Updated on 2022/12/01

写真a

 
KAKU Masaru
 
Organization
Academic Assembly Institute of Medicine and Dentistry SHIGAKU KEIRETU Associate Professor
Faculty of Dentistry School of Dentistry Associate Professor
Graduate School of Medical and Dental Sciences Oral Life Science Oral Health Science Associate Professor
Title
Associate Professor
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Degree

  • 歯学博士(歯学) ( 2004.3   東京医科歯科大学 )

Research Areas

  • Life Science / Regenerative dentistry and dental engineering

  • Life Science / Oral biological science

  • Life Science / Prosthodontics

Research History (researchmap)

  • University of Texas McGovern Medical School at Houston   Department of Pediatrics   Adjunct Associate Professor

    2017.5 - 2018.8

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  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Health Science   Associate Professor

    2012.9

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  • Niigata University   Faculty of Dentistry School of Dentistry   Associate Professor

    2012.9

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  • Niigata University   University Medical and Dental Hospital Dental Health   Lecturer

    2010.12 - 2012.8

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  • Niigata University   University Medical and Dental Hospital Dental Health   Assistant Professor

    2009.4 - 2010.11

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  • University of North Carolina at Chapel Hill   Dental Research Center   Researcher

    2004.6 - 2009.3

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  • Tokyo Medical and Dental University   Graduate School of Medical and Dental Sciences

    2004.4 - 2008.3

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Research History

  • Niigata University   Faculty of Dentistry School of Dentistry   Associate Professor

    2012.9

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Health Science   Associate Professor

    2012.9

  • Niigata University   University Medical and Dental Hospital Dental Health   Lecturer

    2010.12 - 2012.8

  • Niigata University   University Medical and Dental Hospital Dental Health   Assistant Professor

    2009.4 - 2010.11

Education

  • Tokyo Medical and Dental University   医歯学総合研究科

    2000.4 - 2004.3

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    Country: Japan

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  • Tokyo Medical and Dental University   Faculty of Dentistry   歯学科

    1994.4 - 2000.3

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    Country: Japan

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Professional Memberships

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Qualification acquired

  • Dentist

 

Papers

  • Involvement of Rab11 in osteoblastic differentiation: Its up-regulation during the differentiation and by tensile stress. International journal

    Lay Thant, Yoshito Kakihara, Masaru Kaku, Megumi Kitami, Kohei Kitami, Masaru Mizukoshi, Takeyasu Maeda, Isao Saito, Makio Saeki

    Biochemical and biophysical research communications   624   16 - 22   2022.7

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    Rab GTPases, the largest group of small monomeric GTPases, have been shown to participate in membrane trafficking involving many cellular processes. However, their roles during osteoblastic differentiation remain to be elucidated. In this study, we investigated Rab GTPase involvement in osteoblastic differentiation. Protein levels of a series of Rabs (Rab4, Rab5, Rab7, Rab9a, Rab11a/b, and Rab27) were increased during osteoblastic differentiation of MC3T3-E1 cells, and the Rab11a/b levels were particularly pronounced in the presence of Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, an activator of osteoblastogenesis. We subsequently investigated the functional contribution of Rab11a and Rab11b during osteoblastic differentiation. The alkaline phosphatase (ALP) levels were reduced by Rab11b depletion but not by Rab11a depletion. Because our result suggested that Rab11a and Rab11b could be regulated downstream of Runx2 (Runt-related transcription factor 2), a key transcription factor for osteoblastic differentiation, we investigated the effects of the double knockdown of Runx2 and Rab11a or Rab11b on osteoblastic phenotypes. The double knockdown significantly reduced ALP activity as well as collagen deposition compared with single Runx2 knockdown. Furthermore, the Rab11a and Rab11b response to mechanical stress in vivo was investigated using a mouse orthodontic tooth movement model. Rab11a and Rab11b expression was enhanced in the periodontal ligament, where bone formation is activated by tensile stress. This study shows that Rab11a and Rab11b are regulated downstream of Runx2 in osteoblastic differentiation, and their expressions are also controlled by tensile stress.

    DOI: 10.1016/j.bbrc.2022.07.061

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  • Extracellular Matrix-Oriented Proteomic Analysis of Periodontal Ligament Under Mechanical Stress International journal

    Lay Thant, Masaru Kaku, Yoshito Kakihara, Masaru Mizukoshi, Megumi Kitami, Moe Arai, Kohei Kitami, Daiki Kobayashi, Yutaka Yoshida, Takeyasu Maeda, Isao Saito, Katsumi Uoshima, Makio Saeki

    Frontiers in Physiology   13   899699 - 899699   2022.5

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    The periodontal ligament (PDL) is a specialized connective tissue that provides structural support to the tooth and is crucial for oral functions. The mechanical properties of the PDL are mainly derived from the tissue-specific composition and structural characteristics of the extracellular matrix (ECM). The ECM also plays key roles in determining cell fate in the cellular microenvironment thus crucial in the PDL tissue homeostasis. In the present study, we determined the comprehensive ECM profile of mouse molar PDL using laser microdissection and mass spectrometry-based proteomic analysis with ECM-oriented data curation. Additionally, we evaluated changes in the ECM proteome under mechanical loading using a mouse orthodontic tooth movement (OTM) model and analyzed potential regulatory networks using a bioinformatics approach. Proteomic changes were evaluated in reference to the novel second harmonic generation (SHG)-based fiber characterization. Our ECM-oriented proteomics approach succeeded in illustrating the comprehensive ECM profile of the mouse molar PDL. We revealed the presence of type II collagen in PDL, possibly associated with the load-bearing function upon occlusal force. Mechanical loading induced unique architectural changes in collagen fibers along with dynamic compositional changes in the matrisome profile, particularly involving ECM glycoproteins and matrisome-associated proteins. We identified several unique matrisome proteins which responded to the different modes of mechanical loading in PDL. Notably, the proportion of type VI collagen significantly increased at the mesial side, contributing to collagen fibrogenesis. On the other hand, type XII collagen increased at the PDL-cementum boundary of the distal side. Furthermore, a multifaceted bioinformatics approach illustrated the potential molecular cues, including PDGF signaling, that maintain ECM homeostasis under mechanical loading. Our findings provide fundamental insights into the molecular network underlying ECM homeostasis in PDL, which is vital for clinical diagnosis and development of biomimetic tissue-regeneration strategies.

    DOI: 10.3389/fphys.2022.899699

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  • 矯正的歯の移動時の歯根膜におけるSPARCの局在について

    新井 萌生, 北見 公平, 加来 賢, 水越 優, Thant Lay, 岩間 基, 魚島 勝美, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   80回   148 - 148   2021.11

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  • 加齢によりマウス臼歯の有細胞セメント質表層に生じる無細胞セメント質様組織の解析

    岩間 基, 北見 公平, 加来 賢, Thant Lay, 新井 萌生, 水越 優, 魚島 勝美, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   80回   147 - 147   2021.11

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  • マウス臼歯歯根膜におけるLabel Retaining Cellの局在と特性

    水越 優, 加来 賢, 北見 公平, 新井 萌生, 岩間 基, 魚島 勝美, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   80回   151 - 151   2021.11

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  • メカニカルストレス下における歯根膜細胞外基質タンパクのプロテオーム解析

    Thant Lay, 加来 賢, 柿原 嘉人, 水越 優, 北見 恩美, 北見 公平, 小林 大記, 吉田 豊, 魚島 勝美, 齋藤 功, 佐伯 万騎男

    日本結合組織学会学術大会プログラム・抄録集   53回   137 - 137   2021.6

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  • In vivo cell proliferation analysis and cell-tracing reveal the global cellular dynamics of periodontal ligament cells under mechanical-loading. International journal

    Masaru Mizukoshi, Masaru Kaku, Lay Thant, Kohei Kitami, Moe Arai, Isao Saito, Katsumi Uoshima

    Scientific reports   11 ( 1 )   9813 - 9813   2021.5

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    Periodontal ligament (PDL) is a uniquely differentiated tissue that anchors the tooth to the alveolar bone socket and plays key roles in oral function. PDL cells can respond rapidly to mechanical stimuli, resulting in accelerated tissue remodeling. Cell proliferation is an initial event in tissue remodeling and participates in maintaining the cell supply; therefore, analyzing cell-proliferative activity might provide a comprehensive view of cellular dynamics at the tissue level. In this study, we investigated proliferating cells in mouse molar PDL during orthodontic tooth movement (OTM)-induced tissue remodeling. Our results demonstrated that the mechanical stimuli evoked a dynamic change in the proliferative-cell profile at the entire PDL. Additionally, cell-tracing analysis revealed that the proliferated cells underwent further division and subsequently contributed to tissue remodeling. Moreover, OTM-induced proliferating cells expressed various molecular markers that most likely arise from a wide range of cell types, indicating the lineage plasticity of PDL cells in vivo. Although further studies are required, these findings partially elucidated the global views of the cell trajectory in mouse molar PDL under mechanical-loading conditions, which is vital for understanding the cellular dynamics of the PDL and beneficial for dental treatment in humans.

    DOI: 10.1038/s41598-021-89156-w

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  • Molecular Cloning of Mouse Homologue of Enamel Protein C4orf26 and Its Phosphorylation by FAM20C. International journal

    Nattanan Govitvattana, Masaru Kaku, Yoshio Ohyama, Haytham Jaha, I-Ping Lin, Hanna Mochida, Prasit Pavasant, Yoshiyuki Mochida

    Calcified tissue international   109 ( 4 )   445 - 454   2021.4

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    It is widely accepted that cellular processes are controlled by protein phosphorylation and has become increasingly clear that protein degradation, localization and conformation as well as protein-protein interaction are the examples of subsequent cellular events modulated by protein phosphorylation. Enamel matrix proteins belong to members of the secretory calcium binding phosphoprotein (SCPP) family clustered on chromosome 4q21, and most of the SCPP phosphoproteins have at least one S-X-E motifs (S; serine, X; any amino acid, E; glutamic acid). It has been reported that mutations in C4orf26 gene, located on chromosome 4q21, are associated with autosomal recessive type of Amelogenesis Imperfecta (AI), a hereditary condition that affects enamel formation/mineralization. The enamel phenotype observed in patients with C4orf26 mutations is hypomineralized and partially hypoplastic, indicating that C4orf26 protein may function at both secretory and maturation stages of amelogenesis. The previous in vitro study showed that the synthetic phosphorylated peptide based on C4orf26 protein sequence accelerates hydroxyapatite nucleation. Here we show the molecular cloning of Gm1045, mouse homologue of C4orf26, which has 2 splicing isoforms. Immunohistochemical analysis demonstrated that the immunolocalization of Gm1045 is mainly observed in enamel matrix in vivo. Our report is the first to show that FAM20C, the Golgi casein kinase, phosphorylates C4orf26 and Gm1045 in cell cultures. The extracellular localization of C4orf26/Gm1045 was regulated by FAM20C kinase activity. Thus, our data point out the biological importance of enamel matrix-kinase control of SCPP phosphoproteins and may have a broad impact on the regulation of amelogenesis and AI.

