Updated on 2025/10/23

写真a

 
OKAMOTO Kuniaki
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • (BLANK) ( Kyushu University )

Research Interests

  • osteoclast

  • oral cancer

  • intercellular transport

Research Areas

  • Life Science / Oral biological science

Professional Memberships

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Papers

  • P. gingivalis–Infected Macrophage Extracellular Vesicles Cause Adverse Pregnancy Outcomes

    A. Tanai, Y. Fukuhara, T. Eguchi, H. Kawai, K. Ueda, K. Ochiai, M. Ikegame, K. Okamoto, H. Okamura

    Journal of Dental Research   104 ( 1 )   54 - 63   2024.12

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    Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

    Periodontitis is a chronic inflammatory disease triggered by oral bacterial infection, with the bacterium Porphyromonas gingivalis being a major causative agent. The association between periodontitis and various systemic diseases has been demonstrated. Recent research has also highlighted the relationship between the aggravation of maternal periodontitis and adverse pregnancy outcomes such as preterm birth and low birth weight. However, the molecular mechanisms underlying how factors from periodontitis influence pregnancy and fetal development remain unclear. Extracellular vesicles (EVs) are nano-sized spherical particles secreted into the tissue microenvironment by various types of cells. EVs have garnered interest in recent years due to their role in intercellular communication. In the present study, we investigated whether EVs derived from P. gingivalis–infected macrophages (Pg-inf EVs) reach the feto-placental unit and influence fetal development. Through a series of in vivo experiments in mice, we demonstrated that Pg-inf EVs translocated to the feto-placental unit and impaired fetal development in size and weight. Histological analysis revealed disoriented blood vessel alignment and impaired angiogenesis in the placentas of Pg-inf EV–injected groups, indicative of compromised placental function. Proteome analysis revealed a significant decrease in Vegfr1 expression in the placentas of the experimental group. Moreover, Pg-inf EVs reduced VEGFR1 expression in cultured human vascular endothelial cells, highlighting a potential molecular mechanism through which these EVs exert their effects on placental angiogenesis. This is the first study to reveal a novel pathway in which oral bacteria–infected macrophage EVs in maternal periodontitis affect pregnancy via the feto-placental unit.

    DOI： 10.1177/00220345241285132

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    Other Link： https://journals.sagepub.com/doi/full-xml/10.1177/00220345241285132

  • Herbal medicine Ninjinyoeito inhibits RANKL-induced osteoclast differentiation and bone resorption activity by regulating NF-κB and MAPK pathway

    Kaung Htike, Kunihiro Yoshida, Takanori Eguchi, Katsuki Takebe, Xueming Li, Yaxin Qu, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Journal of Oral Biosciences   66 ( 4 )   49 - 57   2024.12

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

    DOI： 10.1016/j.job.2024.09.007

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  • Dennd2c Negatively Controls Multinucleation and Differentiation in Osteoclasts by Regulating Actin Polymerization and Protrusion Formation

    Yu Koyanagi, Eiko Sakai, Yu Yamaguchi, Fatima Farhana, Yohsuke Taira, Kuniaki Okamoto, Hiroshi Murata, Takayuki Tsukuba

    International Journal of Molecular Sciences   25 ( 21 )   11479 - 11479   2024.10

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    Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages.

    DOI： 10.3390/ijms252111479

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  • New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family

    Katsuki Takebe, Mamoru Suzuki, Yumiko Hara, Takuya Katsutani, Naomi Motoyoshi, Tadashi Itagaki, Shuhei Miyakawa, Kuniaki Okamoto, Kaori Fukuzawa, Hiroko Kobayashi

    ACS Bio & Med Chem Au   4 ( 5 )   257 - 267   2024.9

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    Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acsbiomedchemau.4c00046

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  • Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

    Tatsuo Ogawa, Kisho Ono, Shoji Ryumon, Hotaka Kawai, Tomoya Nakamura, Koki Umemori, Kunihiro Yoshida, Hideka Kanemoto, Kyoichi Obata, Norie Yoshioka, Tatsuo Okui, Kuniaki Okamoto, Hitoshi Nagatsuka, Soichiro Ibaragi

    Head & Neck   46 ( 3 )   636 - 650   2024.1

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

    Abstract

    Background

    Cisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP‐resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC.

    Methods

    We established CDDP‐resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression.

    Results

    The CDDP‐resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell‐killing effect.

    Conclusions

    EVs were involved in the ATP7B‐mediated mechanism underlying CDDP resistance. Further clarification of the EV‐induced CDDP‐resistance mechanism may lead to novel therapeutic strategies for HNSCC.

    DOI： 10.1002/hed.27620

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  • Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. Reviewed International journal

    Kunihiro Yoshida, Kaung Htike, Takanori Eguchi, Hotaka Kawai, Htoo Shwe Eain, Manh Tien Tran, Chiharu Sogawa, Koki Umemori, Tatsuo Ogawa, Hideka Kanemoto, Kisho Ono, Hitoshi Nagatsuka, Akira Sasaki, Soichiro Ibaragi, Kuniaki Okamoto

    Journal of oral biosciences   2023.12

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

    OBJECTIVES: Rab11(Rab11a and Rab11b) localizes primarily along recycling endosomes in cells and is involved in various intracellular trafficking processes, including membrane receptor recycling and secretion of exosomes or small extracellular vesicles (EVs). Although Rab11 is closely associated with the progression and metastasis of various cancer types, little is known about Rab11' role in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the roles of Rab11a and Rab11b in HNSCC. METHODS: The clinical significance of Rab11 expression in HNSCC was investigated using a public database and tissue microarray analysis. Stable cell lines with loss and gain of Rab11a or Rab11b were originally established to investigate their roles in the proliferative, migratory, and invasive capabilities of HNSCC cells. RESULTS: Database analysis revealed a significant association between Rab11b mRNA expression and a favorable patient survival rate in HNSCC. Tissue microarray analysis revealed that Rab11b expression was the highest in normal tissues and gradually decreased across the stages of HNSCC progression. Overexpression of Rab11a or Rab11b resulted in a decrease in epidermal growth factor receptor (EGFR), Epithelial cell adhesion molecule (EpCAM) exosome secretion, and the migratory and invasive potential of HNSCC cells. The knockdown of Rab11a or Rab11b increased EpCAM/CD9 exosome secretion in addition to the migratory and invasive potential of HNSCC cells. CONCLUSIONS: Rab11 suppresses HNSCC by regulating EGFR recycling and EpCAM exosome secretion in HNSCC cells. Our results indicate that Rab11b is a superior prognostic indicator of HNSCC and holds promise for developing novel therapeutic strategies.

    DOI： 10.1016/j.job.2023.11.007

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  • Abr, a Rho-regulating protein, modulates osteoclastogenesis by enhancing lamellipodia formation by interacting with poly(ADP-ribose) glycohydrolase. Reviewed International journal

    Fatima Farhana, Eiko Sakai, Yu Koyanagi, Yu Yamaguchi, Mohammad Ibtehaz Alam, Kuniaki Okamoto, Takayuki Tsukuba

    Molecular biology reports   2023.7

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

    BACKGROUND: Osteoclasts are multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage lineage. During osteoclast differentiation, Rho GTPases are involved in various processes, including cell migration, adhesion, and polarity. However, the role of Rho-regulatory molecules in the regulation of osteoclast differentiation remains unclear. In this study, among these genes, we focused on active breakpoint cluster region-related (Abr) protein that is a multifunctional regulator of Rho GTPases. METHODS AND RESULTS: We examined using knockdown and overexpression experiments in RANKL-stimulated RAW-D macrophages whether Abr regulates osteoclast differentiation and cell morphology. We observed an increase in Abr expression during osteoclast differentiation and identified expression of a variant of the Abr gene in osteoclasts. Knockdown of Abr suppressed osteoclast differentiation and resorption. Abr knockdown markedly inhibited the expression of osteoclast markers, such as Nfatc1, c-fos, Src, and Ctsk in osteoclasts. Conversely, overexpression of Abr enhanced the formation of multinucleated osteoclasts, bone resorption activity, and osteoclast marker gene expression. Moreover, Abr overexpression accelerated lamellipodia formation and induced the formation of well-developed actin in osteoclasts. Importantly, the Abr protein interacted with poly(ADP-ribose) glycohydrolase (PARG) and Rho GTPases, including RhoA, Rac1/2/3, and Cdc42 in osteoclasts. CONCLUSIONS: Taken together, these results indicate that Abr modulates osteoclastogenesis by enhancing lamellipodia formation via its interaction with PARG.

    DOI： 10.1007/s11033-023-08690-0

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  • Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy. Reviewed International journal

    Mayuko Noguromi, Yu Yamaguchi, Keiko Sato, Shun Oyakawa, Kuniaki Okamoto, Hiroshi Murata, Takayuki Tsukuba, Tomoko Kadowaki

    International journal of molecular sciences   24 ( 2 )   2023.1

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

    Rab44 was recently identified as an atypical Rab GTPase that possesses EF-hand and coiled-coil domains at the N-terminus, and a Rab-GTPase domain at the C-terminus. Rab44 is highly expressed in immune-related cells such as mast cells, macrophages, osteoclasts, and granulocyte-lineage cells in the bone marrow. Therefore, it is speculated that Rab44 is involved in the inflammation and differentiation of immune cells. However, little is known about the role of Rab44 in inflammation. In this study, we showed that Rab44 was upregulated during the early phase of differentiation of M1- and M2-type macrophages. Rab44-deficient mice exhibited impaired tumor necrosis factor alpha and interleukin-10 production after lipopolysaccharide (LPS) stimulation. The number of granulocytes in Rab44-deficient mice was lower, but the lymphocyte count in Rab44-deficient mice was significantly higher than that in wild-type mice after LPS stimulation. Moreover, Rab44-deficient macrophages showed impaired nickel-induced toxicity, and Rab44-deficient mice showed impaired nickel-induced hypersensitivity. Upon nickel hypersensitivity induction, Rab44-deficient mice showed different frequencies of immune cells in the blood and ears. Thus, it is likely that Rab44 is implicated in immune cell differentiation and inflammation, and Rab44 deficiency induces impaired immune responses to nickel allergies.

    DOI： 10.3390/ijms24020994

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  • HSP90 drives the Rab11a‐mediated vesicular transport of the cell surface receptors in osteoclasts Reviewed International journal

    Manh Tien Tran, Yuka Okusha, Kaung Htike, Chiharu Sogawa, Takanori Eguchi, Tomoko Kadowaki, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Cell Biochemistry and Function   40 ( 8 )   838 - 855   2022.12

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

    Rab11a, which ubiquitously localizes to early and recycling endosomes, is required for regulating the vesicular transport of cellular cargos. Interestingly, our previous study revealed that Rab11a served as a negative regulator of osteoclastogenesis by facilitating the lysosomal proteolysis of (1) colony-stimulating factor-1 (c-fms) receptor and (2) receptor activator of nuclear factor-κB (RANK) receptor, thereby resulting in inhibition of osteoclast (OC) differentiation, maturation, and bone-resorbing activity. However, the molecular mechanisms of how Rab11a negatively affected osteoclastogenesis were largely unknown. Heat shock protein (HSP90), including two isoforms HSP90α and HSP90β, necessitates the stability, maturation, and activity of a broad range of its clients, and is essentially required for a vast array of signal transduction pathways in nonstressful conditions. Furthermore, cumulative evidence suggests that HSP90 is a vital element of the vesicular transport network. Indeed, our recent study revealed that HSP90, a novel effector protein of Rab11b, modulated Rab11b-mediated osteoclastogenesis. In this study, we also found that Rab11a interacted with both HSP90α and HSP90β in OCs. Upon blockade of HSP90 ATPase activity by a specific inhibitor(17-allylamino-demethoxygeldanamycin), we showed that (1) the ATPase domain of HSP90 was a prerequisite for the interaction between HSP90 and Rab11a, and (2) the interaction of HSP90 to Rab11a sufficiently maintained the inhibitory effects of Rab11a on osteoclastogenesis. Altogether, our findings undoubtedly indicate a novel role of HSP90 in regulating Rab11a-mediated osteoclastogenesis.

    DOI： 10.1002/cbf.3745

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cbf.3745

  • Coronin 1CはGDP特異的Rab44エフェクターでありマクロファージの細胞運動を調節することで破骨細胞形成を制御する

    山口 優, 門脇 知子, 相原 希美, 大山 要, 岡元 邦彰, 坂井 詠子, 筑波 隆幸

    日本生化学会大会プログラム・講演要旨集   95回   1P - 175   2022.11

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    Language：Japanese   Publisher：(公社)日本生化学会  

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  • HSP90 drives the Rab11a-Mediated Vesicular Transport of the Cell Surface Receptors in Osteoclasts Reviewed International coauthorship

    Tran MT, Okusha Y, Htike K, Sogawa C, Eguchi E, Kadowaki T, Sakai E, Tsukuba T, Okamoto K.

    Cell Biochem Funct   40 ( 8 )   828 - 855   2022.9

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    DOI： 10.1002/cbf.3745.

  • 高転移性癌細胞由来の細胞外小胞に搭載されたMMP3によるCtgf/Ccn2発現調節機能と癌転移促進(Extracellular vesicles enriched with moonlighting metalloproteinase are highly transmissive, Pro-tumorigenic, and trans-activates cellular communication network factor(CCN2/CTGF): CRISPR against cancer)

    奥舎 有加, 江口 傑徳, Tran Manh T., 十川 千春, 吉田 賀弥, 板垣 まみ, Taha Eman A., 小野 喜章, 青山 絵理子, 岡村 裕彦, 小崎 健一, Calderwood Stuart K., 滝川 正春, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2022   35 - 35   2022.9

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    Language：Japanese   Publisher：(一社)歯科基礎医学会  

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  • 細胞外小胞に搭載されたムーンライティングMMPによるマトリックス制御と転移促進(Metalloproteinase on extracellular vesicles regulates ECM in tumor microenvironment and promotes invasion and metastasis)

    奥舎 有加, タハ・エマン, 陸 彦因, シータ・モナ, 河合 穂高, 十川 千春, 岡元 邦彰, 江口 傑徳

    日本癌学会総会記事   81回   P - 1118   2022.9

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    Language：English   Publisher：(一社)日本癌学会  

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  • Coronin1C Is a GDP-Specific Rab44 Effector That Controls Osteoclast Formation by Regulating Cell Motility in Macrophages. Reviewed International journal

    Yu Yamaguchi, Tomoko Kadowaki, Nozomi Aibara, Kaname Ohyama, Kuniaki Okamoto, Eiko Sakai, Takayuki Tsukuba

    International journal of molecular sciences   23 ( 12 )   2022.6

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    Osteoclasts are multinucleated bone-resorbing cells that are formed by the fusion of macrophages. Recently, we identified Rab44, a large Rab GTPase, as an upregulated gene during osteoclast differentiation that negatively regulates osteoclast differentiation. However, the molecular mechanisms by which Rab44 negatively regulates osteoclast differentiation remain unknown. Here, we found that the GDP form of Rab44 interacted with the actin-binding protein, Coronin1C, in murine macrophages. Immunoprecipitation experiments revealed that the interaction of Rab44 and Coronin1C occurred in wild-type and a dominant-negative (DN) mutant of Rab44, but not in a constitutively active (CA) mutant of Rab44. Consistent with these findings, the expression of the CA mutant inhibited osteoclast differentiation, whereas that of the DN mutant enhanced this differentiation. Using a phase-contrast microscope, Coronin1C-knockdown osteoclasts apparently impaired multinuclear formation. Moreover, Coronin1C knockdown impaired the migration and chemotaxis of RAW-D macrophages. An in vivo experimental system demonstrated that Coronin1C knockdown suppresses osteoclastogenesis. Therefore, the decreased cell formation and fusion of Coronin1C-depleted osteoclasts might be due to the decreased migration of Coronin1C-knockdown macrophages. These results indicate that Coronin1C is a GDP-specific Rab44 effector that controls osteoclast formation by regulating cell motility in macrophages.

