely impairs the individual’s quality of life, and thus a standard therapeutic strategy for it has already been established. The topical application of a bioactive agent is quite easy, and a strong anti-inflammatory agent can be used without significant adverse effects. In contrast, natural products with relatively mild bioactivity are used for systemic intervention. However, new aspects of classical drugs used in these established therapeutic methods have recently been discovered, which is expanding the utility of these compounds to other oral diseases such as osteoarthritis of temporomandibular joints (TMJ-OA). In this review article, after summarizing the general concept and pathobiology of stomatitis, its established therapeutics are explained. Thereafter, recent advances in the research into related compounds, which is uncovering new biological functions of the agents used therein, are introduced. Indeed, regenerative therapeutics for TMJ-OA may be developed with the classical compounds currently being used.

DOI： 10.3390/medicines5040118

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Understanding the mechanisms that control cutaneous wound healing is crucial to successfully manage repair of damaged skin. The goal of the current study was to uncover novel extracellular matrix (ECM) components that control the wound healing process. Full thickness skin defects were created in mice and used to show CCN4 up-regulation during wound-healing as early as 1 day after surgery, suggesting a role in inflammation and subsequent dermal migration and proliferation. To determine how CCN4 could regulate wound healing we used Ccn4-KO mice and showed they had delayed wound closure accompanied by reduced expression of Col1a1 and Fn mRNA. Boyden chamber assays using Ccn4-deficient dermal fibroblasts showed they have reduced migration and proliferation compared to WT counterparts. To confirm CCN4 has a role in proliferation and migration of dermal cells, siRNA knockdown and transduction of CCN4 adenoviral transduction were used and resulted in reduced or enhanced migration of human adult dermal fibroblast (hADF) cells respectively. The induced migration of the dermal fibroblasts by CCN4 appears to work via alpha 5 beta 1 integrin receptors that further stimulates down-stream ERK/JNK signaling. The regulation of CCN4 by TNF-alpha prompted us look further at their potential relationship. Treatment of hADFs with CCN4 and TNF-alpha alone or together showed CCN4 counteracted the inhibition of TNF-alpha on COL1A1 and FN mRNA expression and the stimulation of TNF-alpha on MMP-1 and MMP3 mRNA expression. CCN4 appeared to counterbalance the effects of TNF-alpha by inhibiting downstream NF-kappa B/p-65 signaling. Taken together we show CCN4 stimulates dermal fibroblast cell migration, proliferation and inhibits TNF-alpha stimulation, all of which could regulate wound healing. Published by Elsevier B.V.

DOI： 10.1016/j.matbio.2018.01.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Keratinized mucosa is of fundamental importance to maintain healthy gingival tissue, and understanding the mechanisms of oral mucosa keratinization is crucial to successfully manage healthy gingiva. Previous studies have shown a strong involvement of the basement membrane in the proliferation and differentiation of epithelial cells. Therefore, first, to identify the keratinized mucosa-specific basement membrane components, immunohistochemical analysis for the six alpha chains of type IV collagen was performed in 8-week-old mice. No difference in the expression pattern of type IV collagen alpha 1(IV) and alpha 2(IV) chains was observed in the keratinized and non-keratinized mucosa. Interestingly, however, type IV collagen alpha 5(IV) and alpha 6(IV) chains specifically were strongly detected in the keratinized mucosa. To analyze the functional roles of the type IV collagen isoform alpha 6(IV) in oral mucosa keratinization, we analyzed Col4a6-knockout mice. Epithelial developmental delay and low levels of KRT10 were observed in new-born Col4a6-knockout mice. Additionally, in vitro experiments with loss-of function analysis using human gingival epithelial cells confirmed the important role of a6(IV) chain in epithelial keratinization. These findings indicate that alpha 112: alpha 556 (IV) network, which is the only network that includes the alpha 6(IV) chain, is one regulator of KRT10 expression in keratinization of oral mucosal epithelium.

DOI： 10.1038/s41598-018-21000-0

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その他リンク： http://www.nature.com/articles/s41598-018-21000-0.pdf

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<p>Chondrocyte burst was associated with mineralization. Manipulation of chondrocyte burst could be additional approach for cartilage and bone tissue engineering.</p>

DOI： 10.1039/c7ib00130d

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掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Singapore  

DOI： 10.1007/978-981-13-1002-7_22

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Company of Biologists  

DOI： 10.1242/jcs.196907

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

DOI： 10.1038/srep44522

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science ({PLoS})  

DOI： 10.1371/journal.pone.0176453

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記述言語：日本語   出版者・発行元：日本結合組織学会  

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記述言語：英語   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11325-015-1281-0

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その他リンク： http://link.springer.com/article/10.1007/s11325-015-1281-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER HEIDELBERG  