    DOI: 10.1007/s00223-021-00847-y

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  • FAM20C directly binds to and phosphorylates Periostin. International journal

    Ju-Hsien Lin, I-Ping Lin, Yoshio Ohyama, Hanna Mochida, Akira Kudo, Masaru Kaku, Yoshiyuki Mochida

    Scientific reports   10 ( 1 )   17155 - 17155   2020.10

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    It is widely accepted that FAM20C functions as a Golgi casein kinase and has large numbers of kinase substrates within the secretory pathway. It has been previously reported that FAM20C is required for maintenance of healthy periodontal tissues. However, there has been no report that any extracellular matrix molecules expressed in periodontal tissues are indeed substrates of FAM20C. In this study, we sought to identify the binding partner(s) of FAM20C. FAM20C wild-type (WT) and its kinase inactive form D478A proteins were generated. These proteins were electrophoresed and the Coomassie Brilliant Blue (CBB)-positive bands were analyzed to identify FAM20C-binding protein(s) by Mass Spectrometry (MS) analysis. Periostin was found by the analysis and the binding between FAM20C and Periostin was investigated in cell cultures and in vitro. We further determined the binding region(s) within Periostin responsible for FAM20C-binding. Immunolocalization of FAM20C and Periostin was examined using mouse periodontium tissues by immunohistochemical analysis. In vitro kinase assay was performed using Periostin and FAM20C proteins to see whether FAM20C phosphorylates Periostin in vitro. We identified Periostin as one of FAM20C-binding proteins by MS analysis. Periostin interacted with FAM20C in a kinase-activity independent manner and the binding was direct in vitro. We further identified the binding domain of FAM20C in Periostin, which was mapped within Fasciclin (Fas) I domain 1-4 of Periostin. Immunolocalization of FAM20C was observed in periodontal ligament (PDL) extracellular matrix where that of Periostin was also immunostained in murine periodontal tissues. FAM20C WT, but not D478A, phosphorylated Periostin in vitro. Consistent with the overlapped expression pattern of FAM20C and Periostin, our data demonstrate for the first time that Periostin is a direct FAM20C-binding partner and that FAM20C phosphorylates Periostin in vitro.

    DOI: 10.1038/s41598-020-74400-6

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  • 咬合支持域の減少による咀嚼障害をインプラントにて補綴した症例 Reviewed

    加来 賢

    日本補綴歯科学会誌   12 ( 1 )   103 - 106   2020.1

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    症例の概要:69歳の女性。右下臼歯部欠損による咀嚼障害のために受診した。装着されている補綴物の咬耗からブラキシズムを有することが示唆された。左上臼歯部ブリッジの支台歯も抜歯の適応であり、欠損部はインプラント補綴装置で治療を行った。考察:ブラキシズムを有する患者のインプラント治療では、インプラントに対する負担過重を軽減するため、スプリント等による咬合管理を行う必要がある。結論:臼歯部の咬合支持を喪失しつつある患者に対して、インプラントによる機能回復を行ったのち、夜間スプリント装着による咬合管理と定期的なメインテナンスを行うことで、4年6ヵ月間にわたり良好な経過を得ている。(著者抄録)

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  • Response to Letter to the Editor: Concerns on modeling postmenopausal osteoporosis in young female rats. Reviewed International journal

    Juan Marcelo Rosales Rocabado, Masaru Kaku, Kosuke Nozaki, Takako Ida, Megumi Kitami, Yujin Aoyagi, Katsumi Uoshima

    Journal of orthopaedic surgery and research   14 ( 1 )   451 - 451   2019.12

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  • Collagen Crosslinks and Bone Metabolism Involved in Osseointegration Invited Reviewed

    KAKU Masaru

    32 ( 2 )   26 - 32   2019.6

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  • Valproic Acid contribute to Bone Cavity Healing in Rats. Reviewed

    Rashid M, Akiba Y, Eguchi K Akiba N, Kaku M, Nagasawa M, Uoshima K

    Dentistry   3   539 - 546   2019.4

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  • IFT20 is required for the maintenance of cartilaginous matrix in condylar cartilage. Reviewed International journal

    Megumi Kitami, Hiroyuki Yamaguchi, Masayuki Ebina, Masaru Kaku, Di Chen, Yoshihiro Komatsu

    Biochemical and biophysical research communications   509 ( 1 )   222 - 226   2019.1

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    Condylar cartilage is a joint cartilage essential for smooth jaw movement. The importance of ciliary proteins in condylar cartilage development has been reported. However, little is known about how ciliary proteins control the homeostasis of condylar cartilage. Here we show that intraflagellar transport 20 (IFT20), a ciliary protein, is required for the maintenance of cartilaginous matrix in condylar cartilage. Utilizing NG2-CreER mice expressed in condylar cartilage, we deleted Ift20 by tamoxifen treatment at juvenile-to-adult stages. In wild-type condylar cartilage, IFT20 was robustly produced in the cis-Golgi, but deletion of Ift20 by tamoxifen induction of NG2-CreER (Ift20:NG2-CreER) resulted in reduced cell proliferation and decreased Golgi size in condylar cartilage. Importantly, while the primary cilia were present in cartilage cells in the condylar layers of wild-type mice, no primary cilia were present in the Ift20:NG2-CreER condylar layers. Consistent with this finding, ciliary-mediated Hedgehog signaling was severely attenuated in Ift20 mutant chondrocytes, and thus the production levels of type X collagen were significantly reduced in Ift20:NG2-CreER mice. These results suggest that IFT20 is required for Golgi size and Hedgehog signaling to maintain cartilaginous matrix in condylar cartilage. Our study highlights the unique function of IFT20 in the homeostasis of condylar cartilage.

    DOI: 10.1016/j.bbrc.2018.12.107

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  • Regeneration of Bone/ Periodontal ligament and Mechanical load ± ([SORULQJ WKH VLJQL¿FDQFH LQ 3URVWKRGRQWLF 7UHDWPHQWV ± Reviewed

    Katsumi Uoshima, Masaru Kaku, Masako Nagasawa

    Ann Jpn Prosthodont Soc   11 ( 1 )   14 - 19   2019.1

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  • A multi-factorial analysis of bone morphology and fracture strength of rat femur in response to ovariectomy. Reviewed International journal

    Juan Marcelo Rosales Rocabado, Masaru Kaku, Kosuke Nozaki, Takako Ida, Megumi Kitami, Yujin Aoyagi, Katsumi Uoshima

    Journal of orthopaedic surgery and research   13 ( 1 )   318 - 318   2018.12

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    BACKGROUND: Postmenopausal osteoporosis develops due to a deficiency of estrogen that causes a decrease in bone mass and changes in the macro- and micro-architectural structure of the bone, leading to the loss of mechanical strength and an increased risk of fracture. Although the assessment of bone mineral density (BMD) has been widely used as a gold standard for diagnostic screening of bone fracture risks, it accounts for only a part of the variation in bone fragility; thus, it is necessary to consider other determinants of bone strength. Therefore, we aimed to comprehensively evaluate the architectural changes of the bone that influence bone fracture strength, together with the different sensitivities of cortical and trabecular bone in response to ovariectomy (OVX). METHODS: Bone morphology parameters were separately analyzed both in cortical and in trabecular bones, at distal-metaphysis, and mid-diaphysis of OVX rat femurs. Three-point bending test was performed at mid-diaphysis of the femurs. Correlation of OVX-induced changes of morphological parameters with breaking force was analyzed using Pearson's correlation coefficient. RESULTS: OVX resulted in a decline in the bone volume of distal-metaphysis trabecular bone, but an increase in distal-metaphysis and mid-diaphysis cortical bone volume. Tissue mineral density (TMD) remained unchanged in both the trabecular and cortical bone of the distal metaphysis but decreased in cortical bone of the mid-diaphysis. The OVX significantly increased the breaking force at mid-diaphysis of the femurs. CONCLUSIONS: OVX decreased the trabecular bone volume of the distal-metaphysis and increased the cortical bone volume of the distal-metaphysis and mid-diaphysis. Despite the reduction in TMD and increased cortical porosity, bone fracture strength increased in the mid-diaphysis after OVX. These results indicate that analyzing a single factor, i.e., BMD, is not sufficient to predict the absolute fracture risk of the bone, as OVX-induced bone response vary, depending on the bone type and location. Our results strongly support the necessity of analyzing bone micro-architecture and site specificity to clarify the true etiology of osteoporosis in a clinical setting.

    DOI: 10.1186/s13018-018-1018-4

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  • VWC2 Increases Bone Formation Through Inhibiting Activin Signaling. Reviewed International journal

    Ahmad Almehmadi, Yoshio Ohyama, Masaru Kaku, Ahmed Alamoudi, Dina Husein, Michitsuna Katafuchi, Yuji Mishina, Yoshiyuki Mochida

    Calcified tissue international   103 ( 6 )   663 - 674   2018.12

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    By a bioinformatics approach, we have identified a novel cysteine knot protein member, VWC2 (von Willebrand factor C domain containing 2) previously known as Brorin. Since Brorin has been proposed to function as a bone morphogenetic protein (BMP) antagonist, we investigated the binding of Brorin/VWC2 to several BMPs; however, none of the BMPs tested were bound to VWC2. Instead, the βA subunit of activin was found as a binding partner among transforming growth factor (TGF)-β superfamily members. Here, we show that Vwc2 gene expression is temporally upregulated early in osteoblast differentiation, VWC2 protein is present in bone matrix, and localized at osteoblasts/osteocytes. Activin A-induced Smad2 phosphorylation was inhibited in the presence of exogenous VWC2 in MC3T3-E1 osteoblast cell line and primary osteoblasts. The effect of VWC2 on ex vivo cranial bone organ cultures treated with activin A was investigated, and bone morphometric parameters decreased by activin A were restored with VWC2. When we further investigated the biological mechanism how VWC2 inhibited the effects of activin A on bone formation, we found that the effects of activin A on osteoblast cell growth, differentiation, and mineralization were reversed by VWC2. Taken together, a novel secretory protein, VWC2 promotes bone formation by inhibiting Activin-Smad2 signaling pathway.

    DOI: 10.1007/s00223-018-0462-9

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  • BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development. Reviewed International journal

    Kohei Kitami, Megumi Kitami, Masaru Kaku, Bin Wang, Yoshihiro Komatsu

    PLoS genetics   14 ( 5 )   e1007340   2018.5

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    Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1-deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo, indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation.