    DOI： 10.3390/ijms23126619

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  • Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis Reviewed

    Yunxia Feng, Manh Tien Tran, Yanyin Lu, Kaung Htike, Yuka Okusha, Chiharu Sogawa, Takanori Eguchi, Tomoko Kadowaki, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Cell Biochemistry and Function   2022.3

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

    DOI： 10.1002/cbf.3691

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cbf.3691

  • 口腔癌のエクソソームを介した腫瘍進展機序の解明と新規治療戦略の開発に向けて 分子シャペロン搭載エクソソームの可能性

    小野 喜章, 江口 傑徳, 十川 千春, 奥舎 有加, 岡元 邦彰, 佐々木 朗

    口腔組織培養学会誌   31 ( 1 )   33 - 34   2022.3

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    Language：Japanese   Publisher：日本口腔組織培養学会  

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  • Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment Reviewed

    May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Shuta Tomida, Takanori Eguchi, Kisho Ono, Qiusheng Shan, Toshiaki Ohara, Saori Yoshida, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Kuniaki Okamoto, Akira Sasaki, Hitoshi Nagatsuka

    JCI Insight   2021.12

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    Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

    DOI： 10.1172/jci.insight.148960

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  • A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport Reviewed

    Manh Tien Tran, Yuka Okusha, Yunxia Feng, Chiharu Sogawa, Takanori Eguchi, Tomoko Kadowaki, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research   1868 ( 10 )   119096 - 119096   2021.9

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

    DOI： 10.1016/j.bbamcr.2021.119096

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  • Exosome-Based Molecular Transfer Activity of Macrophage-Like Cells Involves Viability of Oral Carcinoma Cells: Size Exclusion Chromatography and Concentration Filter Method Reviewed International journal

    Yanyin Lu, Takanori Eguchi, Chiharu Sogawa, Eman A. Taha, Manh Tien Tran, Toshiki Nara, Penggong Wei, Shiro Fukuoka, Takuya Miyawaki, Kuniaki Okamoto

    Cells   10 ( 6 )   1328 - 1328   2021.5

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    Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    Extracellular vesicles (EV) heterogeneity is a crucial issue in biology and medicine. In addition, tumor-associated macrophages are key components in cancer microenvironment and immunology. We developed a combination method of size exclusion chromatography and concentration filters (SEC-CF) and aimed to characterize different EV types by their size, cargo types, and functions. A human monocytic leukemia cell line THP-1 was differentiated to CD14-positive macrophage-like cells by stimulation with PMA (phorbol 12-myristate 13-acetate) but not M1 or M2 types. Using the SEC-CF method, the following five EV types were fractionated from the culture supernatant of macrophage-like cells: (i) rare large EVs (500–3000 nm) reminiscent of apoptosomes, (ii) EVs (100–500 nm) reminiscent of microvesicles (or microparticles), (iii) EVs (80–300 nm) containing CD9-positive large exosomes (EXO-L), (iv) EVs (20–200 nm) containing unidentified vesicles/particles, and (v) EVs (10–70 nm) containing CD63/HSP90-positive small exosomes (EXO-S) and particles. For a molecular transfer assay, we developed a THP-1-based stable cell line producing a GFP-fused palmitoylation signal (palmGFP) associated with the membrane. The THP1/palmGFP cells were differentiated into macrophages producing palmGFP-contained EVs. The macrophage/palmGFP-secreted EXO-S and EXO-L efficiently transferred the palmGFP to receiver human oral carcinoma cells (HSC-3/palmTomato), as compared to other EV types. In addition, the macrophage-secreted EXO-S and EXO-L significantly reduced the cell viability (ATP content) in oral carcinoma cells. Taken together, the SEC-CF method is useful for the purification of large and small exosomes with higher molecular transfer activities, enabling efficient molecular delivery to target cells.

    DOI： 10.3390/cells10061328

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  • Macrophage-Derived Small Exosomes: Efficient Transmission and Cytotoxicity to Cancer Cells Reviewed

    Yanyin Lu, Takanori Eguchi, Chiharu Sogawa, Eman A. Taha, Manh Tien Tran, Toshiki Nara, Penggong Wei, Shiro Fukuoka, Takuya Miyawaki, Kuniaki Okamoto

    2021.4

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    Tumor-associated macrophages are a key component in the tumor microenvironment, secreting extracellular vesicles (EVs) such as exosomes and other various factors for intercellular communication. However, macrophage-derived EVs heterogeneity and their cytotoxicity to cancer cells has not been well understood. Here, we aimed to separately isolate various types of macro-phage-EVs by size exclusion chromatography (SEC) method and investigate EV transmission and cytotoxicity to oral cancer cells. For fluorescence-labeling of cellular and EV membranes, palmitoylation signal-fused GFP and tdTomato were expressed in THP-1 monocytic cells and HSC-3 oral cancer cells, respectively. We found that fluorescence-labeled EVs secreted by macrophages were highly transmissive to oral cancer cells than those from parental monocytic cells. In a co-culture system and conditioned medium (CM), a macrophage-secreted unidentified factor was cytotoxic to oral cancer cells. We fractionated macrophage-derived EVs by the SEC method and performed western blotting to characterize various EV types. Three fractions were characterized: small exosomes (EXO-S: < 50 nm) fraction containing HSP90α, HSP90β, CD63 (EV marker) and β-actin; large exosomes (EXO-L: 50-200 nm) fraction containing CD9 (EV marker) and HSP90β; large EVs (100-500 nm) fraction. Notably, the macrophage-derived small exosomes fraction was cytotoxic to oral cancer cells, while large exosomes and large EVs were not. There-fore, it was implicated that macrophage-derived small exosomes are cytotoxic with high trans-mission potential to cancer cells.

    DOI： 10.20944/preprints202104.0464.v1

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  • Rab44 isoforms similarly promote lysosomal exocytosis, but exhibit differential localization in mast cells Reviewed

    Tomoko Kadowaki, Yu Yamaguchi, Kohei Ogawa, Mitsuko Tokuhisa, Kuniaki Okamoto, Takayuki Tsukuba

    FEBS Open Bio   11 ( 4 )   1165 - 1185   2021.4

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

    DOI： 10.1002/2211-5463.13133

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/2211-5463.13133

  • Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer. Reviewed International journal

    Chiharu Sogawa, Takanori Eguchi, Yuri Namba, Yuka Okusha, Eriko Aoyama, Kazumi Ohyama, Kuniaki Okamoto

    Cells   10 ( 2 )   2021.2

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    Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have been reported using 2D culture systems, whereas 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aimed to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyrosine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter the tumoroid growth of metastatic colorectal cancer (mCRC). Gene expression signatures of highly metastatic aggregative CRC (LuM1 cells) vs. low-metastatic, non-aggregative CRC (Colon26 and NM11 cells) were analyzed using microarray. To establish a 3D culture-based multiplexing reporter assay system, LuM1 was stably transfected with the Mmp9 promoter-driven ZsGreen fluorescence reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate®, a gel-free 3D culture device. LuM1 cells highly expressed mRNA encoding ABCG2 (a drug resistance pump, i.e., CSC/CIC marker), other CSC/CIC markers (DLL1, EpCAM, podoplanin, STAT3/5), pluripotent stem cell markers (Sox4/7, N-myc, GATA3, Nanog), and metastatic markers (MMPs, Integrins, EGFR), compared to the other two cell types. Hoechst efflux stem cell-like side population was increased in LuM1 (7.8%) compared with Colon26 (2.9%), both of which were markedly reduced by verapamil treatment, an ABCG2 inhibitor. Smaller cell aggregates of LuM1 were more sensitive to Cisplatin (at 10 μM), whereas larger tumoroids with increased ABCG2 expression were insensitive. Notably, Cisplatin (2 μM) and Imatinib (10 μM) at low concentrations significantly promoted tumoroid formation (cell aggregation) and increased Mmp9 promoter activity in mCRC LuM1/m9, while not cytotoxic to them. On the other hand, 5-FU significantly inhibited tumoroid growth, although not completely. Thus, drug resistance in cancer with increased stem cell properties was modeled using the gel-free 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance.

    DOI： 10.3390/cells10020344

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  • Liquid-based 3D Cultured Tumoroids Modeling Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer Reviewed

    Chiharu Sogawa, Takanori Eguchi, Yuri Namba, Eriko Aoyama, Kazumi Ohyama, Kuniaki Okamoto

    2020.12

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    Researchers have developed and used several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids. Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anticancer drugs have been done in 2D culture systems, where-as 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aim to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyro-sine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter tumoroid growth of metastatic colorectal cancer (mCRC). To establish a liquid-based 3D multiplexing reporter assay system, LuM1 (a murine mCRC cell line) was stably transfected with the Mmp9 promoter-driven ZsGreen reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate (NCP), a 3D culture device. The larger tumoroids were not sensitive to Cisplatin and ex-pressed ABCG2 (a marker of cancer stem cells, a.k.a. a drug efflux transporter), whereas smaller cell-aggregates were more sensitive to Cisplatin. Both Imatinib and Cisplatin significantly in-creased tumoroid growth (larger than 300 μm2) and Mmp9 promoter activity and were not cytotoxic to the mCRC tumoroids. On the other hand, 5-FU was cytotoxic to the tumoroids and significantly inhibited tumoroid growth, although not completely. Thus, platinum resistance and imatinib resistance in mCRC were modeled using the liquid-based 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance.

    DOI： 10.20944/preprints202012.0582.v1

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  • The Inhibitory Role of Rab11b in Osteoclastogenesis through Triggering Lysosome-Induced Degradation of c-Fms and RANK Surface Receptors Reviewed

    Manh Tien Tran, Yuka Okusha, Yunxia Feng, Masatoshi Morimatsu, Penggong Wei, Chiharu Sogawa, Takanori Eguchi, Tomoko Kadowaki, Eiko Sakai, Hirohiko Okamura, Keiji Naruse, Takayuki Tsukuba, Kuniaki Okamoto

    International Journal of Molecular Sciences   21 ( 24 )   9352 - 9352   2020.12

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    Rab11b, abundantly enriched in endocytic recycling compartments, is required for the establishment of the machinery of vesicle trafficking. Yet, no report has so far characterized the biological function of Rab11b in osteoclastogenesis. Using in vitro model of osteoclasts differentiated from murine macrophages like RAW-D cells or bone marrow-derived macrophages, we elucidated that Rab11b served as an inhibitory regulator of osteoclast differentiation sequentially via (i) abolishing surface abundance of RANK and c-Fms receptors; and (ii) attenuating nuclear factor of activated T-cells c1 (NFATc-1) upstream signaling cascades, following RANKL stimulation. Rab11b was localized in early and late endosomes, Golgi complex, and endoplasmic reticulum; moreover, its overexpression enlarged early and late endosomes. Upon inhibition of lysosomal function by a specific blocker, chloroquine (CLQ), we comprehensively clarified a novel function of lysosomes on mediating proteolytic degradation of c-Fms and RANK surface receptors, drastically ameliorated by Rab11b overexpression in RAW-D cell-derived osteoclasts. These findings highlight the key role of Rab11b as an inhibitor of osteoclastogenesis by directing the transport of c-Fms and RANK surface receptors to lysosomes for degradation via the axis of early endosomes-late endosomes-lysosomes, thereby contributing towards the systemic equilibrium of the bone resorption phase.

    DOI： 10.3390/ijms21249352

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  • Rab11A Functions as a Negative Regulator of Osteoclastogenesis through Dictating Lysosome-Induced Proteolysis of c-fms and RANK Surface Receptors Reviewed

    Yuka Okusha, Manh Tien Tran, Mami Itagaki, Chiharu Sogawa, Takanori Eguchi, Tatsuo Okui, Tomoko Kadowaki, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Cells   9 ( 11 )   2384 - 2384   2020.10

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    Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). Rab11A GTPase, belonging to Rab11 subfamily representing the largest branch of Ras superfamily of small GTPases, has been identified as one of the crucial regulators of cell surface receptor recycling. Nevertheless, the regulatory role of Rab11A in osteoclast differentiation has been completely unknown. In this study, we found that Rab11A was strongly upregulated at a late stage of osteoclast differentiation derived from bone marrow-derived macrophages (BMMs) or RAW-D murine osteoclast precursor cells. Rab11A silencing promoted osteoclast formation and significantly increased the surface levels of c-fms and receptor activator of nuclear factor-κB (RANK) while its overexpression attenuated osteoclast formation and the surface levels of c-fms and RANK. Using immunocytochemical staining for tracking Rab11A vesicular localization, we observed that Rab11A was localized in early and late endosomes, but not lysosomes. Intriguingly, Rab11A overexpression caused the enhancement of fluorescent intensity and size-based enlargement of early endosomes. Besides, Rab11A overexpression promoted lysosomal activity via elevating the endogenous levels of a specific lysosomal protein, LAMP1, and two key lysosomal enzymes, cathepsins B and D in osteoclasts. More importantly, inhibition of the lysosomal activity by chloroquine, we found that the endogenous levels of c-fms and RANK proteins were enhanced in osteoclasts. From these observations, we suggest a novel function of Rab11A as a negative regulator of osteoclastogenesis mainly through (i) abolishing the surface abundance of c-fms and RANK receptors, and (ii) upregulating lysosomal activity, subsequently augmenting the degradation of c-fms and RANK receptors, probably via the axis of early endosomes–late endosomes–lysosomes in osteoclasts.