To evaluate correlations between serotonin transporter (SERT) uptake ability in human peripheral platelets and sleep bruxism (SB) frequency.Subjects were consecutively recruited from sixth-year students at Okayama University Dental School. Subjects were excluded if they (1) were receiving orthodontic treatment, (2) had a dermatological disease, (3) had taken an antidepressant within 6 months, or (4) had used an oral appliance within 6 months. SB frequency was determined as the summary score of three consecutive night assessments using a self-contained electromyography detector/analyzer in their home. Fasting peripheral venous blood samples were collected in the morning following the final SB assessment. SERT amount and platelet number were quantified via an ELISA assay and flow cytometry, respectively. Functional SERT characterization, 5-hydroxytryptamine (5-HT) uptake, maximum velocity (V (max)), and an affinity constant (K (m) ) were assessed with a [H-3] 5-HT uptake assay. The correlations between these variables and SB level were evaluated.Among 50 eligible subjects (26 males, mean age 25.4 +/- 2.41 years), 7 were excluded because of venipuncture failure, smoking, and alcohol intake during the experimental period. A small but significant negative correlation between SB level and [H-3] 5-HT uptake was observed (Spearman's correlation R (2) = 0.063, p = 0.04). However, there were no significant correlations between SB level and total platelet amount, SERT, V (max), and K (m) values (p = 0.08, 0.12, 0.71, and 0.68, respectively).Platelet serotonin uptake is significantly associated with SB frequency, yet only explains a small amount of SB variability.

DOI： 10.1007/s11325-015-1281-0

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bone.2015.11.007

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Growth factors are crucial regulators of cell differentiation towards tissue and organ development. Insulin and transforming growth factor-β (TGF-β) have been used as the major factors for chondrogenesis in vitro, by activating the AKT and Smad signaling pathways. Previous reports demonstrated that AKT and Smad3 have a direct interaction that results in the inhibition of TGF-β-mediated cellular responses. However, the result of this interaction between AKT and Smad3 during the chondrogenesis of human bone marrow-derived stem/progenitor cells (hBMSCs) is unknown. In this study, we performed functional analyses by inducing hBMSCs into chondrogenesis with insulin, TGF-β3 or in combination, and found that TGF-β3, when applied concomitantly with insulin, significantly decreases an insulin-induced increase in mRNA levels of the master regulator of chondrogenesis, SOX9, as well as the regulators of the 2 major chondrocyte markers, ACAN and COL2A1. Similarly, the insulin/TGF-β3-treated group presented a significant decrease in the deposition of cartilage matrix as detected by safranin O staining of histological sections of hBMSC micromass cultures when compared to the group stimulated with insulin alone. Intracellular analysis revealed that insulin-induced activation of AKT suppressed Smad3 activation in a dose-dependent manner. Accordingly, insulin/TGF-β3 significantly decreased the TGF-β3-induced increase in mRNA levels of the direct downstream factor of TGF-β/Smad3, CCN2/CGTF, compared to the group stimulated with TGF-β3 alone. On the other hand, insulin/TGF-β3 stimulation did not suppress insulin-induced expression of the downstream targets TSC2 and DDIT4/REDD1. In summary, insulin and TGF-β3 have antagonistic effects when applied concomitantly, with a minimal number of factors. The application of an insulin/TGF-β3 combination without further supplementation should be used with caution in the chondrogenic differentiation of hBMSCs.

DOI： 10.1159/000442411

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記述言語：英語   出版者・発行元：日本バイオマテリアル学会  

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記述言語：英語   出版者・発行元：(一社)日本骨代謝学会  

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記述言語：日本語   出版者・発行元：(一社)日本骨代謝学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2015.04.003

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2014.12.001

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2015.05.003

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記述言語：日本語   出版者・発行元：日本再生歯科医学会  

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記述言語：日本語   出版者・発行元：(公社)日本補綴歯科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Introduction: During normal pulp tissue healing, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukins, act in the initial 48 hours (inflammatory phase) and play important roles not only as chemo- attractants of inflammatory cells and stem/progenitor cells but also in inducing a cascade of reactions toward tissue regeneration or reparative dentin formation or both. Previous reports have shown that inflammatory cytokines regulate the differentiation capacity of dental pulp stem/progenitor cells (DPCs), but none has interrogated the impact of these cytokines on the stem cell phenotype of stem/progenitor cells. This study investigated the effects of a short-term treatment with TNF-alpha on the stem cell phenotype and differentiation ability of human DPCs.Methods: An in vivo mouse model of pulp exposure was performed for analysis of expression of the mesenchymal stem cell marker CD146 in DPCs during the initial stage of inflammatory response. For in vitro studies, human DPCs were isolated and incubated with TNF-alpha for 2 days and passaged to eliminate TNF-alpha completely. Analysis of stem cell phenotype was performed by quantification of cells positive for mesenchymal stem cell markers SSEA-4 (stage-specific embryonic antigen 4) and CD146 by flow cytometry as well as by quantitative analysis of telomerase activity and mRNA levels of OCT-4 and NANOG. Cell migration, colony-forming ability, and differentiation toward odontogenesis and adipogenesis were also investigated.Results: The pulp exposure model revealed a strong staining for CD146 during the initial inflammatory response, at 2 days after pulp exposure. In vitro experiments demonstrated that a short-term (2-day) treatment of TNF-alpha increased by twofold the percentage of SSEA-4(+) cells. Accordingly, STRO-1, CD146, and SSEA-4 protein levels as well as OCT-4 and NANOG mRNA levels were also significantly upregulated upon TNF-alpha treatment. A short-term TNF-alpha treatment also enhanced DPC function, including the ability to form cell colonies, to migrate, and to differentiate into odontogenic and adipogenic lineages.Conclusions: A short-term treatment with TNF-alpha enhanced the stem cell phenotype, migration, and differentiation ability of DPCs.