    DOI: 10.1371/journal.pgen.1007340

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  • A paradigm shift for bone quality in prosthetic dentistry Reviewed

    Kuroshima Shinichiro, Kaku Masaru, Ishimoto Takuya, Sasaki Muneteru, Nakano Takayoshi, Sawase Takashi

    Annals of Japan Prosthodontic Society   10 ( 1 )   1 - 15   2018.1

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  • Extracellular matrix with defective collagen cross-linking affects the differentiation of bone cells. Reviewed International journal

    Takako Ida, Masaru Kaku, Megumi Kitami, Masahiko Terajima, Juan Marcelo Rosales Rocabado, Yosuke Akiba, Masako Nagasawa, Mitsuo Yamauchi, Katsumi Uoshima

    PloS one   13 ( 9 )   e0204306   2018

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    Fibrillar type I collagen, the predominant organic component in bone, is stabilized by lysyl oxidase (LOX)-initiated covalent intermolecular cross-linking, an important determinant of bone quality. However, the impact of collagen cross-linking on the activity of bone cells and subsequent tissue remodeling is not well understood. In this study, we investigated the effect of collagen cross-linking on bone cellular activities employing a loss-of-function approach, using a potent LOX inhibitor, β-aminopropionitrile (BAPN). Osteoblastic cells (MC3T3-E1) were cultured for 2 weeks in the presence of 0-2 mM BAPN to obtain low cross-linked collagen matrices. The addition of BAPN to the cultures diminished collagen cross-links in a dose-dependent manner and, at 1 mM level, none of the major cross-links were detected without affecting collagen production. After the removal of cellular components from these cultures, MC3T3-E1, osteoclasts (RAW264.7), or mouse primary bone marrow-derived stromal cells (BMSCs) were seeded. MC3T3-E1 cells grown on low cross-link matrices showed increased alkaline phosphatase (ALP) activity. The number of multinucleate tartrate-resistant acid phosphatase (TRAP)-positive cells increased in RAW264.7 cells. Initial adhesion, proliferation, and ALP activity of BMSCs also increased. In the animal experiments, 4-week-old C57BL/6 mice were fed with BAPN-containing diet for 8 weeks. At this point, biochemical analysis of bone demonstrated that collagen cross-links decreased without affecting collagen content. Then, the diet was changed to a control diet to minimize the direct effect of BAPN. At 2 and 4 weeks after the change, histological samples were prepared. Histological examination of femur samples at 4 weeks showed a significant increase in the number of bone surface osteoblasts, while the bone volume and surface osteoclast numbers were not significantly affected. These results clearly demonstrated that the extent of collagen cross-linking of bone matrix affected the differentiation of bone cells, underscoring the importance of collagen cross-linking in the regulation of cell behaviors and tissue remodeling in bone. Characterization of collagen cross-linking in bone may be beneficial to obtain insight into not only bone mechanical property, but also bone cellular activities.

    DOI: 10.1371/journal.pone.0204306

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  • A paradigm shift for bone quality in dentistry: A literature review. Reviewed International journal

    Shinichiro Kuroshima, Masaru Kaku, Takuya Ishimoto, Muneteru Sasaki, Takayoshi Nakano, Takashi Sawase

    Journal of prosthodontic research   61 ( 4 )   353 - 362   2017.10

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    PURPOSE: The aim of this study was to present the current concept of bone quality based on the proposal by the National Institutes of Health (NIH) and some of the cellular and molecular factors that affect bone quality. STUDY SELECTION: This is a literature review which focuses on collagen, biological apatite (BAp), and bone cells such as osteoblasts and osteocytes. RESULTS: In dentistry, the term "bone quality" has long been considered to be synonymous with bone mineral density (BMD) based on radiographic and sensible evaluations. In 2000, the NIH proposed the concept of bone quality as "the sum of all characteristics of bone that influence the bone's resistance to fracture," which is completely independent of BMD. The NIH defines bone quality as comprising bone architecture, bone turnover, bone mineralization, and micro-damage accumulation. Moreover, our investigations have demonstrated that BAp, collagen, and bone cells such as osteoblasts and osteocytes play essential roles in controlling the current concept of bone quality in bone around hip and dental implants. CONCLUSION: The current concept of bone quality is crucial for understanding bone mechanical functions. BAp, collagen and osteocytes are the main factors affecting bone quality. Moreover, mechanical loading dynamically adapts bone quality. Understanding the current concept of bone quality is required in dentistry.

    DOI: 10.1016/j.jpor.2017.05.006

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  • An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. Reviewed International journal

    Koichi Tabeta, Xin Du, Kei Arimatsu, Mai Yokoji, Naoki Takahashi, Norio Amizuka, Tomoka Hasegawa, Karine Crozat, Tomoki Maekawa, Sayuri Miyauchi, Yumi Matsuda, Takako Ida, Masaru Kaku, Kasper Hoebe, Kinji Ohno, Hiromasa Yoshie, Kazuhisa Yamazaki, Eva Marie Y Moresco, Bruce Beutler

    Scientific reports   7 ( 1 )   11717 - 11717   2017.9

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    GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue."

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  • Recruitment of bone marrow-derived cells to the periodontal ligament via the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis Reviewed

    M. Kaku, M. Kitami, J. M. Rosales Rocabado, T. Ida, Y. Akiba, K. Uoshima

    Journal of Periodontal Research   52 ( 4 )   686 - 694   2017.8

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    © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Background/Objectives: The periodontal ligament (PDL) is a non-mineralized connective tissue that exists between the alveolar bone and root surface cementum and plays important roles in tooth function. The PDL harbors a remarkable reserve of multipotent stem cells, which maintain various types of cells. However, the sources of these stem cells, other than their developmental origin, are not well understood. Material and Methods: To elucidate the recruitment of bone marrow (BM)-derived stem cells in the PDL, green fluorescent protein (GFP)-expressing BM-derived cells were transplanted into the femoral BM of immunodeficient rats, and the distribution and expression of stem cell markers in the PDL were analyzed in vivo. To evaluate the functional significance of BM-derived cells to the PDL, tooth replantation was performed and the expression of stromal cell-derived factor (SDF)-1, a critical chemotactic signal for mesenchymal stem cell recruitment, was analyzed. To confirm the SDF-1-dependency of BM-derived cell migration to the PDL, PDL-conditioned medium (CM) was prepared, and BM-derived cell migration was analyzed using a transwell culture system. Results: Four weeks after cell transplantation, GFP-positive cells were detected in the PDL, and some of them were also positive for stem cell markers (i.e., CD29, SSEA4, and αSMA). Seven days after tooth replantation, the number of GFP- and SDF-1-positive cells significantly increased in PDL. Concurrently, the concentration of SDF-1 and the number of colony-forming units of fibroblasts in peripheral blood were increased. BM-derived cell migration increased in PDL-CM and was inhibited by an inhibitor of C-X-C chemokine receptor type 4 (CXCR4), an SDF-1 receptor. Conclusion: These results indicate that stem cells and their progeny in PDL are not only derived from their developmental origin but are also supplied from the BM via the blood as the need arises. Moreover, this BM-derived cell recruitment appears to be regulated, at least partially, by the SDF-1/CXCR4 axis.

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  • Functional Diversity of Ciliary Proteins in Bone Development and Disease. Reviewed International journal

    Masaru Kaku, Yoshihiro Komatsu

    Current osteoporosis reports   15 ( 2 )   96 - 102   2017.4

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    PURPOSE OF REVIEW: The primary cilium is a non-motile microtubule-based organelle that senses a diverse range of extracellular signals. While recent studies highlight the importance of ciliary-dependent developmental signals, including Hedgehog, Wnt, and platelet-derived growth factor, it is not well understood whether and how bone morphogenetic protein (BMP) signaling, a key regulator of skeletogenesis, is involved in cilia-related bone developmental aspects and in the etiology of skeletal disorders. RECENT FINDINGS: Increasing evidence suggests that osteoblast- or osteocyte-specific deletion of ciliary proteins leads to diverse skeletal malformations, reinforcing the idea that primary cilia are indispensable for regulating bone development and maintenance. Furthermore, it became evident that ciliary proteins not only contribute to ciliogenesis but also orchestrate cellular trafficking. This review summarizes the current understanding of ciliary proteins in bone development and discusses the potential role of BMP signaling in primary cilia, enabling us to unravel the potential pathogenesis of skeletal ciliopathies.

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  • Medication-related osteonecrosis of the jaw; what should we do as prosthodontists? Reviewed International journal

    Shinichiro Kuroshima, Masaru Kaku, Takashi Matsuura, Ikiru Atsuta, Yasunori Ayukawa, Takashi Sawase

    Journal of prosthodontic research   60 ( 4 )   229 - 230   2016.10

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  • Prolonged Survival of Transplanted Osteoblastic Cells Does Not Directly Accelerate the Healing of Calvarial Bone Defects. Reviewed International journal

    Megumi Kitami, Masaru Kaku, Juan Marcelo Rosales Rocabado, Takako Ida, Nami Akiba, Katsumi Uoshima

    Journal of cellular physiology   231 ( 9 )   1974 - 82   2016.9

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    Considering the increased interest in cell-based bone regeneration, it is necessary to reveal the fate of transplanted cells and their substantive roles in bone regeneration. The aim of this study was to analyze the fate of transplanted cells and the effect of osteogenic cell transplantation on calvarial bone defect healing. An anti-apoptotic protein, heat shock protein (HSP) 27, was overexpressed in osteoblasts. Then, the treated osteoblasts were transplanted to calvarial bone defect and their fate was analyzed to evaluate the significance of transplanted cell survival. Transient overexpression of Hsp27 rescued MC3T3-E1 osteoblastic cells from H2 O2 -induced apoptosis without affecting osteoblastic differentiation in culture. Transplantation of Hsp27-overexpressing cells, encapsulated in collagen gel, showed higher proliferative activity, and fewer apoptotic cells in comparison with control cells. After 4-week of transplantation, both control cell- and Hsp27 overexpressed cell-transplanted groups showed significantly higher new bone formation in comparison with cell-free gel-transplantation group. Interestingly, the prolonged survival of transplanted osteoblastic cells by Hsp27 did not provide additional effect on bone healing. The transplanted cells in collagen gel survived for up to 4-week but did not differentiate into bone-forming osteoblasts. In conclusion, cell-containing collagen gel accelerated calvarial bone defect healing in comparison with cell-free collagen gel. However, prolonged survival of transplanted cells by Hsp27 overexpression did not provide additional effect. These results strongly indicate that cell transplantation-based bone regeneration cannot be explained only by the increment of osteogenic cells. Further studies are needed to elucidate the practical roles of transplanted cells that will potentiate successful bone regeneration. J. Cell. Physiol. 231: 1974-1982, 2016. © 2016 Wiley Periodicals, Inc.

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  • Prosthodontics: A multidisciplinary field in dentistry. Reviewed International journal

    Masaru Kaku

    Journal of prosthodontic research   60 ( 3 )   143 - 4   2016.7

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    DOI: 10.1016/j.jpor.2016.05.001

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  • FAM20A binds to and regulates FAM20C localization. Reviewed International journal

    Yoshio Ohyama, Ju-Hsien Lin, Nattanan Govitvattana, I-Ping Lin, Sundharamani Venkitapathi, Ahmed Alamoudi, Dina Husein, Chunying An, Hak Hotta, Masaru Kaku, Yoshiyuki Mochida

    Scientific reports   6   27784 - 27784   2016.6

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    Mutations in the Family with sequence similarity (FAM) 20 gene family are associated with mineralized tissue phenotypes in humans. Among these genes, FAM20A mutations are associated with Amelogenesis Imperfecta (AI) with gingival hyperplasia and nephrocalcinosis, while FAM20C mutations cause Raine syndrome, exhibiting bone and craniofacial/dental abnormalities. Although it has been demonstrated that Raine syndrome associated-FAM20C mutants prevented FAM20C kinase activity and secretion, overexpression of the catalytically inactive D478A FAM20C mutant was detected in both cell extracts and the media. This suggests that FAM20C secretion doesn't require its kinase activity, and that another molecule(s) may control the secretion. In this study, we found that extracellular FAM20C localization was increased when wild-type (WT), but not AI-forms of FAM20A was co-transfected. On the other hand, extracellular FAM20C was absent in the conditioned media of mouse embryonic fibroblasts (MEFs) derived from Fam20a knock-out (KO) mouse, while it was detected in the media from WT MEFs. We also showed that cells with the conditioned media of Fam20a WT MEFs mineralized, but those with the conditioned media of KO MEFs failed to mineralize in vitro. Our data thus demonstrate that FAM20A controls FAM20C localization that may assist in the extracellular function of FAM20C in mineralized tissues.