    DOI： 10.3390/cells9112384

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  • 発生と疾患にみる新たな細胞間コミュニケーション オルガノイドと細胞外小胞を癌研究に応用する

    江口 傑徳, 十川 千春, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2020   118 - 118   2020.9

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  • Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver Reviewed

    Mariko Seyama, Kaya Yoshida, Kayo Yoshida, Natsumi Fujiwara, Kisho Ono, Takanori Eguchi, Hotaka Kawai, Jiajie Guo, Yao Weng, Yuan Haoze, Kenta Uchibe, Mika Ikegame, Akira Sasaki, Hitoshi Nagatsuka, Kuniaki Okamoto, Hirohiko Okamura, Kazumi Ozaki

    Biochimica et Biophysica Acta - Molecular Basis of Disease   1866 ( 6 )   2020.6

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    DOI： 10.1016/j.bbadis.2020.165731

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  • Dimethyl fumarate prevents osteoclastogenesis by decreasing NFATc1 expression, inhibiting of erk and p38 MAPK phosphorylation, and suppressing of HMGB1 release Reviewed

    Tsuyoshi Nishioku, Momomi Kawamoto, Ryuya Okizono, Eiko Sakai, Kuniaki Okamoto, Takayuki Tsukuba

    Biochemical and Biophysical Research Communications   2020.6

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    DOI： 10.1016/j.bbrc.2020.05.088

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  • Knockout of MMP3 Weakens Solid Tumor Organoids and Cancer Extracellular Vesicles Reviewed

    Eman Taha, Chiharu Sogawa, Yuka Okusha, Hotaka Kawai, May Oo, Abdellatif Elseoudi, Yanyin Lu, Hitoshi Nagatsuka, Satoshi Kubota, Ayano Satoh, Kuniaki Okamoto, Takanori Eguchi

    Cancers   12 ( 5 )   1260 - 1260   2020.5

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    The tumor organoid (tumoroid) model in three-dimensional (3D) culture systems has been developed to reflect more closely the in vivo tumors than 2D-cultured tumor cells. Notably, extracellular vesicles (EVs) are efficiently collectible from the culture supernatant of gel-free tumoroids. Matrix metalloproteinase (MMP) 3 is a multi-functional factor playing crucial roles in tumor progression. However, roles of MMP3 within tumor growth and EVs have not unveiled. Here, we investigated the protumorigenic roles of MMP3 on integrities of tumoroids and EVs. We generated MMP3-knockout (KO) cells using the CRISPR/Cas9 system from rapidly metastatic LuM1 tumor cells. Moreover, we established fluorescent cell lines with palmitoylation signal-fused fluorescent proteins (tdTomato and enhanced GFP). Then we confirmed the exchange of EVs between cellular populations and tumoroids. LuM1-tumoroids released large EVs (200–1000 nm) and small EVs (50–200 nm) while the knockout of MMP3 resulted in the additional release of broken EVs from tumoroids. The loss of MMP3 led to a significant reduction in tumoroid size and the development of the necrotic area within tumoroids. MMP3 and CD9 (a category-1 EV marker tetraspanin protein) were significantly down-regulated in MMP3-KO cells and their EV fraction. Moreover, CD63, another member of the tetraspanin family, was significantly reduced only in the EVs fractions of the MMP3-KO cells compared to their counterpart. These weakened phenotypes of MMP3-KO were markedly rescued by the addition of MMP3-rich EVs or conditioned medium (CM) collected from LuM1-tumoroids, which caused a dramatic rise in the expression of MMP3, CD9, and Ki-67 (a marker of proliferating cells) in the MMP3-null/CD9-low tumoroids. Notably, MMP3 enriched in tumoroids-derived EVs and CM deeply penetrated recipient MMP3-KO tumoroids, resulting in a remarkable enlargement of solid tumoroids, while MMP3-null EVs did not. These data demonstrate that EVs can mediate molecular transfer of MMP3, resulting in increasing the proliferation and tumorigenesis, indicating crucial roles of MMP3 in tumor progression.

    DOI： 10.3390/cancers12051260

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  • The large GTPase Rab44 regulates granule exocytosis in mast cells and IgE-mediated anaphylaxis. Reviewed International journal

    Tomoko Kadowaki, Yu Yamaguchi, Mizuho A Kido, Takaya Abe, Kohei Ogawa, Mitsuko Tokuhisa, Weiqi Gao, Kuniaki Okamoto, Hiroshi Kiyonari, Takayuki Tsukuba

    Cellular & molecular immunology   17 ( 12 )   1287 - 1289   2020.4

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  • Extracellular vesicles enriched with moonlighting metalloproteinase are highly transmissive, pro-tumorigenic, and trans-activates cellular communication network factor (Ccn2/ctgf): Crispr against cancer Reviewed

    Yuka Okusha, Takanori Eguchi, Manh T. Tran, Chiharu Sogawa, Kaya Yoshida, Mami Itagaki, Eman A. Taha, Kisho Ono, Eriko Aoyama, Hirohiko Okamura, Ken Ichi Kozaki, Stuart K. Calderwood, Masaharu Takigawa, Kuniaki Okamoto

    Cancers   12 ( 4 )   2020.4

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    DOI： 10.3390/cancers12040881

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  • Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells. Reviewed International journal

    Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Masaki Matsumoto, Manh Tien Tran, Yuka Okusha, Benjamin J Lang, Kuniaki Okamoto, Stuart K Calderwood

    Cells   9 ( 3 )   2020.3

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    Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as a soluble form known as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in the release of EV proteins including CD9 and epithelial-to-mesenchymal transition (EMT), a key event in tumor progression. EVs derived from CRPC cells promoted EMT in normal prostate epithelial cells. Some HSP family members and their potential receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein types found by mass spectrometry. The small EVs (30-200 nm in size) were released even in a non-heated condition from the prostate cancer cells, whereas the EMT-coupled release of EVs (200-500 nm) and damaged membrane vesicles with associated HSP90α was increased after heat shock stress (HSS). GAPDH and lactate dehydrogenase, a marker of membrane leakage/damage, were also found in conditioned media upon HSS. During this stress response, the intracellular chaperone CDC37 was transcriptionally induced by heat shock factor 1 (HSF1), which activated the CDC37 core promoter, containing an interspecies conserved heat shock element. In contrast, knockdown of CDC37 decreased EMT-coupled release of CD9-containing vesicles. Triple siRNA targeting CDC37, HSP90α, and HSP90β was required for efficient reduction of this chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, we define "stressome" as cellular stress-induced all secretion products, including EVs (200-500 nm), membrane-damaged vesicles and remnants, and extracellular HSP90 and GAPDH. Our data also indicated that CDC37 is crucial for the release of vesicular proteins and tumor progression in prostate cancer.

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  • Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3 Reviewed

    Chiharu Sogawa, Takanori Eguchi, Manh Tien Tran, Masayuki Ishige, Kilian Trin, Yuka Okusha, Eman Ahmed Taha, Yanyin Lu, Hotaka Kawai, Norio Sogawa, Masaharu Takigawa, Stuart K. Calderwood, Kuniaki Okamoto, Ken-ichi Kozaki

    Cancers   12 ( 2 )   523 - 523   2020.2

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    Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

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  • Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer Reviewed

    Yuka Okusha, Takanori Eguchi, Manh Tien Tran, Chiharu Sogawa, Kaya Yoshida, Mami Itagaki, Eman Ahmed Taha, Kisho Ono, Eriko Aoyama, Hirohiko Okamura, Ken-ichi Kozaki, Stuart K. Calderwood, Masaharu Takigawa, Kuniaki Okamoto

    Preprints   doi: 10.20944/preprints202002.0281.v1   2020.2

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    Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

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  • CDC37 and HSP90 are Essential for Stressome Release and Tumor Progression in Resistant Prostate Cancer Reviewed

    Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Masaki Matsumoto, Manh Tien Tran, Yuka Okusha, Benjamin Lang, Kuniaki Okamoto, Stuart Calderwood

    2020.2

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    Tumor cells exhibit a resistance-associated secretory phenotype involving extracellular vesicles (EVs) and heat shock proteins (HSPs). This response occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as in free form as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in stressome release, epithelial-to-mesenchymal transition (EMT), and tumor progression. A number of HSP family members and their common receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein species. The small EVs (30 to 200 nm in size, potentially exosomes) were released even in a non-heated condition from the prostate cancer cells, whereas EMT-coupled release of EVs (200 to 500 nm, likely ectosomes) with associated HSP90α was increased after heat shock stress (HSS). Lactate dehydrogenase, a marker of membrane leakage/damage of cells, was also released upon HSS from the prostate cancer cells. During this stress response, intracellular CDC37 was also transcriptionally inducible by heat shock factor 1, and knockdown of CDC37 decreased EMT-coupled release of EVs. Triple knockdown of CDC37, HSP90α, and HSP90β was required for efficient reduction of the chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, the data indicated that CDC37 and HSP90 are essential for stressome release and for tumorigenesis in resistant cancer.

    DOI： 10.20944/preprints202002.0148.v1

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  • Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer Reviewed

    Kisho Ono, Chiharu Sogawa, Hotaka Kawai, Manh Tien Tran, Eman A. Taha, Yanyin Lu, May Wathone Oo, Yuka Okusha, Hirohiko Okamura, Soichiro Ibaragi, Masaharu Takigawa, Ken-Ichi Kozaki, Hitoshi Nagatsuka, Akira Sasaki, Kuniaki Okamoto, Stuart K. Calderwood, Takanori Eguchi

    Journal of Extracellular Vesicles   9 ( 1 )   1769373 - 1769373   2020.1

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

    DOI： 10.1080/20013078.2020.1769373

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  • (-)-Epigallocatechin-3-gallate inhibits RANKL-induced osteoclastogenesis via downregulation of NFATc1 and suppression of HO-1-HMGB1-RAGE pathway. Reviewed

    Tsuyoshi Nishioku, Toshiki Kubo, Tsukushi Kamada, Kuniaki Okamoto, Takayuki Tsukuba, Takuhiro Uto, Yukihiro Shoyama

    Biomedical research (Tokyo, Japan)   41 ( 6 )   269 - 277   2020

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    Osteoporosis disturbs the balance of bone metabolism, and excessive bone resorption causes a decrease in bone density, thus increasing the risk of fracture. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin contained in green tea. EGCG has a variety of pharmacological activities. Recently, it was reported that EGCG inhibits osteoclast differentiation, but the details of the mechanism underlying the EGCG-mediated suppression of osteoclastogenesis are unknown. In this study, we investigated the effects of EGCG on several signaling pathways in osteoclastogenesis. EGCG suppressed the expression of the nuclear factor of activated T cells cytoplasmic-1 (NFATc1), the master regulator of osteoclastogenesis. EGCG decreased the expression of cathepsin K, c-Src, and ATP6V0d2 and suppressed bone resorption. We also found that EGCG upregulated heme oxygenase-1 (HO-1) and suppressed the extracellular release of high-mobility group box 1 (HMGB1). In addition, EGCG decreased the expression of the receptor for advanced glycation end products (RAGE), which is the receptor of HMGB1, in osteoclastogenesis. In summary, our study showed that EGCG could inhibit osteoclast differentiation through the downregulation of NFATc1 and the suppression of the HO-1-HMGB1-RAGE pathway. EGCG might have the potential to be a lead compound that suppresses bone resorption in the treatment of osteoporosis.

    DOI： 10.2220/biomedres.41.269

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  • Exosome Release of Drugs: Coupling with Epithelial-Mesenchymal Transition Reviewed

    Takanori Eguchi, Kisho Ono, Stuart Calderwood, Kuniaki Okamoto

    2019.12

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    Extracellular vesicles (EVs), such as exosomes or oncosomes are released with molecules unfavorable for survival from cells. In addition, accumulating evidence has shown that tumor cells often eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing, drug resistance phenotype is often coupled with cellular dedifferentiation and transformation, cells undergoing epithelial-mesenchymal transition (EMT) and taking on a cancer stem cell phenotype. Recent studies have shown that the release of EVs is also involved in immunosuppression. The concept of the resistance-associated secretory phenotype (RASP) is reviewed herein.

    DOI： 10.20944/preprints201912.0386.v1

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  • オルガノイドを応用したドラッグリポジショニング開発

    十川 千春, 江口 傑徳, Tran Tien Manh, 石毛 真行, 河合 穂高, 奥舎 有加, 中野 敬介, 十川 紀夫, 小崎 健一, 岡元 邦彰

    岡山歯学会雑誌   38 ( 2 )   89 - 89   2019.12

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  • 新しい腫瘍オルガノイド多元評価システムの開発

    十川 チハル, 江口 傑徳, 大山 和美, 奥舎 有加, 中野 敬介, 十川 紀夫, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2019   165 - 165   2019.10

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  • Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. Reviewed

    Yoshida S, Kawai H, Eguchi T, Sukegawa S, Oo MW, Anqi C, Takabatake K, Nakano K, Okamoto K, Nagatsuka H

    Cells   8 ( 7 )   2019.7

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  • KBTBD11, a novel BTB-Kelch protein, is a negative regulator of osteoclastogenesis through controlling Cullin3-mediated ubiquitination of NFATc1. Reviewed

    Narahara S, Sakai E, Kadowaki T, Yamaguchi Y, Narahara H, Okamoto K, Asahina I, Tsukuba T

    Scientific Report   9 ( 1 )   3523   2019.3

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  • A reporter system evaluates tumorigenesis, metastasis, β-catenin/MMP regulation, and druggability. Invited Reviewed

    Sogawa C, Eguchi T, C, i, auth, Corresponding author, Okusha Y, Ono K, Ohyama K, Iizuka M, Kawasaki R, Hamada Y, Takigawa M, Sogawa N, Okamoto K, Kozaki K

    Tissue Engineering Part A.   2019.2

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  • Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma. Reviewed

    Shimizu R, Ibaragi S, Eguchi T, Kuwajima D, Kodama S, Nishioka T, Okui T, Obata K, Takabatake K, Kawai H, Ono K, Okamoto K, Nagatsuka H, Sasaki A

    International journal of oncology   54 ( 1 )   283 - 294   2019.1

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    DOI： 10.3892/ijo.2018.4631

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  • Depletion of choresterol lipid efflux pump ABCG1 triggers accumulation of exosomes and regression of tumors

    Eguchi Takanori, Sogawa Chiharu, Namba Yuri, Okusha Yuka, Kawai Hotaka, Ono Kisho, Itagaki Mami, Murakami Jun, Ohyama Kazumi, Asaumi Junichi, Okamoto Kuniaki

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   92   2-YIA-26   2019

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    The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10% to 35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs, their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

    DOI： 10.1254/jpssuppl.92.0_2-yia-26

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  • Drug repositioning using three-dimensional, MMP9 promoter activity-based anticancer drug screening

    Sogawa Chiharu, Eguchi Takanori, Okusha Yuka, Ohyama Kazumi, Ono Kisho, Sogawa Norio, Okamoto Kuniaki

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   92   1-P-096   2019

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    Cancer is one of the most serious diseases all over the world, especially metastasis and drug resistance are leading causes of death. There is an urgent need to establish new strategies for drug discovery. Success in the drug discovery depends on the development of appropriate tumor models that correspond closely to native tumor situation. Matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis and are regulators of tumor milieu. The cancer stem cell model fits well with tumorigenesis, metastasis and drug resistance. We have shown that cancer cell aggregation led to hypoxic tumoroids with marked upregulation of reprogramming and stemness genes as increased cancer stem cell using a 3D culture system. In the present study, we established a novel MMP9 promoter-driven cell-based reporter system using a rapidly metastatic colon cancer cell in the 3D culture system that evaluates cancer stemness and invasiveness. We used a concept of drug repositioning-using known molecules for new indications. We selected several compounds with inhibition to both tumoroid formation and MMP9 promoter activity. One of the compounds inhibited primary tumor formation, invasion and metastasis.