DOI： 10.1186/scrt420

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その他リンク： https://link.springer.com/article/10.1186/scrt420/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.bone.2013.11.010

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0022034514549377

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

In this study we performed a microRNA (miRNA) array to characterize a stem cell population from human dental pulp-derived mesenchymal stromal cells (hDPSCs). miRNA-720 was found to regulate the stem cell phenotype of hDPSCs by targeting the pluripotency factor NANOG.

DOI： 10.1109/MHS.2014.7006080

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その他リンク： http://orcid.org/0000-0001-7374-3487

掲載種別：研究論文（学術雑誌）  

DOI： 10.1159/000356947

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2014.06.003

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1159/000369061

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Stem Cell Biology and Tissue Engineering in Dental Sciences  

DOI： 10.1016/B978-0-12-397157-9.00068-0

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記述言語：英語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：(公社)日本補綴歯科学会  

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記述言語：日本語   出版者・発行元：(公社)日本補綴歯科学会  

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/joor.12026

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Prosthodontic Society  

DOI： 10.1016/j.jpor.2012.08.005

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0058796

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2013.03.003

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/joor.12029

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0083545

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpor.2013.08.001

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掲載種別：研究論文（学術雑誌）  

DOI： 10.11607/ijp.3120

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Small, self-contained electromyographic (EMG) detector/analyzer (D/A) devices have become available for the detection of jaw muscle activity events above threshold. These devices claim to be less intrusive to the subjects sleep so it is less prone to induce disturbed sleep. The objective of this study was to evaluate for night-to-night variability and examine for a systematic alteration on the first night in EMG levels.Ten asymptomatic healthy volunteers (mean age, 26.8 +/- 3.78) were recorded for six sequential nights in their home environment using EMG D/A system. The device yields a nightly EMG level above threshold score on a 0-4 level. Because the data are categorical and nonparametric, the data of the ten subjects across six nights were submitted to a Friedman repeated measures ANOVA. The significant level was set as alpha equal to 0.05.The median and mode values of the subjects were tabulated and analyzed and we did not find a significant difference in EMG D/A level across the six nights (p = 0.287, Kendall's coefficient of concordance = 0.124, Friedman two-way repeated measures ANOVA). The data did show clear and substantial night-to-night variability.Substantial night-to-night variability in masseter EMG activity levels was clearly observed in our subjects. There was no evidence of a suppressed or elevated first-night effect-like variability on masseter muscle EMG level seen in these subjects using a small portable self-contained EMG detector/analyzer. These data suggest that recordings should be at least 5-6-nights duration to establish a reasonable measure of an individual's average nightly masseter EMG level.

DOI： 10.1007/s11325-011-0602-1

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その他リンク： http://link.springer.com/article/10.1007/s11325-011-0602-1/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Prosthodontic Society  

Purpose: Current clinical procedures to control or regenerate bone loss due to peri-implantitis are not predictable neither accomplish complete resolution. Therefore, early detection of the onset and the active periods of bone loss are crucial for prevention of extensive pen-implant bone resorption. This study aimed to determine a possible association between the presence of collagenases (MMP-1, MMP-8 and MMP-13) in peri-implant sulcular fluid (PISF) and active periods of bone loss by annually adjusted vertical bone loss (AVBL) measurements.Methods: Intended sample consisted of 76 consecutive patients who received oral implant treatment at the Fixed Prosthodontic Clinic of Okayama University Hospital from 1990 to 2000. Twelve subjects were lost to follow-up or refused to participate. Consequently, the actual sample consisted of 64 patients who were followed-up for at least one year. Those patients with AVBL > 0.6 mm were included in the severe peri-implantitis group, and randomly selected, age-, gender- and implantation site-matched healthy patients (AVBL <0.3 mm) comprised the control group. PISF samples were collected from both groups and further analyzed by western blot for detection of collagenases.Results: Four patients presented severe peri-implantitis. MMP-8 was the only collagenase detected in pen-implant sites with ongoing bone loss. PISF samples from control group showed no positive reactions to any collagenase.Conclusion: This study showed MMP-8 as a possible marker for progressive bone loss in peri-implantitis. (C) 2012 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

DOI： 10.1016/j.jpor.2012.07.002

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/j.1365-2842.2012.02300.x

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記述言語：日本語   出版者・発行元：(公社)日本歯科医師会  

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記述言語：日本語   出版者・発行元：(公社)日本補綴歯科学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/j.1365-2842.2011.02241.x

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(一社)日本顎関節学会  

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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