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  • Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Reviewed International journal

    Kazuo Noda, Megumi Kitami, Kohei Kitami, Masaru Kaku, Yoshihiro Komatsu

    Proceedings of the National Academy of Sciences of the United States of America   113 ( 19 )   E2589-97 - E2597   2016.5

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    The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRα) was present on the surface of primary cilia in wild-type osteoblasts, disruption of Ift20 down-regulated PDGFRα production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally in Ift20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression, Ift20 mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development.

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  • Mechanical Loading Stimulates Expression of Collagen Cross-Linking Associated Enzymes in Periodontal Ligament. Reviewed International journal

    Masaru Kaku, Juan Marcelo Rosales Rocabado, Megumi Kitami, Takako Ida, Yosuke Akiba, Mitsuo Yamauchi, Katsumi Uoshima

    Journal of cellular physiology   231 ( 4 )   926 - 33   2016.4

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    Type I collagen, a major extracellular component of the periodontal ligament (PDL), is post-translationally modified by a series of specific enzymes. Among the collagen-modifying enzymes, lysyl oxidase (LOX) is essential to initiate collagen cross-linking and lysyl hydroxylases (LHs) to regulate the cross-linking pathways that are important for tissue specific mechanical properties. The purpose of this study was to investigate the effects of mechanical loading on the expression of collagen-modifying enzymes and subsequent tissue changes in PDL. Primary human PDL cells were subjected to mechanical loading in a 3D collagen gel, and gene expression and collagen component were analyzed. Wistar rats were subjected to excessive occlusal loading with or without intra-peritoneal injection of a LOX inhibitor, β-aminopropionitrile (BAPN). Upon mechanical loading, gene expression of LH2 and LOX was significantly elevated, while that of COL1A2 was not affected on hPDL-derived cells. The mechanical loading also elevated formation of collagen α-chain dimers in 3D culture. The numbers of LH2 and LOX positive cells in PDL were significantly increased in an excessive occlusal loading model. Notably, an increase of LH2-positive cells was observed only at the bone-side of PDL. Intensity of picrosirius red staining was increased by excessive occlusal loading, but significantly diminished by BAPN treatment. These results demonstrated that mechanical loading induced collagen maturation in PDL by up-regulating collagen-modifying enzymes and subsequent collagen cross-linking which are important for PDL tissue maintenance. J. Cell. Physiol. 231: 926-933, 2016. © 2015 Wiley Periodicals, Inc.

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  • Correlation Between Stress Distributions and Biological Reactions in Bone Surrounding Implants That Support Cantilevers in Supraocclusal Contact in Rats. Reviewed International journal

    Ryohei Takano, Masako Nagasawa, Megumi Kitami, Juan Marcelo Rosales Rocabado, Masaru Kaku, Roxana Stegaroiu, Katsumi Uoshima

    Implant dentistry   25 ( 2 )   204 - 13   2016.4

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    PURPOSE: To investigate the relationship between stress distributions and peri-implant bone reactions around maxillary implants that support cantilevers in supraocclusal contact. MATERIALS AND METHODS: After molar extraction, 16 Wistar rats received a titanium implant unilaterally. After healing, 8 rats (control group) were killed and the others received implant-supported cantilever superstructures in supraocclusion (loaded group). After 5 days, they were killed. The maxillae of all rats were scanned by microcomputed tomography (μ-CT). Based on the μ-CT images, bone volumes were measured. For the loaded group, 3D finite element models were created and analyzed under 20-N vertical and 5-N lateral forces, successively. After μ-CT scanning, sections were prepared and observed histologically. RESULTS: When compared with the controls, the bone volume tended to decrease in the loaded group, but the difference was not statistically significant. On average, marginal bone resorption and stresses tended to be higher in 2 rats that occluded on the cantilever arm than in the others, which occluded right on the implant, nevertheless, calculated stress did not surpass the maximum elastic stress (yielding strength) of rat bone. However, at the implant-bone interface of these samples, partial bone resorption surrounded by signs of active resorption was histologically found. CONCLUSION: These findings suggest that in this occlusally loaded rat model, the stress distributions correlated to some extent with bone volume and morphological changes observed on μ-CT images and histological sections.

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  • Immunohistochemical localization of tenascin-C in rat periodontal ligament with reference to alveolar bone remodeling. Reviewed

    Rei Sato, Hiroki Fukuoka, Tamaki Yokohama-Tamaki, Masaru Kaku, Shunichi Shibata

    Anatomical science international   91 ( 2 )   196 - 206   2016.3

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    We investigated the immunohistochemical localization of tenascin-C in 8-week-old rat periodontal ligaments. Tenascin-C immunoreactivity was detected in zones along with cementum and alveolar bone, and more intensely on the resorption surface of alveolar bone than on the formation surface. On the resorbing surface, tenascin-C immunoreactivity was detected in Howship's lacunae without osteoclasts, and in the interfibrous space of the periodontal ligaments, indicating that this molecule works as an adhesion molecule between bone and fibers of periodontal ligaments. Upon experimental tooth movement by inserting elastic bands (Waldo method), the physiological resorption surface of alveolar bone under compressive force showed enhanced bone resorption and enhanced tenascin-C immunoreactivity. However, on the physiological bone formation surface under compressive force, bone resorption was seen only occasionally, and no enhanced tenascin-C immunoreactivity was noted. In an experiment involving excessive occlusal loading to rat molars, transient bone resorption occurred within interradicular septa, but no enhanced tenascin-C immunoreactivity was seen in the periodontal ligaments. These results indicate that tenascin-C works effectively on the bone resorbing surface of physiological alveolar bone remodeling sites, rather than on the non-physiological transient bone resorbing surface. Fibronectin immunoreactivity was distributed evenly in the periodontal ligaments under experimental conditions. Co-localization of tenascin-C and fibronectin immunoreactivity was observed in many regions, but mutually exclusive expression patterns were also seen in some regions, indicating that fibronectin might not be directly involved in alveolar bone remodeling, but may play a role via interaction with tenascin-C.

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  • Cell-based bone regeneration for alveolar ridge augmentation--cell source, endogenous cell recruitment and immunomodulatory function. Reviewed International journal

    Masaru Kaku, Yosuke Akiba, Kentaro Akiyama, Daisuke Akita, Masahiro Nishimura

    Journal of prosthodontic research   59 ( 2 )   96 - 112   2015.4

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    Alveolar ridge plays a pivotal role in supporting dental prosthesis particularly in edentulous and semi-dentulous patients. However the alveolar ridge undergoes atrophic change after tooth loss. The vertical and horizontal volume of the alveolar ridge restricts the design of dental prosthesis; thus, maintaining sufficient alveolar ridge volume is vital for successful oral rehabilitation. Recent progress in regenerative approaches has conferred marked benefits in prosthetic dentistry, enabling regeneration of the atrophic alveolar ridge. In order to achieve successful alveolar ridge augmentation, sufficient numbers of osteogenic cells are necessary; therefore, autologous osteoprogenitor cells are isolated, expanded in vitro, and transplanted to the specific anatomical site where the bone is required. Recent studies have gradually elucidated that transplanted osteoprogenitor cells are not only a source of bone forming osteoblasts, they appear to play multiple roles, such as recruitment of endogenous osteoprogenitor cells and immunomodulatory function, at the forefront of bone regeneration. This review focuses on the current consensus of cell-based bone augmentation therapies with emphasis on cell sources, transplanted cell survival, endogenous stem cell recruitment and immunomodulatory function of transplanted osteoprogenitor cells. Furthermore, if we were able to control the mobilization of endogenous osteoprogenitor cells, large-scale surgery may no longer be necessary. Such treatment strategy may open a new era of safer and more effective alveolar ridge augmentation treatment options.

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  • Analysis of Patients Visiting Niigata University Medical and Dental Hospital with Chief Complaints of Metal Allergy and/or Focal Infection in the Previous 8 Years Reviewed

    Akiba Y, Tomizuka K, Kaku M, Kawasaki M, Nagasawa M, Takano R, Uoshima K.

    The Indonesian Journal of Dental Research   1 ( 2 )   2015

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  • Mechano-regulation of collagen biosynthesis in periodontal ligament. Reviewed International journal

    Masaru Kaku, Mitsuo Yamauchi

    Journal of prosthodontic research   58 ( 4 )   193 - 207   2014.10

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    Periodontal ligament (PDL) plays critical roles in the development and maintenance of periodontium such as tooth eruption and dissipation of masticatory force. The mechanical properties of PDL are mainly derived from fibrillar type I collagen, the most abundant extracellular component. The biosynthesis of type I collagen is a long, complex process including a number of intra- and extracellular post-translational modifications. The final modification step is the formation of covalent intra- and intermolecular cross-links that provide collagen fibrils with stability and connectivity. It is now clear that collagen post-translational modifications are regulated by groups of specific enzymes and associated molecules in a tissue-specific manner; and these modifications appear to change in response to mechanical force. This review focuses on the effect of mechanical loading on collagen biosynthesis and fibrillogenesis in PDL with emphasis on the post-translational modifications of collagens, which is an important molecular aspect to understand in the field of prosthetic dentistry.

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  • ヒストン脱アセチル化酵素阻害剤(HDACI)を用いたエピジェネティクス制御による細胞分化制御を利用した新規骨増成法に関する研究

    秋葉 陽介, 江口 香里, Rashid Md. Mamunur, 加来 賢, 秋葉 奈美, 魚島 勝美

    日本歯科医学会誌   33   44 - 48   2014.3

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    ヒストン脱アセチル化酵素阻害剤(HDACI)は抗癌剤、抗てんかん薬として臨床応用される薬剤である。HDACIは遺伝子発現過程においてクロマチンリモデリングに関与し、遺伝子発現を活性化することが知られている。骨形成関連においてはRunx2の安定化に関与し骨芽細胞の分化を促進する作用が報告されている。そこで本研究では、はじめに上顎骨円筒形骨欠損修復モデルを用いてHDACIの全身投与における骨形成能の賦活化を検討することとした。HDACIにはバルプロ酸(Valproic acid(VPA))を使用し、投与法は腹腔内投与、投与期間は円筒形骨欠損形成前7日間とした。VPA全身投与群では窩洞内新生骨形成能促進、円筒形骨欠損治癒促進を示す像が窩洞形成14日から21日後にかけて観察された。次に頭蓋骨限界径骨欠損細胞移植モデルを作製し、大腿骨より採取した骨髄間質細胞をVPA処理し欠損部へ移植した。VPA処理細胞移植窩洞では対照群と比較して窩洞内の石灰化の亢進が観察された。本研究より骨増成法におけるHDACIの有効性が示され、更にHDACIの多機能性を応用した新規骨増成法開発の可能性が示唆された。(著者抄録)

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  • Royal jelly affects collagen crosslinking in bone of ovariectomized rats Reviewed

    Masaru Kaku, Juan Marcelo Rosales Rocabado, Megumi Kitami, Takako Ida, Katsumi Uoshima

    Journal of Functional Foods   7 ( 1 )   398 - 406   2014

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    Royal jelly (RJ) is an essential food for queen bees, and it reportedly has estrogen-like activity. The objective of this study was to evaluate the effect of RJ intake on bone quality with a focus on the posttranslational modifications of type I collagen. RJ was fed to ovariectomized (OVX) rats for 12. weeks. RJ intake did not affect OVX-induced reduction in bone volume at the femur epiphysis; however, the reduction of collagen crosslinks (pyridinoline and deoxypyridinoline), which represent an aspect of bone quality, were significantly mitigated. In cultured MC3T3-E1osteoblasts, RJ treatment did not affect cell proliferation, cell differentiation, matrix formation, or mineralization. However, RJ treatment did stimulate expression of plods, which encode lysyl hydroxylase isoforms that control the collagen crosslinking pathway, and it also affected collagen crosslinking. These results indicate that oral intake of RJ could improve bone quality by modulating the posttranslational modification of type I collagen. © 2014 Elsevier Ltd.