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  • Regulatory Roles of HSP90-Rich Extracellular Vesicles Reviewed

    Takanori Eguchi, Kisho Ono, Kazumi Kawata, Kuniaki Okamoto, Stuart K. Calderwood

    Heat Shock Proteins   3 - 17   2019

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    Publishing type：Part of collection (book)   Publisher：Springer International Publishing  

    DOI： 10.1007/978-3-030-23158-3_1

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  • 破骨細胞分化を制御する新規Rabタンパク質の同定と機能解析

    奥舎 有加, 板垣 まみ, 十川 千春, 江口 傑徳, 岡元 邦彰

    岡山歯学会雑誌   37 ( 2 )   82 - 82   2018.12

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  • Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. Reviewed International journal

    Toshifumi Fujiwara, Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Jun Murakami, Soichiro Ibaragi, Jun-Ichi Asaumi, Stuart K Calderwood, Kuniaki Okamoto, Ken-Ichi Kozaki

    Oral oncology   86   251 - 257   2018.11

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    Overexpression and increased signaling from the epidermal growth factor receptor (EGFR) often changes oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed the roles of OSCC-derived extracellular vesicles (EVs), including exosomes in the trafficking of cetuximab and in epithelial-mesenchymal transition (EMT) of epithelial cells. OSCC cells abundantly expressed EGFR, which was secreted from cells with OSCC-EVs upon EGF stimulations. The OSCC-EGFR-EVs were then able to enter into and transform epithelial cells leading to increased mesenchymal traits with increased vimentin and spindle-like shapes. EGF priming of OSCC cells further increased this EMT-initiating effect of the OSCC-EVs. The internalization and pro-EMT effects of the OSCC-EVs were largely blocked by cetuximab. Thus, OSCC-derived EVs transform normal epithelial cells into a mesenchymal phenotype and anti-EGFR therapeutic antibody cetuximab inhibits such a carcinogenic effect of the OSCC-EVs.

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    DOI： 10.1016/j.oraloncology.2018.09.030

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  • Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells. Reviewed International journal

    Namba Y, Sogawa C, Okusha Y, Kawai H, Itagaki M, Ono K, Murakami J, Aoyama E, Ohyama K, Asaumi JI, Takigawa M, Okamoto K, Calderwood SK, Kozaki KI, Eguchi T

    Front Oncol.   8   376 - 376   2018.10

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    The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10-35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

    File： 72. Namba (Frontiers in Oncol).pdf

    DOI： 10.3389/fonc.2018.00376

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  • Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. Reviewed International journal

    Toshifumi Fujiwara, Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Jun Murakami, Soichiro Ibaragi, Jun-Ichi Asaumi, Kuniaki Okamoto, Stuart K Calderwood, Ken-Ichi Kozaki

    Biochemical and biophysical research communications   503 ( 3 )   1267 - 1272   2018.9

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    Genetic amplification, overexpression, and increased signaling from the epidermal growth factor receptor (EGFR) are often found in oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed effects of cetuximab in control of EGF-driven malignant traits of OSCC cells. EGF stimulation promoted progression level of mesenchymal traits in OSCC cells, which were attenuated by cetuximab but incompletely. We pursued a potential mechanism underlying such incomplete attenuation of OSCC malignant traits. Cetuximab promoted secretion of EGFR-EVs by OSCC cells and failed to inhibit EGF-driven secretion of EGFR-EVs. Cetuximab was also found to be robustly secreted with the EGFR-EVs by the OSCC cells. Thus, EGF promotes the level of mesenchymal traits of OSCC cells and secretion of EGFR-EVs, which involve cetuximab resistance.

    File： 69. Fujiwara (BBRC).pdf

    DOI： 10.1016/j.bbrc.2018.07.035

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  • HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. Reviewed International journal

    Kisho Ono, Takanori Eguchi, Chiharu Sogawa, Stuart K Calderwood, Junya Futagawa, Tomonari Kasai, Masaharu Seno, Kuniaki Okamoto, Akira Sasaki, Ken-Ichi Kozaki

    Journal of cellular biochemistry   119 ( 9 )   7350 - 7362   2018.9

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    Cancer cells often secrete extracellular vesicles (EVs) that carry heat shock proteins (HSPs) with roles in tumor progression. Oral squamous cell carcinoma (OSCC) belongs to head and neck cancers (HNC) whose lymph-node-metastases often lead to poor prognosis. We have examined the EV proteome of OSCC cells and found abundant secretion of HSP90-enriched EVs in lymph-node-metastatic OSCC cells. Double knockdown of HSP90α and HSP90β, using small interfering RNA significantly reduced the survival of the metastatic OSCC cells, although single knockdown of each HSP90 was ineffective. Elevated expression of these HSP90 family members was found to correlate with poor prognosis of HNC cases. Thus, elevated HSP90 levels in secreted vesicles are potential prognostic biomarkers and therapeutic targets in metastatic OSCC.

    File： 68. Ono (J Cell Biochem).pdf

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  • 急速転移性癌細胞株由来細胞外小胞による破骨細胞分化および癌細胞浸潤の制御

    板垣 まみ, 十川 千春, 奥舎 有加, 江口 傑徳, 小野 喜章, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2018   347 - 347   2018.9

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  • 破骨細胞分化を負に制御するRabタンパク質の同定

    奥舎 有加, 板垣 まみ, 十川 千春, 江口 傑徳, 坂井 詠子, 筑波 隆幸, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2018   219 - 219   2018.9

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  • Rutaecarpine attenuates osteoclastogenesis by impairing macrophage colony stimulating factor and receptor activator of nuclear factor κ-B ligand-stimulated signalling pathways. Reviewed International journal

    Yutaka Fukuma, Eiko Sakai, Shunsuke Komaki, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    Clinical and experimental pharmacology & physiology   45 ( 8 )   863 - 865   2018.8

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    Rutaecarpine is a major alkaloid isolated from Evodia rutaecarpa. Here, we investigated the effects of rutaecarpine on osteoclast differentiation induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κ-B ligand (RANKL) in bone marrow-derived macrophages (BMMs). Treatment with rutaecarpine significantly inhibited osteoclastogenesis and prevented bone resorption of BMM-derived osteoclasts. Mechanistically, rutaecarpine decreased the protein level of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) and the phosphorylation of other signalling pathways during the osteoclast differentiation. Thus, rutaecarpine may be useful as a therapeutic agent for the treatment of bone diseases.

    DOI： 10.1111/1440-1681.12941

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  • Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment Reviewed

    Takanori Eguchi, Chiharu Sogawa, Yuka Okusha, Kenta Uchibe, Ryosuke Iinuma, Kisho Ono, Keisuke Nakano, Jun Murakami, Manabu Itoh, Kazuya Arai, Toshifumi Fujiwara, Yuri Namba, Yoshiki Murata, Kazumi Ohyama, Manami Shimomura, Hirohiko Okamura, Masaharu Takigawa, Tetsuya Nakatsura, Ken-ichi Kozaki, Kuniaki Okamoto, Stuart K. Calderwood

    PLoS ONE   13 ( 2 )   2018.2

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    DOI： 10.1371/journal.pone.0191109

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  • Actin binding LIM 1 (abLIM1) negatively controls osteoclastogenesis by regulating cell migration and fusion. Reviewed International journal

    Haruna Narahara, Eiko Sakai, Yu Yamaguchi, Shun Narahara, Mayumi Iwatake, Kuniaki Okamoto, Noriaki Yoshida, Takayuki Tsukuba

    Journal of cellular physiology   234 ( 1 )   486 - 499   2018.1

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    Actin binding LIM 1 (abLIM1) is a cytoskeletal actin-binding protein that has been implicated in interactions between actin filaments and cytoplasmic targets. Previous biochemical and cytochemical studies have shown that abLIM1 interacts and co-localizes with F-actin in the retina and muscle. However, whether abLIM1 regulates osteoclast differentiation has not yet been elucidated. In this study, we examined the role of abLIM1 in osteoclast differentiation and function. We found that abLIM1 expression was upregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and that a novel transcript of abLIM1 was exclusively expressed in osteoclasts. Overexpression of abLIM1 in the murine monocytic cell line, RAW-D suppressed osteoclast differentiation and decreased expression of several osteoclast-marker genes. By contrast, small interfering RNA-induced knockdown of abLIM1 enhanced the formation of multinucleated osteoclasts and markedly increased the expression of the osteoclast-marker genes. Mechanistically, abLIM1 regulated the localization of tubulin, migration, and fusion in osteoclasts. Thus, these results indicate that abLIM1 negatively controls osteoclast differentiation by regulating cell migration and fusion mediated via actin formation.

    File： 65. Narahara(J Cell Physiol).pdf

    DOI： 10.1002/jcp.26605

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  • Transcription factor EB (TFEB) influences invasion and migration in oral squamous cell carcinomas. Reviewed International journal

    Sakamoto H, Yamashita K, Okamoto K, Kadowaki T, Umeda M, Tsukuba T

    Oral Dis.   24 ( 5 )   741 - 748   2018

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    OBJECTIVE: Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25. Knockdown of TFEB using small interfering RNA in HSC2 and HSC4 cells was performed. Cell morphology was observed by immunofluorescence microscopy. Cell proliferation, invasion, and adhesion were analyzed. RESULTS: Expression levels of TFEB were high in HSC2, moderate in HSC4 and SCC25, and low in HSC3 and OSC20 cells. Knockdown of TFEB did not affect proliferation of HSC2 and HSC4 cells, but did induced enlargement of lysosomes and endosomes in HSC4 cells. TFEB silencing reduced invasion and migration of these HSC cell squamous carcinoma cells; however, increased cell adhesion was also observed. CONCLUSION: TFEB knockdown reduces invasion and migration of cancer cells, likely through lysosomal regulation. Taken together, TFEB influences cell invasion and migration of oral squamous cell carcinomas.

    File： 63. Sakamoto (Oral Dis).pdf

    DOI： 10.1111/odi.12826

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  • Rutaecarpine attenuates osteoclastogenesis by impairing M-CSF and RANKL-stimulated signaling pathways. Reviewed

    Fukuma Y, Sakai E, Komaki S, Nishishita K, Okamoto K, Tsukuba T

    Clin Exp Pharmacol Physiol.   2018

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  • Dihydroartemisinin represses osteoclastogenesis of bone marrow macrophages through reduced NFATc1 expression and impaired phosphorylation of IκBα. Reviewed

    Shunsuke Komaki, Eiko Sakai, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    Biomedical research (Tokyo, Japan)   39 ( 4 )   169 - 177   2018

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    Osteoclasts are multinucleated bone resorbing cells whose differentiation is regulated by several important signaling pathways. Several lines of evidence indicate that dihydroartemisinin (DHA), an anti-malarial drug, inhibits osteoclast differentiation with little cytotoxicity. However, the detailed inhibitory mechanisms of DHA on osteoclastogenesis from native cells remain to be elucidated. In this study, we investigated the effects of DHA on the differentiation of bone marrow-derived macrophages into osteoclasts. DHA inhibited receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclast formation and its bone resorbing activity. Mechanistically, DHA treatment markedly abolished phosphorylation of IκBα, and slightly affected a p38 MAPK dependent pathway. Moreover, DHA treatment induced down-regulation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator for osteoclast differentiation and its target proteins, such as Src and cathepsin K. These results indicate that DHA represses RANKL-induced osteoclastogenesis of bone marrow macrophages through reduced NFATc1 expression and impaired phosphorylation of IκBα.

    File： 70. Komaki (Biomed Res).pdf

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  • The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells. Reviewed International journal

    Okusha Y, Eguchi T, Sogawa C, Okui T, Nakano K, Okamoto K, Kozaki KI

    J Cell Biochem.   119 ( 9 )   7363 - 7376   2018

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    Members of matrix metalloproteinase (MMP) family promote cancer cell migration, invasion, and metastasis through alteration of the tumor milieu, intracellular signaling pathways, and transcription. We examined gene expression signatures of colon adenocarcinoma cell lines with different metastatic potentials and found that rapidly metastatic cells powerfully expressed genes encoding MMP3 and MMP9. The non-proteolytic PEX isoform and proteolytic isoforms of MMPs were significantly expressed in the metastatic cells in vitro. Knockdown of MMP3 attenuated cancer cell migration and invasion in vitro and lung metastasis in vivo. Profound nuclear localization of MMP3/PEX was found in tumor-stroma marginal area. In contrast, MMP9 was localized in central area of subcutaneous tumors. Overexpression of the PEX isoform of MMP3 promoted proliferation and migration of the rapidly metastatic cells in vitro. Taken together, the non-proteolytic PEX isoform of MMPs locating in cell nuclei involves proliferation, migration, and subsequent metastasis of aggressive adenocarcinoma cells.