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  • Osteoblastic differentiation and mineralization ability of periosteum-derived cells compared with bone marrow and calvaria-derived cells Reviewed

    Rosales-Rocabado, J. M., Kaku, M., Kitami, M., Akiba, Y., Uoshima, K.

    J Oral Maxillofac Surg   72 ( 4 )   694.e1 - 694.e9   2014

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  • 【力を診る-歯列を守る力のマネジメント-】力が加わったら生体はどう変化するか 生体力学と力の生物学 歯根膜のメカノバイオロジー Reviewed

    魚島 勝美, 加来 賢

    補綴臨床   別冊 ( 力を診る-歯列を守る力のマネジメント- )   46 - 51   2012.12

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  • Identification and characterization of neural crest-derived cells in adult periodontal ligament of mice Reviewed

    Kaku, M., Komatsu, Y., Mochida, Y., Yamauchi, M., Mishina, Y., Ko, C. C.

    Arch Oral Biol   57 ( 12 )   1668 - 1675   2012

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  • Distribution and relative activity of matrix metalloproteinase-2 in human coronal dentin. Reviewed International journal

    Lee W Boushell, Masaru Kaku, Yoshiyuki Mochida, Mitsuo Yamauchi

    International journal of oral science   3 ( 4 )   192 - 9   2011.10

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    The presence of matrix metalloproteinase-2 (MMP-2) in dentin has been reported, but its distribution and activity level in mature human coronal dentin are not well understood. The purpose of this study was to determine the MMP-2 distribution and relative activity in demineralized dentin. Crowns of twenty eight human molars were sectioned into inner (ID), middle (MD), and outer dentin (OD) regions and demineralized. MMP-2 was extracted with 0.33 mol x L(-1) EDTA/2 mol xL(-1) guanidine-HCl, pH 7.4, and MMP-2 concentration was estimated with enzyme-linked immunoabsorbant assay (ELISA). Further characterization was accomplished by Western blotting analysis and gelatin zymography. The mean concentrations of MMP-2 per mg dentin protein in the dentin regions were significantly different (P = 0.043): 0.9 ng (ID), 0.4 ng (MD), and 2.2 ng (OD), respectively. The pattern of MMP-2 concentration was OD > ID > MD. Western blotting analysis detected -.66 and -72 kDa immunopositive proteins corresponding to pro- and mature MMP-2, respectively, in the ID and MD, and a -66 kDa protein in the OD. Gelatinolytic activity consistent with MMP-2 was detected in all regions. Interestingly, the pattern of levels of Western blot immunodetection and gelatinolytic activity was MD > ID > OD. The concentration of MMP-2 in human coronal dentin was highest in the region of dentin that contains the dentinoenamel junction and least in the middle region of dentin. However, levels of Western blot immunodetection and gelatinolytic activity did not correlate with the estimated regional concentrations of MMP-2, potentially indicating region specific protein interactions.

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  • Podocan-like protein: a novel small leucine-rich repeat matrix protein in bone. Reviewed International journal

    Yoshiyuki Mochida, Masaru Kaku, Keiko Yoshida, Michitsuna Katafuchi, Phimon Atsawasuwan, Mitsuo Yamauchi

    Biochemical and biophysical research communications   410 ( 2 )   333 - 8   2011.7

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    Recently, significant attention has been drawn to the biology of small leucine-rich repeat proteoglycans (SLRPs) due to their multiple functionalities in various cell types and tissues. Here, we characterize a novel SLRP member, "Podocan-like (Podnl) protein" identified by a bioinformatics approach. The Podnl protein has a signal peptide, a unique cysteine-rich N-terminal cluster, 21 leucine-rich repeat (LRR) motifs, and one putative N-glycosylation site. This protein is structurally similar to podocan in SLRPs. The gene was highly expressed in mineralized tissues and in osteoblastic cells and the high expression level was observed at and after matrix mineralization in vitro. Podnl was enriched in newly formed bones based on immunohistochemical analysis. When Podnl was transfected into osteoblastic cells, the protein with N-glycosylation was detected mainly in the cultured medium, indicating that Podnl is a secreted N-glycosylated protein. The endogenous Podnl protein was also present in bone matrix. These data provide a new insight into our understanding of the emerging SLRP functions in bone formation.

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  • Effect of cyclic mechanical loading on osteoclast recruitment in periodontal tissue Reviewed

    K. Nozaki, M. Kaku, Y. Yamashita, M. Yamauchi, H. Miura

    Journal of Periodontal Research   45 ( 1 )   8 - 15   2010.2

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    Background and Objective: It is well accepted that cyclic mechanical loading induces osteoclastogenesis in periodontal tissue, but its molecular mechanisms are not well understood, in part because of a lack of appropriate models. In this study, we investigated a novel device that allows cyclic mechanical loading to be performed in a well-controlled manner. Furthermore, by employing this model, the effect of cyclic loading on osteoclast recruitment in the periodontal tissue was described. Material and Methods: By using a newly developed device, the cyclic loading of 20 n (reference loading corresponding to the fracture hardness of dietary pellets) and two excessive loadings (i.e. 30 and 40 n) were applied to maxillary right molars in rats for up to 7 d, and osteoclast recruitment in the periodontal tissue was evaluated by analyzing relevant marker proteins using immunohistochemistry. Results: Osteoclastogenesis was induced by day 3 within alveolar bone subjected to a compression force of 30 n. With both 30 and 40 n loadings, cells that were positive to for tartrate-resistant acid phosphate, receptor activator of nuclear factor-κB ligand and osteoprotegerin were significantly increased in the alveolar bone/periodontal ligament in a time-dependent manner. Conclusion: A new device was developed that allows various levels of cyclic mechanical loading to be exerted. By using this device in rats, early events of osteoclast recruitment in the periodontal tissues were observed with excessive loadings in a time-dependent manner, indicating the usefulness of this model. © 2009 Blackwell Munksgaard.

    DOI: 10.1111/j.1600-0765.2008.01193.x

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  • Lysyl oxidase binds transforming growth factor-beta and regulates its signaling via amine oxidase activity. Reviewed International journal

    Phimon Atsawasuwan, Yoshiyuki Mochida, Michitsuna Katafuchi, Masaru Kaku, Keith S K Fong, Katalin Csiszar, Mitsuo Yamauchi

    The Journal of biological chemistry   283 ( 49 )   34229 - 40   2008.12

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    Lysyl oxidase (LOX), an amine oxidase critical for the initiation of collagen and elastin cross-linking, has recently been shown to regulate cellular activities possibly by modulating the functions of growth factors. In this study, we investigated the interaction between LOX and transforming growth factor-beta1 (TGF-beta1), a potent growth factor abundant in bone, the effect of LOX on TGF-beta1 signaling, and its potential mechanism. The specific binding between mature LOX and mature TGF-beta1 was demonstrated by immunoprecipitation and glutathione S-transferase pulldown assay in vitro. Both proteins were colocalized in the extracellular matrix in an osteoblastic cell culture system, and the binding complex was identified in the mineral-associated fraction of bone matrix. Furthermore, LOX suppressed TGF-beta1-induced Smad3 phosphorylation likely through its amine oxidase activity. The data indicate that LOX binds to mature TGF-beta1 and enzymatically regulates its signaling in bone and thus may play an important role in bone maintenance and remodeling.

    DOI: 10.1074/jbc.M803142200

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  • Immunohistochemical localization of matrixmetalloproteinase-2 in human coronal dentin. Reviewed International journal

    Lee W Boushell, Masaru Kaku, Yoshiyuki Mochida, Robert Bagnell, Mitsuo Yamauchi

    Archives of oral biology   53 ( 2 )   109 - 16   2008.2

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    UNLABELLED: While it is known that matrixmetalloproteinase-2 (MMP-2) is present in dentin, its distribution and role in human dentin formation and pathology are not well understood. OBJECTIVE: To characterize the distribution of MMP-2 in human coronal dentin. METHODS: Immunohistochemistry was used to investigate the distribution of MMP-2 in coronal dentin. Freshly extracted human premolars and third molars (age range 12-30) were fixed with formaldehyde, demineralized with 10% EDTA (pH 7.4) and embedded in paraffin. Serial sections were made and subjected to immunohistochemical analysis using a specific monoclonal anti-MMP-2 antibody. Immunoreactivity was visualized with 3,3'-diaminobenzidine substrate and observed under light microscopy. ImageJ software was used to calculate the relative amount/distribution of MMP-2. RESULTS: The analysis revealed immunoreactivity for MMP-2 throughout human coronal dentin. However, intense immunoreactivities were identified in a 90-200 microm zone adjacent to the pre-dentin as well as a 9-10 microm wide zone adjacent to the dentinoenamel junction (DEJ). CONCLUSION: MMP-2 has a specific distribution in human coronal dentin indicating it's involvement in extracellular matrix organization in predentin and the establishment of the DEJ.

    DOI: 10.1016/j.archoralbio.2007.09.012

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  • 1,25(OH)2D3 regulates collagen quality in an osteoblastic cell culture system Reviewed

    Nagaoka, H., Mochida, Y., Atsawasuwan, P., Kaku, M., Kondoh, T., Yamauchi, M.

    Biochem Biophys Res Commun   377 ( 2 )   674 - 678   2008

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    DOI: 10.1016/j.bbrc.2008.10.036

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  • The effect of hydroxyapatite/gemosil nanocomposites on extracellular matrix patterning through the promotion of osteoblast self-organization Reviewed

    Ching Chang Ko, Alice Ma, Masaru Kaku, Kai Li Liu, T. J.M. Luo, J. F.C. Tulloch, W. S. Hu

    8th World Biomaterials Congress 2008   2   611   2008

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    It was hypothesized that the hydroxyapatite(HAP)/GEMOSIL biomaterial could promote osteoblast (MC3T3) self-organization. This study using MC3T3 cell line demonstrated formation of trabecular bone-like extracellular matrix (ECM) on the material compared to unorganized ECM on the control (no-material). The study also initiated exploratory tests for the underlying mechanisms via gene analysis and proliferation assay.

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  • Post-translational modifications of collagen upon BMP-induced osteoblast differentiation. Reviewed International journal

    Masaru Kaku, Yoshiyuki Mochida, Phimon Atsawasuwan, Duenpim Parisuthiman, Mitsuo Yamauchi

    Biochemical and biophysical research communications   359 ( 3 )   463 - 8   2007.8

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    The pattern of collagen cross-linking is tissue specific primarily determined by the extent of hydroxylation and oxidation of specific lysine residues in the molecule. In this study, murine pre-myoblast cell line, C2C12 cells, were transdifferentiated into osteoblastic cells by bone morphogenetic protein (BMP)-2 treatment, and the gene expression of lysyl hydroxylases (LH1, 2a/b, and 3) and lysyl oxidase (LOX)/lysyl oxidase-like proteins (LOXL1-4), and the extent of hydroxylysine were analyzed. After 24h of treatment, the expression of most isoforms were upregulated up to 96h whereas LH2a and LOXL2 decreased with time. In the treated cells, both hydroxyproline and hydroxylysine were detected at day 7 and increased at day 14. The ratio of hydroxylysine to hydroxyproline was significantly increased at day 14. The results indicate that LHs and LOX/LOXLs are differentially responsive to BMP-induced osteoblast differentiation that may eventually lead to the specific collagen cross-linking pattern seen in bone.