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    DOI： 10.1002/jcb.27040

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  • 扁平上皮癌細胞の増殖能・浸潤能・転移能における転写因子TFEBの役割

    坂元 裕, 山下 健太郎, 岡元 邦彰, 門脇 知子, 梅田 正博, 筑波 隆幸

    生命科学系学会合同年次大会   2017年度   [1P - 1012]   2017.12

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  • 異なる転移能を有する口腔扁平上皮癌細胞由来エクソソームに含まれるプロテオームの特性

    小野 喜章, 江口 傑徳, 十川 千春, 村上 純, 藤原 敏史, 笠井 智成, 妹尾 昌治, 佐々木 朗, 小崎 健一, 岡元 邦彰

    生命科学系学会合同年次大会   2017年度   [1LBA - 052]   2017.12

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  • プロテアーゼ活性を持たないプロテアーゼの炎症および癌における役割

    江口 傑徳, 奥舎 有加, Calderwood Stuart, 岡元 邦彰

    生命科学系学会合同年次大会   2017年度   [2LBA - 028]   2017.12

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  • Keap1遺伝子欠損はNrf2の活性化を介して破骨細胞分化を抑制する

    坂井 詠子, 福間 裕, 西下 一久, 岡元 邦彰, 筑波 隆幸

    生命科学系学会合同年次大会   2017年度   [1P - 0588]   2017.12

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  • 薬剤耐性遺伝子を標的としたがん幹細胞制御

    難波 友里, 江口 傑徳, 十川 千春, 奥舎 有加, 村上 純, 浅海 淳一, 岡元 邦彰, 小崎 健一

    生命科学系学会合同年次大会   2017年度   [1LBA - 050]   2017.12

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  • The Rho-specific guanine nucleotide exchange factor Plekhg5 modulates cell polarity, adhesion, migration, and podosome organization in macrophages and osteoclasts. Reviewed International journal

    Mayumi Iwatake, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    Experimental cell research   359 ( 2 )   415 - 430   2017.10

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    Osteoclasts are multinucleated bone-resorbing cells that are formed by fusion of monocyte/macrophage lineage. Osteoclasts and macrophages generate podosomes that are actin-based dynamic organelles implicated in cell adhesion, spreading, migration, and degradation. However, the detailed mechanisms of podosome organization remain unknown. Here, we identified the Rho-specific guanine-nucleotide exchange factor (Rho-GEF) Plekhg5 as an up-regulated gene during differentiation of osteoclasts from macrophages. Knockdown of Plekhg5 with small interfering RNA in both macrophages and osteoclasts induced larger cell formation with impaired cell polarity and resulted in an elongated and flattened shape. In macrophages, Plekhg5 depletion enhanced random migration, but impaired directional migration, adhesion, and matrix degradation. Plekhg5 in osteoclasts affected random migration, podosome organization, and bone resorption. Plekhg5 depletion affected signaling and localization of several Rho downstream effectors. In fact, end-binding protein 1 (EB1), cofilin and vinculin were abnormally localized in Plekhg5-depleted cells, and mDia1 and LIM kinase (LIMK)1 were upregulated in Plekhg5-depleted cells compared with control cells. However, overexpression of Plekhg5 in macrophages induced an increase in its mRNA level, but failed to increase the protein level, indicating that overexpressed Plekhg5 was degraded in macrophages but not HEK293T cells. Thus, Plekhg5 affects cell polarity, migration, adhesion, degradation, and podosome organization in macrophages and osteoclasts.

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  • Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis Reviewed

    Eiko Sakai, Masanobu Morita, Masahiro Ohuchi, Mizuho A. Kido, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Ken Itoh, Masayuki Yamamoto, Takayuki Tsukuba

    FASEB JOURNAL   31 ( 9 )   4011 - 4022   2017.9

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    File： 60. Sakai (FASEB ).pdf

    DOI： 10.1096/fj.201700177R

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  • Mmp遺伝子を標的とし、高転移性癌細胞の生存と転移を抑制する

    奥舎 有加, 江口 傑徳, 十川 千春, 中野 敬介, 岡元 邦彰, 小崎 健一

    Journal of Oral Biosciences Supplement   2017   378 - 378   2017.9

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  • Keap1遺伝子欠損はIRF-8とMafBの発現上昇を介して破骨細胞分化を抑制する

    坂井 詠子, 城戸 瑞穂, 福間 裕, 西下 一久, 岡元 邦彰, 筑波 隆幸

    Journal of Oral Biosciences Supplement   2017   241 - 241   2017.9

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  • Actin-Binding LIM protein 1は破骨細胞における細胞骨格形成と細胞機能を制御する

    楢原 春菜, 坂井 詠子, 岡元 邦彰, 筑波 隆幸, 吉田 教明

    Journal of Oral Biosciences Supplement   2017   280 - 280   2017.9

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  • 核内タンパク質HMGM1 ヘムオキシゲナーゼ1の発現抑制はカスパーゼ3の活性化、HMGB1の細胞外遊離と破骨細胞分化に必要である

    坂井 詠子, 岡元 邦彰, 筑波 隆幸

    Journal of Oral Biosciences Supplement   2017   124 - 124   2017.9

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  • Rab44, a novel large Rab GTPase, negatively regulates osteoclast differentiation by modulating intracellular carcium levels followd by NFATc1 activation. Reviewed

    Yamaguchi Y, Sakai E, Okamoto K, Kajiya H, Okabe K, Naito M, Kadowaki T, Tsukuba T

    Cell Mol Life Sci.   75   33 - 48   2017.8

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  • The dental resin monomers HEMA and TEGDMA have inhibitory effects on osteoclast differentiation with low cytotoxicity Reviewed

    Hiroyuki Inamitsu, Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Hiroshi Murata, Takayuki Tsukuba

    JOURNAL OF APPLIED TOXICOLOGY   37 ( 7 )   817 - 824   2017.7

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    File： 58. Inamitsu(J Appl Toxicol.pdf

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  • New functions of lysosomes in bone cells Reviewed

    Takayuki Tsukuba, Eiko Sakai, Kazuhisa Nishishita, Tomoko Kadowaki, Kuniaki Okamoto

    Journal of Oral Biosciences   59 ( 2 )   92 - 95   2017.5

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    DOI： 10.1016/j.job.2017.01.004

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  • Cathepsin K modulates invasion, migration and adhesion of oral squamous cell carcinomas invitro Reviewed

    K. Yamashita, M. Iwatake, K. Okamoto, S-i Yamada, M. Umeda, T. Tsukuba

    ORAL DISEASES   23 ( 4 )   518 - 525   2017.5

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    File： 59. Yamashita (Oral Dis).pdf

    DOI： 10.1111/odi.12643

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  • Sanguiin H-6, a constituent of Rubus parvifolius L., inhibits receptor activator of nuclear factor-kappa B ligand-induced osteoclastogenesis and bone resorption in vitro and prevents tumor necrosis factor-alpha-induced osteoclast formation in vivo Reviewed

    Eiko Sakai, Yuri Aoki, Masako Yoshimatsu, Kazuhisa Nishishita, Mayumi Iwatake, Yutaka Fukuma, Kuniaki Okamoto, Takashi Tanaka, Takayuki Tsukuba

    PHYTOMEDICINE   23 ( 8 )   828 - 837   2016.7

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    File： 57. Sakai (Phytomedicine) .pdf

    DOI： 10.1016/j.phymed.2016.04.002

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  • The Transcription Factor EB (TFEB) Regulates Osteoblast Differentiation Through ATF4/CHOP-Dependent Pathway Reviewed

    Erika Yoneshima, Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Noriaki Yoshida, Takayuki Tsukuba

    JOURNAL OF CELLULAR PHYSIOLOGY   231 ( 6 )   1321 - 1333   2016.6

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    File： 56. Yoneshima (J Cellular Physiol).pdf

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  • Dual Effects of Liquiritigenin on the Proliferation of Bone Cells: Promotion of Osteoblast Differentiation and Inhibition of Osteoclast Differentiation Reviewed

    Kaho Uchino, Kuniaki Okamoto, Eiko Sakai, Erika Yoneshima, Mayumi Iwatake, Yutaka Fukuma, Kazuhisa Nishishita, Takayuki Tsukuba

    PHYTOTHERAPY RESEARCH   29 ( 11 )   1714 - 1721   2015.11

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    File： 55. Uchino (Phytother res).pdf

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  • Punicalagin attenuates osteoclast differentiation by impairing NFATc1 expression and blocking Akt- and JNK-dependent pathways Reviewed

    Mayumi Iwatake, Kuniaki Okamoto, Takashi Tanaka, Takayuki Tsukuba

    MOLECULAR AND CELLULAR BIOCHEMISTRY   407 ( 1-2 )   161 - 172   2015.9

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  • Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways Reviewed

    Yuka Yashima, Kuniaki Okamoto, Eiko Sakai, Mayumi Iwatake, Yutaka Fukuma, Kazuhisa Nishishita, Takayuki Tsukuba

    BIOMETALS   28 ( 4 )   725 - 732   2015.8

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    File： 51. Yashima (Biometals).pdf

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  • Cafestol has a weaker inhibitory effect on osteoclastogenesis than kahweol and promotes osteoblast differentiation Reviewed

    Yutaka Fukuma, Eiko Sakai, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    BIOFACTORS   41 ( 4 )   222 - 231   2015.7

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    File： 54. Fukuma (BioFactors).pdf

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  • Castalagin Exerts Inhibitory Effects on Osteoclastogenesis Through Blocking a Broad Range of Signaling Pathways with Low Cytotoxicity Reviewed

    Mayumi Iwatake, Kuniaki Okamoto, Takashi Tanaka, Takayuki Tsukuba

    PHYTOTHERAPY RESEARCH   29 ( 6 )   917 - 924   2015.6

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    DOI： 10.1002/ptr.5333

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  • Rab27A Regulates Transport of Cell Surface Receptors Modulating Multinucleation and Lysosome-Related Organelles in Osteoclasts Reviewed

    Megumi Shimada-Sugawara, Eiko Sakai, Kuniaki Okamoto, Mitsunori Fukuda, Tetsuro Izumi, Noriaki Yoshida, Takayuki Tsukuba

    SCIENTIFIC REPORTS   5   2015.4

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    File： 51. Shimada-Sugawara (Sci Rep).pdf

    DOI： 10.1038/srep09620

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  • Cathepsin E: An Aspartic Protease with Diverse Functions and Biomedical Implications Reviewed

    K. Yamamoto, K. Okamoto, T. Tsukuba

    Encyclopedia of Cell Biology   1   681 - 690   2015.1

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    Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

    DOI： 10.1016/B978-0-12-394447-4.10078-1

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  • Defective adipose tissue development associated with hepatomegaly in cathepsin E-deficient mice fed a high-fat diet Reviewed

    Tomoko Kadowaki, Mizuho A. Kido, Junko Hatakeyama, Kuniaki Okamoto, Takayuki Tsukuba, Kenji Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   446 ( 1 )   212 - 217   2014.3

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    File： 47. Kadowaki (BBRC).pdf

    DOI： 10.1016/j.bbrc.2014.02.089

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  • Repression of cathepsin E expression increases the risk of mammary carcinogenesis and links to poor prognosis in breast cancer Reviewed

    Tomoyo Kawakubo, Atsushi Yasukochi, Tatsuya Toyama, Satoru Takahashi, Kuniaki Okamoto, Takayuki Tsukuba, Seiji Nakamura, Yasuhiko Ozaki, Koichi Nishigaki, Hiroko Yamashita, Kenji Yamamoto

    CARCINOGENESIS   35 ( 3 )   714 - 726   2014.3

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    File： 47. Kawakubo (Carcinogenesis).pdf

    DOI： 10.1093/carcin/bgt373

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  • Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression Reviewed

    Yu Yamaguchi, Eiko Sakai, Hiroshi Sakamoto, Reiko Fumimoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF APPLIED TOXICOLOGY   34 ( 1 )   49 - 56   2014.1

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    File： 48. Yamaguchi (J Appl Toxicol).pdf

    DOI： 10.1002/jat.2827

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  • Cobalt protoporphyrin prevents osteoclastogenesis via blocking of I kappa B phosphorylation Reviewed

    Yuka Yashima, Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   232P - 232P   2014

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  • Cathepsin E Deficiency Impairs Autophagic Proteolysis in Macrophages Reviewed

    Takayuki Tsukuba, Michiyo Yanagawa, Tomoko Kadowaki, Ryosuke Takii, Yoshiko Okamoto, Eiko Sakai, Kuniaki Okamoto, Kenji Yamamoto

    PLOS ONE   8 ( 12 )   2013.12

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    File： 46. Tsukuba (Plosone).pdf

    DOI： 10.1371/journal.pone.0082415

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  • Structural and phylogenetic comparison of napsin genes: The duplication, loss of function and human-specific pseudogenization of napsin B Reviewed

    Kazuhisa Nishishita, Eiko Sakai, Kuniaki Okamoto, Takayuki Tsukuba

    GENE   517 ( 2 )   147 - 157   2013.4

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    File： 44. NIshishita (Gene).pdf

    DOI： 10.1016/j.gene.2013.01.013

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  • Fisetin inhibits osteoclastogenesis through prevention of RANKLInduced ROS production by Nrf2-mediated Up-regulation of Phase II antioxidant enzymes Reviewed

    Eiko Sakai, Megumi Shimada-Sugawara, Yu Yamaguchi, Hiroshi Sakamoto, Reiko Fumimoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    Journal of Pharmacological Sciences   121 ( 4 )   288 - 298   2013

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    File： 45. Sakai (J Pharmacol Sci).pdf

    DOI： 10.1254/jphs.12243FP

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  • Deltamethrin inhibits osteoclast differentiation via regulation of heme oxygenase-1 and NFATc1 Reviewed

    Hiroshi Sakamoto, Eiko Sakai, Reiko Fumimoto, Yu Yamaguchi, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    TOXICOLOGY IN VITRO   26 ( 6 )   817 - 822   2012.9

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    File： 43. Sakamoto (Toxicol In Vitro).pdf

    DOI： 10.1016/j.tiv.2012.05.005

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  • The Coffee Diterpene Kahweol Prevents Osteoclastogenesis via Impairment of NFATc1 Expression and Blocking of Erk Phosphorylation Reviewed

    Reiko Fumimoto, Eiko Sakai, Yu Yamaguchi, Hiroshi Sakamoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118 ( 4 )   479 - 486   2012.4

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    File： 42. Fumimoto (J Pharmacol Sci).pdf

    DOI： 10.1254/jphs.11212FP

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  • Genetic backgrounds and redox conditions influence morphological characteristics and cell differentiation of osteoclasts in mice Reviewed

    Shun Narahara, Haruna Matsushima, Eiko Sakai, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    CELL AND TISSUE RESEARCH   348 ( 1 )   81 - 94   2012.4

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    File： 41. Narahara (Cell Tissue Res).pdf

    DOI： 10.1007/s00441-012-1325-8

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  • Role of the transcription factor Sp1 in regulating the expression of the murine cathepsin E gene Reviewed

    Kuniaki Okamoto, Yoshiko Okamoto, Tomoyo Kawakubo, Jun-ichi Iwata, Yoshiyuki Yasuda, Takayuki Tsukuba, Kenji Yamamoto

    JOURNAL OF BIOCHEMISTRY   151 ( 3 )   263 - 272   2012.3

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    File： 40. Okamoto (j Biochem).pdf

    DOI： 10.1093/jb/mvr135

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  • Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis Reviewed

    Eiko Sakai, Megumi Shimada-Sugawara, Kazuhisa Nishishita, Yutaka Fukuma, Mariko Naito, Kuniaki Okamoto, Koji Nakayama, Takayuki Tsukuba

    JOURNAL OF CELLULAR BIOCHEMISTRY   113 ( 2 )   486 - 498   2012.2

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    DOI： 10.1002/jcb.23372

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  • Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis Reviewed

    Eiko Sakai, Megumi Sugawara, Kazuhisa Nishishita, Yutaka Fukuma, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118 ( 2 )   208P - 208P   2012