    DOI: 10.1016/j.bbrc.2007.05.109

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  • Effects of formalin fixation and collagen cross-linking on T2 and magnetization transfer in bovine nasal cartilage. Reviewed International journal

    Kenneth W Fishbein, Yehezkiel A Gluzband, Masaru Kaku, Hasina Ambia-Sobhan, Sue A Shapses, Mitsuo Yamauchi, Richard G Spencer

    Magnetic resonance in medicine   57 ( 6 )   1000 - 11   2007.6

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    Endogenous collagen cross-links influence cartilage biomechanical properties and resistance to degradation. Formalin fixation modifies collagen residues and forms new cross-links in a dose-dependent manner. We tested the hypothesis that magnetization transfer (MT) effects and T(2) depend on collagen cross-linking in cartilage. These parameters were measured in bovine nasal cartilage (BNC) prior to fixation, after 9 weeks of immersion in formalin solutions ranging in concentration from 0% to 10%, and after NaBH(3)CN reduction and washing. T(2) decreased by 59.4% +/- 1.1% upon fixation in 10% formalin, and was 32.2% +/- 5.2% shorter than initial values after washing. The apparent MT rate increased 25.9% +/- 3.7% and 52.8% +/- 7.1% over baseline under these conditions. Biochemical assays showed no significant differences in water, proteoglycan, natural cross-link, or collagen content between the 0% and 10% formalin-treated samples, while amino acid analysis demonstrated losses in (hydroxy)lysine and tyrosine, and new peaks consistent with methylene cross-links in fixed samples only. We conclude that formalin fixation of cartilage results in significant decreases in T(2) and increases in MT parameters that persist after removal of unreacted formaldehyde. The collagen cross-links thus created are associated with large changes in MT and T(2), indicating that interpretation of T(2) and MT values in terms of cartilage macromolecular content must be made with caution.

    DOI: 10.1002/mrm.21216

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  • Nephrocan, a novel member of the small leucine-rich repeat protein family, is an inhibitor of transforming growth factor-beta signaling. Reviewed International journal

    Yoshiyuki Mochida, Duenpim Parisuthiman, Masaru Kaku, Jun-ichi Hanai, Vikas P Sukhatme, Mitsuo Yamauchi

    The Journal of biological chemistry   281 ( 47 )   36044 - 51   2006.11

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    In a search of new, small leucine-rich repeat proteoglycan/protein (SLRP) family members, a novel gene, nephrocan (NPN), has been identified. The gene consists of three exons, and based on the deduced amino acid sequence, NPN has 17 leucine-rich repeat motifs and unique cysteine-rich clusters both in the N and C termini, indicating that this gene belongs to a new class of SLRP family. NPN mRNA was predominantly expressed in kidney in adult mice, and during mouse embryogenesis, the expression was markedly increased in 11-day-old embryos at a time when early kidney development takes place. In the adult mouse kidney, NPN protein was located in distal tubules and collecting ducts. When NPN was overexpressed in cell culture, the protein was detected in the cultured medium, and upon treatment with N-glycosidase F, the molecular mass was lowered by approximately 14 kDa, indicating that NPN is a secreted N-glycosylated protein. Furthermore, transforming growth factor-beta (TGF-beta)-responsive 3TP promoter luciferase activity was down-regulated, and TGF-beta-induced Smad3 phosphorylation was also inhibited by NPN, suggesting that NPN suppresses TGF-beta/Smad signaling. Taken together, NPN is a novel member of the SLRP family that may play important roles in kidney development and pathophysiology by functioning as an endogenous inhibitor of TGF-beta signaling.

    DOI: 10.1074/jbc.M604787200

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  • Investigation of periodontal ligament reaction upon excessive occlusal load--osteopontin induction among periodontal ligament cells. Reviewed International journal

    Masaru Kaku, Katsumi Uoshima, Yasuo Yamashita, Hiroyuki Miura

    Journal of periodontal research   40 ( 1 )   59 - 66   2005.2

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    OBJECTIVE: The purpose of the present study was to investigate the reaction of the periodontal ligament to excessive occlusal loading by observing the histological changes and osteopontin induction. The possibility of ligand for receptor activator of nuclear factor kappaB (RANKL) participation in osteopontin induction was also discussed. BACKGROUND: The precise mechanism of periodontal ligament breakdown by excessive occlusal loading remains unclear. We established an experimental model for excessive occlusal loading in vivo. Osteopontin is known to be produced upon mechanical loading and is considered to induce the migration of osteoclasts to the resorption site. RANKL is one of the essential factors for osteoclast maturation and induces the constitutive induction of intracellular osteopontin in vitro. METHODS: The occlusal surface of the upper left first molars of rats was raised by steel wire bonding in order to induce occlusal trauma. The destruction of the periodontal ligament was observed and the production of osteopontin and RANKL by periodontal ligament cells was detected via immunohistochemistry. RESULTS: Our model produced wide-ranging destruction of the periodontal ligament. From day 3 to day 7, prominent compression of the periodontal ligament and osteoclast migration were observed at the apical interradicular septum. Osteopontin was detected in some osteoclasts, surrounding fibroblasts, and osteoblasts adjacent to the compression area. RANKL was observed from day 1 to day 7 around the osteoblasts and osteoclasts. CONCLUSIONS: Our model was useful for the detailed investigation of periodontal ligament breakdown during excessive occlusal loading. Although intracellular osteopontin was produced in osteoclasts with intermittent occlusal loading, the role of this protein in the cells was not clear. No correlation between RANKL distribution and osteopontin production in osteoclasts could be found.

    DOI: 10.1111/j.1600-0765.2004.00773.x

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  • Prosthodontics as biological science-mesenchymal stem cell perspective-

    熱田生, 秋山謙太郎, 加来賢

    日本補綴歯科学会誌(Web)   13   2021

  • 本学歯学部学生の歯冠修復学実習における支台歯形成自己評価能力について

    長澤麻沙子, 秋葉奈美, 秋葉陽介, 加来賢, 青柳裕仁, ROCABADO J, M Rosales, 江口香里, 魚島勝美

    日本歯科医学教育学会総会・学術大会プログラム・抄録集   38th   94   2019.6

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  • 矯正的歯の移動時のマウス歯根膜における増殖/静止期細胞の局在

    水越 優, 加来 賢, 北見 公平, 井田 貴子, 魚島 勝美, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   77回   231 - 231   2018.10

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  • A paradigm shift for bone quality in prosthetic dentistry

    黒嶋伸一郎, 黒嶋伸一郎, 加来賢, 加来賢, 石本卓也, 佐々木宗輝, 中野貴由, 澤瀬隆

    日本補綴歯科学会誌(Web)   10 ( 1 )   2018

  • がん抑制遺伝子BRCA1は顎顔面骨の形態形成に必須である

    北見 公平, 北見 恩美, 加来 賢, 小松 義広, 齋藤 功

    新潟歯学会雑誌   46 ( 2 )   112 - 113   2016.12

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  • マウス頭蓋骨発生におけるIFT20の役割

    野田 和男, 北見 恩美, 北見 公平, 加来 賢, 小松 義広

    日本骨代謝学会学術集会プログラム抄録集   34回   193 - 193   2016.7

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  • SDF-1/CXCR4による歯根膜への骨髄由来細胞の誘導

    加来 賢, 北見 恩美, Rosales Rocavado J.M., 井田 貴子, 秋葉 陽介, 魚島 勝美

    日本補綴歯科学会誌   8 ( 特別号 )   237 - 237   2016.7

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  • 骨質研究がもたらす歯科補綴の治療イノベーション

    加来賢, 石本卓也, 佐々木宗輝

    日本補綴歯科学会誌(Web)   8   103 (WEB ONLY)   2016.7

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  • SDF-1/CXCR4による歯根膜への骨髄由来細胞の誘導

    加来賢, 北見恩美, ROCAVADO JM Rosales, 井出貴子, 秋葉陽介, 魚島勝美

    日本補綴歯科学会誌(Web)   8   2016

  • 矯正的歯の移動における歯根膜中のコラーゲン修飾酵素の発現

    北見 公平, 加来 賢, 魚島 勝美, 齋藤 功

    日本矯正歯科学会大会プログラム・抄録集   73回   197 - 197   2014.10

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  • 多機能性エピジェネティクス化合物による骨増成法への多面的アプローチ

    秋葉 陽介, 江口 香里, 秋葉 奈美, 北見 恩美, マルセロ・ロサレス, 加来 賢, 魚島 勝美

    日本補綴歯科学会誌   6 ( 特別号 )   264 - 264   2014.5

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  • 歯根膜には大腿骨骨髄に由来する幹細胞が存在する

    加来 賢, 北見 恩美, Rosales Rocabado Juan Marcelo, 井田 貴子, 秋葉 陽介, 魚島 勝美

    日本補綴歯科学会誌   6 ( 特別号 )   104 - 104   2014.5

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  • 幹細胞を用いた組織再生法の新機軸-内在性幹細胞の動員-

    加来賢, 秋山謙太郎, 秋葉陽介, 秋田大輔

    日本補綴歯科学会学術大会プログラム・抄録集   123rd   2014

  • 歯根膜における骨髄由来細胞の局在と幹細胞マーカーの発現

    加来 賢, 北見 恩美, 井田 貴子, 秋葉 陽介, 魚島 勝美

    Journal of Oral Biosciences Supplement   2013   134 - 134   2013.9

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  • HDACi処理細胞移植による骨増成法の検討

    江口 香里, 秋葉 陽介, 秋葉 奈美, 北見 恩美, 加来 賢, 魚島 勝美

    Journal of Oral Biosciences Supplement   2013   189 - 189   2013.9

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  • 移植細胞の初期動態とストレスタンパク質HSP27導入による影響

    北見 恩美, 加来 賢, 井田 貴子, 秋葉 陽介, 魚島 勝美

    Journal of Oral Biosciences Supplement   2013   155 - 155   2013.9

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  • 移植細胞の初期動態とHSP27過剰発現骨芽細胞に関する分析

    北見 恩美, 加来 賢, 井田 貴子, 秋葉 陽介, 魚島 勝美

    新潟歯学会雑誌   43 ( 1 )   73 - 74   2013.6

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  • 歯根膜における骨髄由来細胞の局在と幹細胞マーカーの発現

    加来 賢, 野澤 恩美, Rosales Juan Marcelo, 井田 貴子, 秋葉 陽介, 魚島 勝美

    日本補綴歯科学会誌   5 ( 特別号 )   222 - 222   2013.5

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  • 各種HDACiが骨分化能、骨形成能に与える影響に関する研究

    江口 香里, 秋葉 奈美, Rosales Juan Marcelo, 野澤 恩美, 加来 賢, 秋葉 陽介, 魚島 勝美

    日本補綴歯科学会誌   5 ( 特別号 )   275 - 275   2013.5

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  • ジルコニア製インプラントドリルの生物学的評価に関する研究

    秋葉 陽介, 江口 香里, 秋葉 奈美, Rosales Juan Marcelo, 野澤 恩美, 加来 賢, 魚島 勝美

    日本補綴歯科学会誌   5 ( 特別号 )   167 - 167   2013.5

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  • 移植細胞の初期動態とHSP27の導入による細胞移植法の検討

    野澤 恩美, 加来 賢, Rosales Juan Marcelo, 井田 貴子, 秋葉 陽介, 魚島 勝美

    日本補綴歯科学会誌   5 ( 特別号 )   248 - 248   2013.5

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  • ラットにおけるHDACI全身投与による骨形成促進作用の検討

    秋葉 陽介, ラシッド・マムヌール, 秋葉 奈美, 野澤 恩美, 加来 賢, 魚島 勝美

    日本補綴歯科学会誌   5 ( 1 )   E128 - E128   2013.1

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  • 歯根膜における骨髄由来細胞の局在と幹細胞マーカーの発現

    加来賢, 北見恩美, 井田貴子, 秋葉陽介, 秋葉陽介, 魚島勝美, 魚島勝美

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • HDACi処理細胞移植による骨増成法の検討

    江口香里, 秋葉陽介, 秋葉陽介, 秋葉奈美, 秋葉奈美, 北見恩美, 北見恩美, 加来賢, 魚島勝美, 魚島勝美

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • 移植細胞の初期動態とストレスタンパク質HSP27導入による影響

    北見恩美, 北見恩美, 加来賢, 井田貴子, 秋葉陽介, 秋葉陽介, 魚島勝美, 魚島勝美

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • ヒストン脱アセチル化阻害剤全身投与による骨形成促進作用の検討

    秋葉 陽介, 野澤 恩美, 加来 賢, 魚島 勝美

    Journal of Oral Biosciences Supplement   2012   164 - 164   2012.9

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  • 機械的刺激に誘導されるコラーゲン修飾酵素が歯根膜組織に及ぼす影響

    加来 賢, 野澤 恩美, 秋葉 陽介, 魚島 勝美

    Journal of Oral Biosciences Supplement   2012   156 - 156   2012.9

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  • HDACIによる骨代謝制御機構を応用した骨造成法

    秋葉 陽介, 加来 賢, 魚島 勝美

    日本歯科医師会雑誌   65 ( 5 )   620 - 620   2012.8

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  • 機械的刺激によるコラーゲン翻訳後修飾を介した歯根膜組織安定化機構

    加来 賢, 野澤 恩美, Rosales J.M. Marcelo, 秋葉 陽介, 魚島 勝美

    日本歯科医師会雑誌   65 ( 5 )   617 - 617   2012.8

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  • 一口腔単位での問題発見・解決能力の涵養を目的とした治療方針立案演習

    秋葉 陽介, 加来 賢, 秋葉 奈美, 長澤 麻沙子, 魚島 勝美

    日本歯科医学教育学会総会・学術大会プログラム・抄録集   31回   68 - 68   2012.7

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  • ラットにおけるHDACI全身投与による骨再生

    秋葉 陽介, ラシッド・マムヌール, 秋葉 奈美, 加来 賢, 魚島 勝美

    日本補綴歯科学会誌   4 ( 特別号 )   198 - 198   2012.5

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  • 機械的刺激に誘導されるコラーゲン修飾酵素が歯根膜組織に及ぼす影響

    加来賢, 野澤恩美, 秋葉陽介, 魚島勝美, 魚島勝美

    Journal of Oral Biosciences Supplement (Web)   2012   2012

  • ヒストン脱アセチル化阻害剤全身投与による骨形成促進作用の検討

    秋葉陽介, 野澤恩美, 加来賢, 魚島勝美

    Journal of Oral Biosciences Supplement (Web)   2012   2012

  • In vitroにおける骨膜由来細胞の造骨細胞分化と石灰化能(Osteoblastic Differentiation and Mineralization Ability of Periosteum Derived Cells in vitro)

    Rocabado Juan Marcelo Rosales, 加来 賢, 野沢 恩美, 秋葉 陽介, 魚島 勝美

    新潟歯学会雑誌   41 ( 2 )   129 - 129   2011.12

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  • ヒストン脱アセチル化酵素阻害薬は骨膜由来細胞に骨原性細胞分化能を与える(Histone Deacetylase inhibitors have osteogenic differentiation effect on periosteum derived cells)

    Bhuiyan Al-Amin Md., 秋葉 陽介, 加来 賢, Rocabado Juan Marcelo Rosales, 魚島 勝美

    新潟歯学会雑誌   41 ( 2 )   129 - 129   2011.12

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  • Stem Cell Capability of Neural Crest Derived Cells in Adult PDL

    KAKU M, KOMATSU Y, MISHINA Y, UOSHIMA K, KO Ching-Chang

    1 ( 118 )   80 - 80   2010.8

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  • 間葉系幹細胞の骨形成系細胞誘導におけるヒストン脱アセチル化阻害剤の影響について

    秋葉陽介, アルアミン ブイアン, 川崎真依子, 加来賢, 加来賢, 魚島勝美, 魚島勝美

    日本補綴歯科学会学術大会プログラム・抄録集   119th   2010

  • 咀嚼能率検査とQOLアンケートによる固定性インプラント義歯と部分床義歯の比較

    川崎真依子, 吉田恵子, 加来賢, 秋葉陽介, 長澤麻沙子, 藤井規孝, ROSALES M J.M., AL-AMIN MD.B, RASHID MD.M, 魚島勝美

    日本補綴歯科学会学術大会プログラム・抄録集   119th   2010

  • コラーゲン修飾酵素の特異的発現が機械的刺激による歯根膜組織の安定化を制御する

    加来賢, 加来賢, 川崎真依子, 秋葉陽介, ROSALES M, RASHID M, 魚島勝美, 魚島勝美

    日本補綴歯科学会学術大会プログラム・抄録集   119th   2010

  • インプラント咬合動物実験モデルにおける骨の組織学的観察

    長澤麻沙子, 加来賢, 秋葉陽介, 吉田恵子, 川崎真依子, ROSALES Marcelo, AL‐AMIN Buiyan, 魚島勝美, 前田健康

    J Oral Biosci   51 ( Supplement )   101   2009.8

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    Language:Japanese  

    J-GLOBAL

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  • Establishment of the Rat Experiment Model to Reference the Mechanism of Occlusal Trauma Pathogenesis

    KAKU M, UOSHIMA K, YAMASHITA Y, MIURA H

    46 ( 107 )   83 - 83   2002.5

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Presentations

  • メカニカルストレスの制御を基盤とした歯科補綴治療戦略 先端テクノロジーが拓く2040年の補綴治療 〜バックキャスティング思考によるイノベーション戦略〜 Invited

    第24回日本歯科医学会学術大会  2021.9 

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  • 間葉系幹細胞による歯根膜維持メカニズムの解明と展望 〜間葉系幹細胞の研究から考える生物科学としての補綴歯科治療〜 Invited

    第130回日本補綴歯科学会学術大会  2021.6 

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  • 骨質をコラーゲンの生合成から理解する. 海外の基礎研究はインプラント治療をどう変えたか? Invited

    第48回公益社団法人日本口腔インプラント学会学術大会  2018 

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  • コラーゲンと細胞の多様性から見た歯根膜 Invited

    BioForum@Dental School 岡山大学  2017 

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  • Mechano-regulations of Collagen Biosynthesis and Related Cell Behaviors in Periodontal Ligament. Invited

    International Symposium on Development of Human Resources in Practical Oral Health and Treatment.  2016 

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  • 骨質研究がもたらす歯科補綴の治療イノベーション Invited

    第125回日本補綴歯科学会学術大会  2016 

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  • 硬軟組織難治性疾患に対する組織再建と研究戦略 Invited

    第124回日本補綴歯科学会学術大会  2015 

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  • コラーゲン生合成における翻訳語修飾とその分子機構 Invited

    第11回北里大学農医連携シンポジウム  2015 

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  • Mechanoregulations of Collagen Biosynthesis in Periodontal Ligament, Invited

    International Symposium on Mechanobiology 2014  2014 

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  • 歯根膜には大腿骨骨髄に由来する幹細胞が存在する Invited

    第123回日本補綴歯科学会  2014 

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  • 幹細胞を用いた組織再生法の新機軸−内在性幹細胞の動員− Invited

    第123回日本補綴歯科学会  2014 

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  • Mechanical Stress Mediated Tissue Homeostasis in Periodontal Ligament, Invited

    International Symposium on Human Resource Development towards Global Initiative  2013 

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  • メカニカルストレスと歯根膜の恒常性維持 Invited

    第121回日本補綴歯科学会  2012 

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  • 機械的刺激による骨組織の安定化機構―コラーゲン修飾酵素によるクロスリンクの生成― Invited

    第27回 歯科医学を中心とした総合的な研究を推進する集い  2011 

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Awards

  • 新潟歯学会賞

    2017.3   新潟歯学会  

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  • 課題口演優秀賞

    2014.5   日本補綴歯科学会  

    加来賢

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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  • Best Oral Presentation Award

    2013.4   Biennial Joint Congress of CPS-JPS-KAP  

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    Award type:Award from international society, conference, symposium, etc.  Country:Japan

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  • デンツプライ賞

    2002.10   日本補綴歯科学会  

    加来賢

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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Research Projects

  • Elucidation of stem cell differentiation mechanism by genetic cell tracing and gene network analysis

    Grant number:21K19895  2021.7 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)  Grant-in-Aid for Challenging Research (Exploratory)

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    Grant amount:\6240000 ( Direct Cost: \4800000 、 Indirect Cost:\1440000 )

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  • Proteome analysis of periodontal ligament matrix and development of regenerative material

    Grant number:21H03127  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

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  • Trans-omics analysis of the difference between Cortical and Trabecular bone.

    Grant number:21K09998  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

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  • 移植骨の骨細胞ネットワーク再構築と骨質に着目した自家骨移植の至適条件探索

    Grant number:20H03876  2020.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    魚島 勝美, 加来 賢, 長澤 麻沙子, 秋葉 陽介

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    Grant amount:\15600000 ( Direct Cost: \12000000 、 Indirect Cost:\3600000 )

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  • 足場材の硬さの違いを利用した上皮角化・非角化様式解明と培養口腔粘膜作成法への応用

    Grant number:20H03870  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    泉 健次, 芳賀 永, 石原 誠一郎, 加来 賢, 佐藤 大祐, 鈴木 絢子, 凌 一葦

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    Grant amount:\17680000 ( Direct Cost: \13600000 、 Indirect Cost:\4080000 )

    今年度は、コロナの影響で魚うろこコラーゲンの入手がままならず、既製品の魚うろこコラーゲンであるセルキャンパスしか手に入らなかったため、コラーゲンゲルの足場材の硬さをランダムに変えての培養口腔粘膜作成はできなかった。その分、セルキャンパスを用いて、コントロールの硬い培養皿面、同表面でカルシウム濃度をあげた分化培地、および、いわゆるコラーゲンゲルの軟性面で培養したケラチノサイトに対し、運動能解析と外注によるマイクロアレイ解析による網羅的遺伝子発現分析(現在までに2サンプル解析終了し、現在もう2サンプル培養しており、外注予定)を実施し、結果がでたら新たに分担者に加わっていただいた凌先生にヒートマップとクラスター図を作成してもらい、ビッグデータ解析をお願いする。
    細胞運動能解析では驚いたことに、コラーゲンゲル上の細胞運動能が、硬い培養皿面での細胞運動能より上回っていた。これは、いわゆる癌細胞のメカノバイオロジーと真逆の現象である。さらに、運動能が高いにも関わらず、ケラチノサイトの分化マーカー遺伝子発現が更新していることが示唆され、申請者の以前の基盤B研究で報告した結果とも相反するデータを得ており、今後考察を加え、メカニズム解明したい。また、コロナの影響で、研究分担者のいる北海道大学にAFMを用いた細胞の硬さ検索ができなかった。

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  • in vivo analysis of the occlusal force-responsive tissue stem cells in periodontal ligament

    Grant number:19K10200  2019.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • Elucidation of fate path and regulatory factors of periodontal ligament tissue stem cells

    Grant number:18H02989  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

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  • Development of a novel cellulose scaffold to potentiate the transplanted cells survival for bone regeneration

    Grant number:18K09680  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Rosales Marcelo

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    In this investigation, we used Methylcellulose (MC) to develop and optimize a novel scaffold material for bone cell transplantation. A series of MC scaffolds with different porosity, cross-link density, and size were fabricated. Results showed that Sodium Chloride (NaCl) has a great effect on the homogeneity and porosity of the scaffold in a dose-dependent manner. Crosslinking using carbonyldiimidazole (CDI) at different concentrations showed no significant changes in the scaffold’s characteristics. As a result of the lyophilization procedure, the thickness of the scaffold was significantly reduced; consequently, affecting the scaffold's structure and compromising the mechanical strength needed for tissue transplantation. Although the production of MC scaffolds was achieved, homogeneity between samples was rather difficult to obtain. Thus, further optimization is required for the production of viable cell transplantation scaffolds using methylcellulose.