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    File： 39. Sakai (J Cell Biochem).pdf

    DOI： 10.1002/jcb.23372

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  • Cathepsin E is critical for proper trafficking of cell surface proteins Reviewed

    Takayuki Tsukuba, Kuniaki Okamoto, Kenji Yamamoto

    Journal of Oral Biosciences   54 ( 1 )   48 - 53   2012

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    DOI： 10.1016/j.job.2011.10.001

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  • The role of cathepsin E in terminal differentiation of keratinocytes. Reviewed

    Kawakubo T, Yasukochi A, Okamoto K, Okamoto Y, Nakamura S, Yamamoto K

    Biological chemistry   392 ( 6 )   571 - 585   2011.4

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    DOI： 10.1515/BC.2011.060

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  • Cathepsin E-deficient mice show increased susceptibility to bacterial infection associated with the decreased expression of multiple cell surface Toll-like receptors. Reviewed

    Tsukuba T, Yamamoto S, Yanagawa M, Okamoto K, Okamoto Y, Nakayama KI, Kadowaki T, Yamamoto K

    Journal of biochemistry   140 ( 1 )   57 - 66   2006.7

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  • Mutational analysis of residues in two consensus motifs in the active sites of cathepsin E1 Reviewed

    Jian Liu, Takayuki Tsukuba, Kuniaki Okamoto, Masamichi Ohishi, Kenji Yamamoto

    Journal of Biochemistry   132 ( 3 )   493 - 499   2002

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    DOI： 10.1093/oxfordjournals.jbchem.a003247

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  • Characterization of phagosomal subpopulations along endocytic routes in osteoclasts and macrophages. Reviewed

    Sakai E, Miyamoto H, Okamoto K, Kato Y, Yamamoto K, Sakai H

    J Biochem.   130 ( 6 )   823 - 831   2001

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  • Design and synthesis of sensitive fluorogenic substrates specific for Lys-gingipain Reviewed

    Naoko Abe, Atsuyo Baba, Tomoko Kadowaki, Kuniaki Okamoto, Shinji Okazaki, Tetsuji Asao, Kenji Yamamoto

    Journal of Biochemistry   128 ( 5 )   877 - 881   2000

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    DOI： 10.1093/oxfordjournals.jbchem.a022826

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  • Role of N-glycosylation in cathepsin E. A comparative study of cathepsin E with distinct N-linked oligosaccharides and its nonglycosylated mutant Reviewed

    Yoshiyuki Yasuda, Shinobu Ikeda, Hideaki Sakai, Takayuki Tsukuba, Kuniaki Okamoto, Kazuhisa Nishishita, Akifumi Akamine, Yuzo Kato, Kenji Yamamoto

    European Journal of Biochemistry   266 ( 2 )   383 - 391   1999.12

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    DOI： 10.1046/j.1432-1327.1999.00863.x

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  • Genetic analyses of proteolysis, hemoglobin binding, and hemagglutination of Porphyromonas gingivalis : construction of mutants with rgpA, rgpB, kgp, and hagA.

    Shi Y, Ratnayake DB, Okamoto K, Abe N, Yamamoto K, Nakayama K

    Journal of Biological Chemistry   274 ( 25 )   17955 - 17960   1999

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  • カテプシンEにおける糖鎖の生理的意義について

    安田 善之, 岡元 邦彰, 池田 仁子, 西下 一久, 坂井 英昭, 加藤 有三, 山本 健二

    生化学   70 ( 8 )   927 - 927   1998.8

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  • Biochemical and functional properties of lysine-specific cysteine proteinase (Lys-Gingipain) as a virulence factor of Porphyromonas gingivalis in periodontal disease Reviewed

    Naoko Abe, Tomoko Kadowaki, Kuniaki Okamoto, Koji Nakayama, Masamichi Ohishi, Kenji Yamamoto

    Journal of Biochemistry   123 ( 2 )   305 - 312   1998

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    DOI： 10.1093/oxfordjournals.jbchem.a021937

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  • Arg-gingipain acts as a major processing enzyme for various cell surface proteins in Porphyromonas gingivalis. Reviewed

    Kadowaki T, Nakayama K, Yoshimura F, Okamoto K, Abe N, Yamamoto K

    J. Biol. Chem.   273   29072 - 29076   1998

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    DOI： 10.1074/jbc.273.44.29072

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  • Involvement of a Lysine-specific cysteine Proteinase in Hemoglobin Adsorption and Heme Accumulation by Porphyromonas gingivalis. Reviewed

    Okamoto K, Nakayama K, Kadowaki T, Abe N, Ratnayake D.B, Yamamoto K

    J. Biol. Chem.   273   21225 - 21231   1998

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    DOI： 10.1074/jbc.273.33.21225

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  • Possible roles of N-linked oligosaccharides on cathepsin E Reviewed

    H Sakai, S Ikeda, K Nishishita, Y Kato, K Okamoto, T Tsukuba, K Yamamoto

    PROTEOLYSIS IN CELL FUNCTIONS   13   55 - 60   1997

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  • Biosynthesis and trafficking of cathepsin E Reviewed

    K Yamamoto, H Nakanishi, T Tsukuba, K Okamoto, H Sakai, K Nishishita, Y Kato

    PROTEOLYSIS IN CELL FUNCTIONS   13   215 - 222   1997

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  • Cloning and sequencing of the gene encoding a novel lysine-specific cysteine proteinase (Lys-Gingipain) in porphyromonas gingivalis: Structural relationship with the arginine-specific cysteine proteinase (Arg-Gingipain) Reviewed

    Kuniaki Okamoto, Tomoko Kadowaki, Koji Nakayama, Kenji Yamamoto

    Journal of Biochemistry   120 ( 2 )   398 - 406   1996

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

    DOI： 10.1093/oxfordjournals.jbchem.a021426

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  • Structure and function of a novel arginine-specific cysteine proteinase (argingipain) as a major periodontal pathogenic factor from Porphyromonas gingivalis Reviewed

    Kenji Yamamoto, Tomoko Kadowaki, Kuniaki Okamoto, Masahiro Yoneda, Koji Nakayama, Yoshio Misumi, Yukio Ikehara

    Advances in Experimental Medicine and Biology   389   33 - 42   1996

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  • Isolation and sequencing of two cDNA clones encoding rat spleen cathepsin E and analysis of the activation of purified procathepsin E

    Kuniaki Okamoto, Hao Yu, Yoshio Misumi, Yukio Ikehara, Kenji Yamamoto

    Archives of Biochemistry and Biophysics   322 ( 1 )   103 - 111   1995.9

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    DOI： 10.1006/abbi.1995.1441

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  • Structural characterization of argingipain, a novel arginine-specific cysteine proteinase as a major periodontal pathogenic factor from Porphyromonas gingivalis. Reviewed

    Okamoto K, Misumi Y, Kadowaki T, Yoneda M, Yamamoto K

    Arch. Biochem. Biophys.   316   917 - 925   1995

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    DOI： 10.1006/abbi.1995.1123

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  • Construction and characterization of arginine-specific cysteine proteinase(Arg-ginigpain)-deficient mutants of Porphyromonas gingivalis : evidence for singificant contribution of Arg-gingipain to virulence.

    Nakayama K, Kadowaki T, Okamoto K, Yamamoto K

    Journal of Biological Chemistry   270 ( 40 )   23619 - 23626   1995

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Books

  • 第６版現代歯科薬理学

    岡元 邦彰（ Role： Contributor ,  脂質異常治療薬 痛風治療薬）

    医歯薬出版株式会社  2017 

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  • 第５版現代歯科薬理学

    岡元 邦彰（ Role： Contributor ,  血液および造血臓器に作用する薬物 脂質異常治療薬 痛風治療薬）

    医歯薬出版株式会社  2012 

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  • 「第４版現代歯科薬理学」

    岡元 邦彰（ Role： Contributor ,  止血に用いられる薬物 血液および造血臓器に作用する薬物）

    医歯薬出版株式会社  2005 

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  • Arg-gingipain and Lys-gingipain: a novel class of cysteine proteinases.

    Yamamoto K, Kadowaki T, Okamoto K（ Role： Joint author）

    Birkhäusen Verlag  1999 

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  • Possible roles of N-linked oligosaccharides on cathepsin E

    IOS Press  1997 

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  • Possible roles of N-linked oligosaccharides on cathepsin E

    IOS Press  1997 

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  • Structural characterization of pathogenic cysteine proteinase from the oral bacterium Porphysromonas gingivalis

    IOS Press  1997 

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  • Biosynthesis and trafficking of cathepsin E

    IOS Press  1997 

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  • Biosynthesis and trafficking of cathepsin E

    IOS Press  1997 

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  • Structural characterization of pathogenic cysteine proteinase from the oral bacterium Porphysromonas gingivalis

    IOS Press  1997 

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MISC

  • Application of Organoids and Extracellular Vesicles to Cancer Research

    江口傑徳, 江口傑徳, 十川千春, 岡元邦彰

    Journal of Oral Biosciences Supplement (Web)   2020   2020

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  • 分子シャペロントリオによるエクソソーム制御,腫瘍悪性化およびマクロファージ分極について

    江口傑徳, 小野喜章, 小野喜章, 河合穂高, チャン チェンマン, 十川千春, 奥舎有加, 岡元邦彰

    日本臨床ストレス応答学会大会抄録集   14th   2019

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  • 新しい腫瘍オルガノイド多元評価システムの開発

    十川チハル, 江口傑徳, 江口傑徳, 大山和美, 奥舎有加, 中野敬介, 十川紀夫, 岡元邦彰

    Journal of Oral Biosciences Supplement (Web)   2019   2019

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  • ニコチンは口腔扁平上皮癌細胞のセツキシマブ耐性を促進する

    清水 理恵子, 伊原木 聰一郎, 江口 傑徳, 奥井 達雄, 高畠 清文, 河合 穂高, 小野 喜章, 岡元 邦彰, 長塚 仁, 佐々木 朗

    岡山歯学会雑誌   37 ( 2 )   80 - 81   2018.12

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    J-GLOBAL

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  • 口腔扁平上皮癌診断・治療における分子シャペロンHSP90含有細胞外小胞の可能性

    小野 喜章, 江口 傑徳, 十川 千春, 奥舎 有加, 河合 穂高, 中野 敬介, 佐々木 朗, 岡元 邦彰, 小崎 健一

    Journal of Oral Biosciences Supplement   2018   333 - 333   2018.9

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  • 核内およびエクソソーム中に存在するMMPs/PEXの癌進展における役割とその抑制

    奥舎 有加, 江口 傑徳, 十川 千春, 小野 喜章, 奥井 達雄, 中野 敬介, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2018   150 - 150   2018.9

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  • 癌の治療抵抗性と転移におけるHSP90およびMMP3の役割

    江口 傑徳, 小野 喜章, 奥舎 有加, 十川 千春, 内部 健太, 中野 敬介, 奥井 達雄, 滝川 正春, 岡元 邦彰, カルダーウッド・スチュアート

    Journal of Oral Biosciences Supplement   2018   142 - 142   2018.9

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  • 癌の治療抵抗性と転移におけるHSP90およびMMP3の役割

    江口傑徳, 江口傑徳, 小野喜章, 小野喜章, 奥舎有加, 十川千春, 内部健太, 中野敬介, 中野敬介, 奥井達雄, 滝川正春, 岡元邦彰, CALDERWOOD SK

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • 急速転移性癌細胞株由来細胞外小胞による破骨細胞分化および癌細胞浸潤の制御

    板垣まみ, 十川千春, 奥舎有加, 江口傑徳, 江口傑徳, 小野喜章, 岡元邦彰

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • 口腔扁平上皮癌診断・治療における分子シャペロンHSP90含有細胞外小胞の可能性

    小野喜章, 江口傑徳, 江口傑徳, 十川千春, 奥舎有加, 河合穂高, 中野敬介, 佐々木朗, 岡元邦彰, 小崎健一

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • 破骨細胞分化を負に制御するRabタンパク質の同定

    奥舎有加, 板垣まみ, 十川千春, 江口傑徳, 江口傑徳, 坂井詠子, 筑波隆幸, 岡元邦彰

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • 核内およびエクソソーム中に存在するMMPs/PEXの癌進展における役割とその抑制

    奥舎有加, 江口傑徳, 江口傑徳, 十川千春, 小野喜章, 小野喜章, 奥井達雄, 中野敬介, 岡元邦彰

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • 転移性の異なる細胞株を用いた核内MMP3の機能解析とその役割

    奥舎有加, 江口傑徳, 十川千春, 奥井達雄, 中野敬介, 小崎健一, 岡元邦彰

    日本薬理学会近畿部会プログラム・要旨集   133rd   2018

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  • 新規高分子量Gタンパク質Rab44はCa2+流入及びNFATc1経路を介して破骨細胞分化を負に制御する

    山口優, 坂井詠子, 岡元邦彰, 鍜治屋浩, 岡部幸司, 門脇知子, 筑波隆幸

    日本生化学会大会(Web)   90th   2017

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  • 破骨細胞分化を負に制御する新規Kelchタンパク質の同定と機能解析

    楢原峻, 楢原峻, 坂井詠子, 山口優, 楢原春菜, 門脇知子, 岡元邦彰, 朝比奈泉, 筑波隆幸

    日本生化学会大会(Web)   90th   2017

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  • 破骨細胞分化を制御する新規Rabタンパク質の同定と解析

    山口優, 坂井詠子, 岡元邦彰, 門脇知子, 筑波隆幸

    日本病態プロテアーゼ学会学術集会プログラム抄録集   22nd   2017

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  • 口腔扁平上皮癌細胞由来エクソソームに含まれる分子シャペロンについての検討

    小野喜章, 小野喜章, 江口傑徳, 十川千春, 村上純, 藤原敏史, 藤原敏史, 笠井智成, 妹尾昌治, 佐々木朗, 小崎健一, 岡元邦彰

    臨床ストレス応答学会大会抄録集   12th   2017

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  • 癌や炎症性疾患において分子シャペロンHSPsが誘導される新たな経路:核内MMPとヘテロクロマチンタンパク質の相互作用

    江口傑徳, 江口傑徳, 奥舎有加, 小崎健一, 岡元邦彰, CALDERWOOD Stuart K

    臨床ストレス応答学会大会抄録集   12th   2017

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  • Mmp遺伝子を標的とし,高転移性癌細胞の生存と転移を抑制する

    奥舎有加, 江口傑徳, 十川千春, 中野敬介, 岡元邦彰, 小崎健一

    Journal of Oral Biosciences Supplement (Web)   2017   2017

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  • 転移性の異なる癌細胞株の網羅的遺伝子発現解析による浸潤・転移促進因子の探索と機能解明