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  • Analysis of the molecular mechanism of the mechanical stress response in osteoblasts through primary cilia

    Grant number:17K11639  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kakihara Yoshito

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    Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    In this study, we investigated how osteoblasts, which are involved in bone formation, perceive and respond to external stress. Molecular chaperones are known to be involved in a variety of stress responses. We focused our research on Pontin-Reptin chaperone, which is one of the emerging molecular chaperone. Our results suggest that the Pontin-Reptin mediates between cell cycle and primary cilia formation in osteoblasts.

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  • Analysis of the new role of a collagen network for the morphogenesis during the bone modeling

    Grant number:16H05549  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KAMIOKA HIROSHI, ADACHI Taiji, JAGER Edwin

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    Grant type:Competitive

    Grant amount:\17160000 ( Direct Cost: \13200000 、 Indirect Cost:\3960000 )

    We performed three-dimensional construction of collagen fibers in the osteogenic phase by using FIB-SEM. Furthermore, since this analysis extends to a cubic region of 25 micrometers per side, it was possible to capture a cellular network containing multiple osteocytes simultaneously. From these observations, processes extending from the osteoblasts to the matrix side have a certain regularity so as to avoid bundled collagen fibers. Furthermore, the bones pretreated with BAPN, which inhibits collagen fiber aggregation, cell processes extending from osteoblasts have no specific orientation. Thus, it has been revealed that changing the nature of bone matrix affects osteocyte network formation.

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  • Investigation of Bone Marrow-derived Stem Cells in Periodontal Ligament(Fostering Joint International Research)

    Grant number:15KK0337  2016 - 2019

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Fund for the Promotion of Joint International Research (Fostering Joint International Research)  Fund for the Promotion of Joint International Research (Fostering Joint International Research)

    Kaku Masaru

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    Grant amount:\14430000 ( Direct Cost: \11100000 、 Indirect Cost:\3330000 )

    Periodontal ligament plays important roles in the occlusal function therefore, its maintenance/regeneration is essential for achieving healthy longevity of life. It has been speculated that the growth factors and extracellular matrix proteins secreted by periodontal ligament-constituting cells regulate the maintenance/differentiation of periodontal ligament in a site-specific manner. However, the site-specificity of the periodontal ligament-constituting cells are still not well characterized. The present study revealed that not only the cells existing from the developmental stage but also the hematogenously supplied bone marrow-derived cells are present in the periodontal ligament. These cells contribute to the maintenance of periodontal ligament homeostasis.

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  • Development of optimally cross-linked collagen scaffold directed to differentiation control of stem cells

    Grant number:15K15704  2015.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Kaku Masaru

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    This study is based on the idea that control of collagen cross-linking in collagen-based cell transplantation carrier not only changes the mechanical properties of the material but also can promote osteoblast differentiation of mesenchymal stem cells. The aim of this project was to analyze the effect of collagen crosslinking on osteoblast differentiation of mesenchymal stem cells. The addition of a crosslinking inhibitor in the osteoblast culture system under certain conditions has succeeded in selectively reducing collagen crosslinking without affecting the amount of collagen produced. Furthermore, it was revealed that changes in collagen crosslinking affect proliferation, initial adhesion, and osteoblast differentiation of mesenchymal stem cells.

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  • Research on the Effect of Bone Quaility (Collagen) on Bone Metabolism and Its Mechanism

    Grant number:26293408  2014.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Uoshima Katsumi, MUBARAK Suliman

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    Grant type:Competitive

    Grant amount:\15860000 ( Direct Cost: \12200000 、 Indirect Cost:\3660000 )

    An in Vitro experiment using cultured cells was first conducted in order to analyze the influence of bone tissue collagen crosslink formation failure on osteoblast / osteoclast activity. As a result, in the cell culture system, the decrease in the amount of crosslink in the matrix increased the activity of osteoblasts and decreased the activity of osteoclasts. Serum bone formation markers increased in vivo and bone resorption markers tended to decrease. Furthermore, bone grafting experiments and implant installation experiments using an animal model of cross link formation failure resulted in bone formation around transplanted bone faster than control. A large amount of immature bone was formed around the implants earlier than the control.

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  • Investigation of Bone Marrow-derived Stem Cells in Periodontal Ligament

    Grant number:26293407  2014.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KAKU Masaru

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\16640000 ( Direct Cost: \12800000 、 Indirect Cost:\3840000 )

    The periodontal ligament (PDL) plays important roles in tooth function. The PDL harbors a remarkable reserve of multipotent stem cells, which maintain various types of cells. However, the sources of these stem cells, other than their developmental origin, are not well understood. In the present study, to elucidate the recruitment of bone marrow (BM)-derived stem cells in the PDL, green fluorescent protein (GFP)-expressing BM-derived cells were transplanted into the femoral BM of immunodeficient rats. Four weeks after cell transplantation, GFP-positive cells were detected in the PDL. To evaluate the functional significance of these BM-derived cells to the PDL, tooth replantation was performed. Seven days after tooth replantation, the number of GFP-positive cells significantly increased in PDL. These results indicate that the stem cells and their progeny in PDL are not only derived from their developmental origin but are also supplied from the BM via the blood as the need arises.

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  • biological evaluation of curcumin contributions for the bone formation

    Grant number:25462988  2013.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Akiba Nami

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    Grant amount:\4940000 ( Direct Cost: \3800000 、 Indirect Cost:\1140000 )

    Osteoporosis is one of the risk factor for implant therapy. Curcumin is known as a functional healthy food and able to remove active oxygen spices. Curcumin thought to be contributed to help bone formation and save people from osteoporosis. The aim of this study is to elucidate the mechanisms of acceleration for bone formation by curcumin. We fed curcumin to the normal rat and OVX rat, then observed maxillary cylindrical cavity healing, calvarias defect and femoral defect. Among these all samples, there are no significant difference could be seen.

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  • Mechanical Stress Regulates Collagen Crosslinking in Periodontal Ligament

    Grant number:24792068  2012.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAKU Masaru

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    The purpose of this study was to investigate the effects of excessive mechanical loading on the expression of collagen-modifying enzymes and subsequent crosslinking in PDL. Upon mechanical loading, gene expression of LH2, a collagen telopeptide specific Lysyl hydroxylase, was significantly upregulated, while that of COL1A2, encoding type I collagen was not affected. The expression of LH2 in PDL cells was also confirmed on an excessive occlusal loading rat model and expression was limited on the alveolar bone side of PDL in vivo. These results indicate that mechanical loading induces expression of collagen-modifying enzyme and controls subsequent collagen cross-linking, which are important for achieving long-term tissue maintenance and stability of PDL.

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  • Development of Cementum/PDL complex using human neural crest derived stem cells from PDL.

    Grant number:22791875  2010 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAKU Masaru

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    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    The purpose of this study was to characterize the neural crest(NC) derived cells in adult periodontal ligament by using NC-traceable transgenic mice. Our study reveled that the distribution and prevalence of NC derived cells in adult PDL. Furthermore, the distribution of NC stem cell marker and mesenchymal stem cell marker positive cells were distinct.

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  • 新規幹細胞源として期待される神経堤由来幹細胞の歯根膜からの分離解析

    Grant number:21890081  2009 - 2010

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    加来 賢

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    Grant amount:\2600000 ( Direct Cost: \2000000 、 Indirect Cost:\600000 )

    歯根膜は発生段階において間葉のみならず神経堤にも由来しているが、これまでに歯根膜において同定された幹細胞は間葉に由来するものばかりであった。そこで申請者らは神経堤由来細胞を追跡可能な遺伝子改変マウスを用いて免疫組織学的に検索を行ったところ、神経堤由来幹細胞の存在を強く示唆する知見を得る事に成功し、この研究では神経堤由来幹細胞を分離抽出し、その分化能および力学的刺激への応答能を解析し、歯周組織再建に向けた新たな幹細胞源を明らかにすることを目的とした。我々は組織標本上にて歯根膜細胞中のさらなる幹細胞マーカーの発現を検索し、HNK-1/CD57,SOX10の発現が、神経堤由来細胞において高頻度で見られることを明らかにした。現在マウスおよびヒト歯根膜由来細胞を用い、神経堤幹細胞について幹細胞能を維持した状態での培養の至適条件を検索中である。当初予定していた血清を含まない培養条件では生細胞が得られなかったため、神経幹細胞培養に用いられる添加物を使用した条件を検討中であるている。これまでのところ異なる培養条件において異なる形態を示す細胞群の分離に成功しており、さらなる条件の絞り込みをすすめている。また、使用を予定した遺伝子改変マウスはミシガン大学からの移管が大幅に遅れたため、東京医科歯科大学より移管する事とした。現在動物実験施設に於いて手続き中である。

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Teaching Experience (researchmap)

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Teaching Experience

  • 生涯にわたる歯と咬合

    2022
    Institution name:新潟大学

  • 総合模型実習

    2021
    Institution name:新潟大学

  • 固定性補綴治療学IB

    2021
    Institution name:新潟大学

  • 固定性補綴治療学IIB

    2021
    Institution name:新潟大学

  • 固定性補綴治療学IA

    2021
    Institution name:新潟大学

  • 固定性補綴治療学IIA

    2021
    Institution name:新潟大学

  • 歯の形態学

    2020
    Institution name:新潟大学

  • 固定性補綴治療学ⅠA

    2018
    Institution name:新潟大学

  • 欠損補綴学Ⅱ

    2014
    -
    2015
    Institution name:新潟大学

  • 歯冠修復学

    2011
    -
    2017
    Institution name:新潟大学

  • 早期臨床実習Ⅱ

    2011
    -
    2015
    Institution name:新潟大学

  • 選択実習Ⅱ

    2011
    -
    2013
    Institution name:新潟大学

  • 歯の形態と機能

    2010
    -
    2016
    Institution name:新潟大学

  • 生体材料学

    2010
    -
    2014
    Institution name:新潟大学

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