    奥舎有加, 江口傑徳, 十川千春, 中野敬介, 小崎健一, 岡元邦彰

    硬組織再生生物学会学術大会・総会プログラム・抄録集   26th   2017

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  • 破骨細胞分化を制御する新規Rabタンパク質の同定と機能解析

    山口優, 坂井詠子, 岡元邦彰, 鍛治屋浩, 岡部幸司, 筑波隆幸

    Journal of Oral Biosciences Supplement (Web)   2017   2017

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  • tert-ButylhydroquinoneによるIrf8とMafBの発現増加を介した破骨細胞分化抑制機構

    坂井詠子, 山口優, 福間裕, 西下一久, 岡元邦彰, 筑波隆幸

    日本生化学会大会(Web)   89th   2016

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  • Keap1/Nrf2の破骨細胞と骨芽細胞分化における役割

    坂井詠子, 福間裕, 山口優, 西下一久, 岡元邦彰, 筑波隆幸

    日本生化学会大会(Web)   88th   2015

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  • 歯科用モノマーによる破骨細胞分化に対する効果

    稲光 宏之, 岡元 邦彰, 坂井 詠子, 村田 比呂司, 筑波 隆幸

    Journal of Oral Biosciences Supplement   2014   180 - 180   2014.9

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  • Chemical constituent of Sanguisorba officinalis inhibits osteoclastogenesis

    Eiko Sakai, Mayumi Iwatake, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takashi Tanaka, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   232P - 232P   2014

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  • コバルトプロトポルフィリンの破骨細胞分化および活性化に対する影響

    八島由佳, 八島由佳, 岡元邦彰, 坂井詠子, 西下一久, 筑波隆幸

    Journal of Oral Biosciences Supplement (Web)   2014   ROMBUNNO.P2‐33 (WEB ONLY)   2014

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  • Nrf2遺伝子欠損マウスにおける酸化ストレスと骨代謝

    坂井詠子, 山口優, 福間裕, 菅原めぐみ, 菅原めぐみ, 西下一久, 岡元邦彰, 筑波隆幸

    日本生化学会大会(Web)   87th   2014

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  • Up-regulation mechanisms of endosomal/lysosomal proteins during osteoblast differentiation

    Erika Yoneshima, Kuniaki Okamoto, Eiko Sakai, Noriaki Yoshida, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   170P - 170P   2013

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  • Cafestol prevents osteoclastogenesis via impairment of NFATc1 expression and blocking of Erk phosphorylation

    Yutaka Fukuma, Eiko Sakai, Megumi Sugawara, Erika Yoneshima, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   249P - 249P   2013

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  • Identification of two transcrips and in vivo promoter analysis for cathepsin E

    Kuniaki Okamoto, Yoshiko Okamoto, Eiko Sakai, Kazuhisa Nishishita, Kenji Yamamoto, Takayuki Tstikuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   259P - 259P   2012

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  • Accumulation of NADPH oxidase (NOX2) and increased oxidative stress in cathepsin E-deficient macrophages

    Takayuki Tsukuba, Tomoko Kadowaki, Kuniaki Okamoto, Kenji Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   256P - 256P   2012

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  • Fisetinl prevents osteoclastogenesis via impairment of NFATc1 expression and blocking of Erk phosphorylation

    Megumi Sugawara, Eiko Sakai, Kazuhisa Nishishita, Yutaka Fukuma, Kuniaki Okamoto, Noriaki Yoshida, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   164P - 164P   2012

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  • Receptor activator of NF-kappa B ligand dependent heme oxygenase-1 suppression is required for high mobility group box 1 release, caspase-3 activation, and subsequent osteoclastogenesis

    Eiko Sakai, Megumi Shimada, Kazuhisa Nishishita, Yutaka Fukuma, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   219P - 219P   2011

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  • Nrf2 activators inhibit osteoclastogenesis induced by receptor activator of NF-kappa B ligand

    Reiko Fumimoto, Hiroshi Sakamoto, Yu Yamaguchi, Eiko Sakai, Kuniaki Okamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   219P - 219P   2011

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  • tert-Butylhydroquinoneの破骨細胞形成と骨吸収活性への影響

    山口優, 坂井詠子, 岡元邦彰, 筑波隆幸

    Journal of Oral Biosciences   53 ( Supplement )   2011

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  • Transcription factor Sp1 regulates the expression of the murine cathepsin E gene in gastric adenosarcoma cells

    Kuniaki Okamoto, Yoshiko Okamoto, Tomoyo Kawakubo, Kenji Yamamoto, Takayuki Tsukuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   216P - 216P   2010

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  • Autophagy impairment associated with increased aberrant mitochondria and oxidative stress in cathepsin E-deficient macrophages

    Takayuki Tsukuba, Michiyo Yanagawa, Tomoko Kadowaki, Yoshiko Okamoto, Kuniaki Okamoto, Kenji Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   216P - 216P   2010

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  • カテプシンE欠損における破骨細胞分化への影響

    岡元邦彰, 坂井詠子, 西下一久, 福間裕, 坂元裕, 文元玲子, 山口優, 山本健二, 筑波隆幸

    生化学   2010

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  • Carbon dioxide laser irradiation stimulates mineralization in rat dental pulp cells

    Y. Yasuda, E. Ohtomo, T. Tsukuba, K. Okamoto, T. Saito

    INTERNATIONAL ENDODONTIC JOURNAL   42 ( 10 )   940 - 946   2009.10

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  • Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

    Takayuki Tsukuba, Michiyo Yanagawa, Kuniaki Okamoto, Yoshiko Okamoto, Yoshiyuki Yasuda, Keiichi I. Nakayama, Tomoko Kadowaki, Kenji Yamamoto

    JOURNAL OF BIOCHEMISTRY   145 ( 5 )   565 - 573   2009.5

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  • カテプシンE欠損マクロファージにおけるオートファジーの低下とそれに伴うミトコンドリア機能異常と酸化ストレスの上昇

    筑波隆幸, 門脇知子, 坂井詠子, 岡元邦彰, 山本健二

    Journal of Oral Biosciences   51 ( Supplement )   2009

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  • Determination of active site of lysine-specific cysteine proteinase (Lys-gingipain) by use of a Porphyromonas gingivalis plasmid system

    Yutaka Ishida, JinPing Hu, Eiko Sakai, Tomoko Kadowaki, Kenji Yamamoto, Takayuki Tsukuba, Yuzo Kato, Koji Nakayama, Kuniaki Okamoto

    ARCHIVES OF ORAL BIOLOGY   53 ( 6 )   538 - 544   2008.6

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  • Association of cathepsin E deficiency with the increased territorial aggressive response of mice

    Naoki Shigematsu, Takaichi Fukuda, Tsuneyuki Yamamoto, Tsuyoshi Nishioku, Taku Yamaguchi, Masaru Himeno, Keiichi I. Nakayama, Takayuki Tsukuba, Tomoko Kadowaki, Kuniaki Okamoto, Shun Higuchi, Kenji Yamamoto

    JOURNAL OF NEUROCHEMISTRY   105 ( 4 )   1394 - 1404   2008.5

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  • Dentin phosphophoryn promotes cellular migration of human dental pulp cells

    Yoshiyuki Yasuda, Masanobu Izumikawa, Kuniaki Okamoto, Takayuki Tsukuba, Takashi Saito

    JOURNAL OF ENDODONTICS   34 ( 5 )   575 - 578   2008.5

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  • Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappa B and Akt pathways

    Jin-Ping Hu, Kazuhisa Nishishita, Eiko Sakai, Hajime Yoshida, Yuzo Kato, Takayuki Tsukuba, Kuniaki Okamoto

    EUROPEAN JOURNAL OF PHARMACOLOGY   580 ( 1-2 )   70 - 79   2008.2

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  • Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappa B and Akt pathways

    Jin-Ping Hu, Kazuhisa Nishishita, Eiko Sakai, Hajime Yoshida, Yuzo Kato, Takayuki Tsukuba, Kuniaki Okamoto

    EUROPEAN JOURNAL OF PHARMACOLOGY   580 ( 1-2 )   70 - 79   2008.2

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  • カテプシンE欠損はオートファジーの低下とそれに伴うミトコンドリア機能異常と酸化ストレスを引き起こす。

    筑波隆幸, 柳川三千代, 門脇知子, 岡本美子, 岡元邦彰, 中山敬一, 山本健二

    生化学   2008

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  • カテプシンE欠損マウスにおける高脂血症および脂肪肝の誘導

    門脇知子, 岡元邦彰, 山本健二, 筑波隆幸

    Journal of Oral Biosciences   50 ( Supplement )   2008

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  • カテプシンE欠損による遊走能および細胞接着能の低下

    筑波隆幸, 柳川三千代, 岡元邦彰, 門脇知子, 山本健二

    Journal of Oral Biosciences   50 ( Supplement )   2008

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  • Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface

    Tomoyo Kawakubo, Kuniaki Okamoto, Jun-Ichi Lwata, Masashi Shin, Yoshiko Okamoto, Atsushi Yasukochi, Keiichi I. Nakayama, Tomoko Kadowaki, Takayuki Tsukuba, Kenji Yamamoto

    CANCER RESEARCH   67 ( 22 )   10869 - 10878   2007.11

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  • Construction of recombinant hemagglutinin derived from the gingipain-encoding gene of Porphyromonas gingivalis, identification of its target protein on erythrocytes, and inhibition of hemagglutination by an interdomain regional peptide. International journal

    Eiko Sakai, Mariko Naito, Keiko Sato, Hitoshi Hotokezaka, Tomoko Kadowaki, Arihide Kamaguchi, Kenji Yamamoto, Kuniaki Okamoto, Koji Nakayama

    Journal of bacteriology   189 ( 11 )   3977 - 86   2007.6

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    Porphyromonas gingivalis, an anaerobic gram-negative bacterium associated with chronic periodontitis, can agglutinate human erythrocytes. In general, hemagglutination can be considered the ability to adhere to host cells; however, P. gingivalis-mediated hemagglutination has special significance because heme markedly accelerates growth of this bacterium. Although a number of studies have indicated that a major hemagglutinin of P. gingivalis is intragenically encoded by rgpA, kgp, and hagA, direct evidence has not been obtained. We demonstrated in this study that recombinant HGP44(720-1081), a fully processed HGP44 domain protein, had hemagglutinating activity but that an unprocessed form, HGP44(720-1138), did not. A peptide corresponding to residues 1083 to 1102, which was included in HGP44(720-1138) but not in HGP44(720-1081), could bind HGP44(720-1081) in a dose-dependent manner and effectively inhibited HGP44(720-1081)-mediated hemagglutination, indicating that the interdomain regional amino acid sequence may function as an intramolecular suppressor of hemagglutinating activity. Analyses by solid-phase binding and chemical cross-linking suggested that HGP44 interacted with glycophorin A on the erythrocyte membrane. Glycophorin A and, more effectively, asialoglycophorin, which were added exogenously, inhibited HGP44(720-1081)-mediated hemagglutination. Treatment of erythrocytes with RgpB proteinase resulted in degradation of glycophorin A on the membrane and a decrease in HGP44(720-1081)-mediated hemagglutination. Surface plasmon resonance detection analysis revealed that HGP44(720-1081) could bind to asialoglycophorin with a dissociation constant of 3.0 x 10(-7) M. These results indicate that the target of HGP44 on the erythrocyte membrane appears to be glycophorin A.

    DOI： 10.1128/JB.01691-06

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  • Cathepsin E deficiency induces a novel form of lysosomal storage disorder showing the accumulation of lysosomal membrane sialoglycoproteins and the elevation of lysosomal pH in macrophages

    Michiyo Yanagawa, Takayuki Tsukuba, Tsuyoshi Nishioku, Yoshiko Okamoto, Kuniaki Okamoto, Ryosuke Takii, Yoshihiro Terada, Keiichi I. Nakayama, Tomoko Kadowaki, Kenji Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY   282 ( 3 )   1851 - 1862   2007.1

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  • Cathepsin E mediates membrane trafficking in macrophages

    Takayuki Tsukuba, Shinya Yamamoto, Michiyo Yanagawa, Yoshiko Okamoto, Kuniaki Okamoto, Kenji Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   103   214P - 214P   2007

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  • カテプシンE欠損によるミトコンドリア機能異常と酸化ストレス亢進

    筑波隆幸, 柳川三千代, 柳川三千代, 岡元邦彰, 門脇知子, 山本健二

    Journal of Oral Biosciences   49 ( Supplement )   2007

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  • P.gingivalis感染とインスリン抵抗性に関する実験的解析

    門脇知子, 瀧井良祐, 筑波隆幸, 岡元邦彰, 山本健二

    Journal of Oral Biosciences   49 ( Supplement )   2007

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  • カテプシンE欠損はマクロファージの膜蛋白質輸送異常とミトコンドリア機能異常を起こす

    筑波隆幸, 柳川三千代, 岡元邦彰, 岡本美子, 門脇知子, 山本健二

    生化学   2007

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  • Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation. International journal

    Hajime Yoshida, Kuniaki Okamoto, Tsutomu Iwamoto, Eiko Sakai, Kazuhiro Kanaoka, Jin-Ping Hu, Mitsue Shibata, Hitoshi Hotokezaka, Kazuhisa Nishishita, Akio Mizuno, Yuzo Kato

    Journal of biochemistry   139 ( 3 )   583 - 90   2006.3

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    Pepstatin A is well known to be an inhibitor of aspartic proteinases such as pepsin, cathepsins D and E. Except for its role as a proteinase inhibitor, however, the pharmacological action of pepstatin A upon cells remain unclear. In this study, we found that pepstatin A suppressed receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. Pepstatin A suppressed the formation of multinuclear osteoclasts dose-dependently. This inhibition of the formation only affected osteoclast cells, i.e., not osteoblast-like cells. Furthermore, pepstatin A also suppressed differentiation from pre-osteoclast cells to mononuclear osteoclast cells dose-dependently. This inhibition seems to be independent of the activities of proteinases such as cathepsin D, because the formation of osteoclasts was not suppressed with the concentration that inhibited the activity of cathepsin D. Cell signaling analysis indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkappaB and Akt showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cells c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression.

    DOI： 10.1093/jb/mvj066

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  • Characterization of rat cathepsin E and mutants with changed active-site residues and lacking propeptides and N-glycosylation, expressed in human embryonic kidney 293T cells

    T Tsukuba, S Ikeda, K Okamoto, Y Yasuda, E Sakai, T Kadowaki, H Sakai, K Yamamoto

    FEBS JOURNAL   273 ( 1 )   219 - 229   2006.1

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  • Gingipains inactivate a cell surface ligand on Porphyromonas gingivalis that induces TLR2- and TLR4-independent signaling

    M Kishimoto, A Yoshimura, M Naito, K Okamoto, K Yamamoto, DT Golenbock, Y Hara, K Nakayama

    MICROBIOLOGY AND IMMUNOLOGY   50 ( 4 )   315 - 325   2006

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  • Berberine inhibits RANKL-, TNF alpha-, LPS- and PGN-induced mature osteoclasts survival

    JP Hu, K Nishishita, E Sakai, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   100   268P - 268P   2006

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  • Involvement of glycosphingolipids in LPS mediated survival of mature osteoclasts

    E Sakai, S Fukumoto, K Nishishita, JP Hu, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   100   65P - 65P   2006

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  • カテプシンE欠損マクロファージにおける膜タンパク質の輸送異常

    筑波隆幸, 山本晋也, 山本晋也, 柳川三千代, 柳川三千代, 岡元邦彰, 門脇知子, 山本健二

    Journal of Oral Biosciences   48 ( Supplement )   2006

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  • P.gingivalis感染の生活習慣病増悪機序について

    門脇知子, 筑波隆幸, 瀧井良祐, 重松直樹, 岡元邦彰, 山本健二

    Journal of Oral Biosciences   48 ( Supplement )   2006

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  • The role of the cathepsin E propeptide in correct folding, maturation and sorting to the endosome

    Y Yasuda, T Tsukuba, K Okamoto, T Kadowaki, K Yamamoto

    JOURNAL OF BIOCHEMISTRY   138 ( 5 )   621 - 630   2005.11

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  • Identification of a new membrane-associated protein that influences transport/maturation of gingipains and adhesins of Porphyromonas gingivalis

    K Sato, E Sakai, PD Veith, M Shoji, Y Kikuchi, H Yukitake, N Ohara, M Naito, K Okamoto, EC Reynolds, K Nakayama

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 10 )   8668 - 8677   2005.3

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  • Alteration of substance P levels in various regions of mouse brain caused by cathepsin E-deficiency

    N Shigematsu, T Nishioku, T Tsukuba, T Fukuda, T Yamamoto, T Yamaguchi, S Kohsaka, K Okamoto, Y Okamoto, Y Tanaka, M Himeno, S Higuchi, K Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   72P - 72P   2005

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  • Up-regulation, Enhanced Maturation, and Secretion of Cathepsin E in Mouse Macrophages Treated with Interferon-γ or Lipopolysaccharide

    Michiyo Yanagawa, Takayuki Tsukuba, Kuniaki Okamoto, Ryosuke Takii, Yoshihiro Terada, Tomoko Kadowaki, Kenji Yamamoto

    journal of oral biosciences   48 ( 3 )   218 - 225   2005

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  • Porphyromonas gingivalisの産生するシステインプロテアーゼ(Kgp)の活性中心の決定

    岡元邦彰, HU P J, 坂井詠子, 西下一久, 門脇知子, 山本健二, 中山浩次, 加藤有三

    Journal of Oral Biosciences   47 ( Supplement )   2005

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  • Cathepsin E is important for endosomal/lysosomal systems in macrophages against a bacterial infection

    T Tsukuba, M Yanagawa, Y Okamoto, K Okamoto, K Yanamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   78P - 78P   2005

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  • Glycosphingolipids regulate osteoclastgenesis mediated by lipopolysaccharide

    E Sakai, S Fukumoto, Y Narita, M Tanaka, M Tachi, H Hotokezaka, K Kanaoka, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   178P - 178P   2005

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  • Roles of Arg- and Lys-gingipains in coaggregation of Porphyromonas gingivalis: identification of its responsible molecules in translation products of rgpA, kgp, and hagA genes

    N Abe, A Baba, R Takii, K Nakayama, A Kamaguchi, Y Shibata, Y Abiko, K Okamoto, T Kadowaki, K Yamamoto

    BIOLOGICAL CHEMISTRY   385 ( 11 )   1041 - 1047   2004.11

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  • ベルベリンのマウス骨髄細胞からの破骨細胞形成への抑制作用

    胡 錦萍, 西下 一久, 柴田 光枝, 坂井 詠子, 金岡 和博, 吉田 一, 岡元 邦彰, 加藤 有三

    Journal of oral biosciences   46 ( 5 )   463 - 463   2004.9

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  • カテプシンEによる免疫アレルギー性疾患の制御機構

    筑波 隆幸, 柳川 三千代, 甲村 恵子, 梯 裕恵, 岡元 邦彰, 山本 健二

    Journal of oral biosciences   46 ( 5 )   474 - 474   2004.9

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  • KIAA0377遺伝子産物の破骨細胞様細胞形成におよぼす影響

    西下 一久, 石田 豊, 東洋 一, 岡元 邦彰, 加藤 有三

    Journal of oral biosciences   46 ( 5 )   465 - 465   2004.9

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  • Laminin alpha 2 is essential for odontoblast differentiation regulating dentin sialoprotein expression

    K Yuasa, S Fukumoto, Y Kamasaki, A Yamada, E Fukumoto, K Kanaoka, K Saito, H Harada, E Arikawa-Hirasawa, Y Miyagoe-Suzuki, S Takeda, K Okamoto, Y Kato, T Fujiwara

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 ( 11 )   10286 - 10292   2004.3

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  • Cathepsin E deficiency and brain functions

    N Shigematsu, T Nishioku, T Tsukuba, S Kohsaka, K Okamoto, Y Okamoto, T Yamamoto, M Himeno, K Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   94   89P - 89P   2004

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  • Glycosphingolipids regulate osteoclastgenesis mediated by receptor activator of NF-kB ligand and lipopolysaccharide

    E Sakai, S Fukumoto, H Hotokezaka, E Fukumoto, M Shibata, K Kanaoka, T Iwamoto, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   94   184P - 184P   2004

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  • Effect of Pepstatin A in osteoclast

    H Yoshida, K Okamoto, M Shibata, E Sakai, K Kanaoka, K Yuasa, A Mizuno, K Nishishita, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   94   188P - 188P   2004

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  • Association of cathepsin E deficiency with development of atopic dermatitis

    T Tsukuba, K Okamoto, Y Okamoto, M Yanagawa, K Kohmura, Y Yasuda, H Uchi, T Nakahara, M Furue, K Nakayama, T Kadowaki, K Yamamoto, KI Nakayama

    JOURNAL OF BIOCHEMISTRY   134 ( 6 )   893 - 902   2003.12

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  • ベルベリンによる破骨細胞分化因子(RANKL)細胞内シグナリング抑制効果

    胡 錦萍, 西下 一久, 柴田 光枝, 岡元 邦彰, 加藤 有三

    歯科基礎医学会雑誌   45 ( 5 )   374 - 374   2003.9

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  • スフィンゴ糖脂質はRANKやc-Srcのラフトへの局在と破骨細胞形成を調節する

    坂井 詠子, 福本 敏, 金岡 和博, 柴田 光枝, 福本 恵美子, 岩本 勉, 岡元 邦彰, 加藤 有三

    歯科基礎医学会雑誌   45 ( 5 )   343 - 343   2003.9

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  • ラミニンα2の歯の発生における役割

    湯浅 健司, 福本 敏, 釜崎 陽子, 山田 亜矢, 福本 恵美子, 斉藤 幹, 岡元 邦彰, 藤原 卓, 加藤 有三

    歯科基礎医学会雑誌   45 ( 5 )   290 - 290   2003.9

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  • 口腔癌における破骨細胞分化因子の役割

    岩本 勉, 福本 敏, 柳本 惣市, 吉田 一, 岡元 邦彰, 吉冨 泉, 川崎 五郎, 加藤 有三, 水野 明夫

    歯科基礎医学会雑誌   45 ( 5 )   319 - 319   2003.9

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  • Regulation of osteoclast survival and activation by glycosphingolipids.

    K. Kanaoka, S. Fukumoto, K. Yuasa, K. Okamoto, M. Shibata, E. Sakai, Y. Kato, T. Iwamoto, F. Hashimoto, N. Yoshida

    JOURNAL OF DENTAL RESEARCH   82   B358 - B358   2003.6

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  • Subcellular localization of the receptor activator of NF-KappaB and SRC kinase in detergent insoluble fractions of osteoclasts

    E Sakai, S Fukumoto, K Kanaoka, M Shibata, T Iwamoto, E Fukumoto, K Okamoto, Y Kato

    BONE   32 ( 5 )   S155 - S155   2003.5

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  • The regulation of bone resorption in tooth formation and eruption processes in mouse alveolar crest devoid of cathepsin K

    M Okaji, H Sakai, E Sakai, M Shibata, F Hashimoto, Y Kobayashi, N Yoshida, K Okamoto, K Yamamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91 ( 4 )   285 - 294   2003.4

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  • Disruption of structural and functional integrity of alpha(2)-macroglobulin by cathepsin E

    M Shibata, H Sakai, E Sakai, K Okamoto, K Nishishita, Y Yasuda, Y Kato, K Yamamoto

    EUROPEAN JOURNAL OF BIOCHEMISTRY   270 ( 6 )   1189 - 1198   2003.3

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  • Porphyromonas gingivalisの産生するリジン特異的システインプロテアーゼ発現系の確立

    岡元邦彰, 胡錦へい, 柴田光枝, 坂井詠子, 門脇知子, 庄子幹郎, 山本健二, 中山浩次, 加藤有三

    歯科基礎医学会雑誌   45 ( 5 )   2003

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  • Cathepsin E and atopic dermatitis.

    T Tsukuba, K Okamoto, K Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91   13P - 13P   2003

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  • Expression and subcellular localization of caveolin with Src kinase and RANK in osteoclasts.

    E Sakai, S Fukumoto, K Kanaoka, M Shibata, T Iwamoto, E Fukumoto, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91   71P - 71P   2003

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  • Purification and characterization of mouse soluble RANK expressed in a baculovirus system.

    T Imai, M Shibata, K Kanaoka, K Yuasa, A Mizuno, K Okamoto, Y Kato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91   239P - 239P   2003

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  • なぜ,カテプシンK欠損マウスにおいて歯は正常に萌出できるのか?

    岡地 雅代, 柴田 光枝, 坂井 詠子, 岡元 邦彰, 山本 健二

    歯科基礎医学会雑誌   44 ( 5 )   433 - 433   2002.9

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  • Porphyromonas gingivalisによる赤血球凝集機構解明の試み

    坂井 詠子, 佛坂斉祉, 庄子 幹郎, 鎌口 有秀, 岡元 邦彰, 加藤 有三, 中山 浩次

    歯科基礎医学会雑誌   44 ( 5 )   466 - 466   2002.9

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  • The role of propeptide of cathepsin E in its biosynthetic pathway

    Y Yasuda, K Kohmura, K Okamoto, T Tsukuba, K Yamamoto

    JAPANESE JOURNAL OF PHARMACOLOGY   88   183P - 183P   2002

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  • カテプシンD欠損マウスにおける長骨骨端線の消失

    岡元 邦彰, 前田 英史, 加藤 有三, 山本 健二

    歯科基礎医学会雑誌   43 ( 5 )   581 - 581   2001.8

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  • 歯周病原性細菌の蛋白質分解酵素を介する生存戦略 (新世紀における蛋白質科学の進展) -- (第3部 生命現象の理解と医療・創薬に向けて)

    山本 健二, 馬場 貴代, 岡元 邦彰

    蛋白質核酸酵素   46 ( 11 )   1426 - 1427,1781〜1788   2001.8

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  • Pathophysiological roles of two types of gingipains in periodontal diseases

    K. Yamamoto, A. Baba, K. Okamoto, T. Kadowaki

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   46 ( 11 Suppl )   1781 - 1788   2001.8

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  • New functional aspects of cathepsin D and cathepsin E

    T Tsukuba, K Okamoto, Y Yasuda, W Morikawa, H Nakanishi, K Yamamoto

    MOLECULES AND CELLS   10 ( 6 )   601 - 611   2000.12

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  • Porphyromonas gingivalis proteinases as virulence determinants in progression of periodontal diseases

    Tomoko Kadowaki, Koji Nakayama, Kuniaki Okamoto, Naoko Abe, Atsuyo Baba, Yixin Shi, Dinath B. Ratnayake, Kenji Yamamoto

    Journal of Biochemistry   128 ( 2 )   153 - 159   2000.8

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    DOI： 10.1093/oxfordjournals.jbchem.a022735

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  • 歯周病原性細菌の産生するリジン特異的システインプロテアーゼの分布と機能解析

    安部直子, 門脇知子, 岡元邦彰, 岡崎真治, 浅尾哲次, 中山浩次, 山本健二

    歯科基礎医学会雑誌   42 ( 5 )   2000

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  • 歯周病原性細菌のヘムおよびアミノ酸獲得機構

    山本健二, 岡元邦彰, 門脇知子, 安部直子, 馬場貴代, 中山浩次

    生化学   72 ( 8 )   2000

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  • カテプシンDおよびEの性状解析に有用な新しい合成基質の作製

    安田 善之, 岡元 邦彰, 岡本 美子, 景山 節, 内山 安男, 木南 英紀, 山本 健二

    生化学   71 ( 8 )   867 - 867   1999.8

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  • Arginine- and lysine-specific gingipains from Porphyromonas gingivalis as major virulence factors of progressive periodontal disease.

    山本健二, 門脇知子, 岡元邦彰, 安部直子, 中山浩次

    炎症   18 ( 4 )   259 - 264   1998

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  • Structural and functional characterization of periodontal pathogenic cysteine proteinases from Porphyromonas gingivalis

    K. Yamamoto, T. Kadowaki, K. Okamoto, K. Nakayama

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   42 ( 14 Suppl )   2425 - 2432   1997.10

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  • Biological roles of a novel class of cysteine proteinases from Porphyromonas gingivalis in periodontal disease progression

    K Yamamoto, T Kadowaki, K Okamoto, N Abe, K Nakayama

    MEDICAL ASPECTS OF PROTEASES AND PROTEASE INHIBITORS   15   139 - 149   1997

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  • ラットカテプシンE分子のN-結合型糖鎖の役割

    池田 仁子, 西下 一久, 坂井 英昭, 岡元 邦彰, 筑波 隆幸, 加藤 有三, 山本 健二

    日本分子生物学会年会プログラム・講演要旨集   19   255 - 255   1996.8

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  • Processing of exine protein and secretion protein by Porphyromonas gingivalis arginine peculiar cysteine proteinase (Arg-gingipain).

    門脇知子, 中山浩次, 吉村文信, 岡元邦彰, 山本健二

    日本分子生物学会年会プログラム・講演要旨集   19th   1996

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  • Periodontal disease and pathogenic protease.

    山本健二, 門脇知子, 岡元邦彰

    モダンフィジシャン   16 ( 12 )   1996

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  • Structural comparison of the pathogenicity protease gene of Porphyromonas gingivalis.

    岡元邦彰, 門脇知子, 中山浩次, 山本健二

    日本分子生物学会年会プログラム・講演要旨集   19th   1996

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  • 新規腫瘍オルガノイド形成多元評価システムの薬剤スクリーニングへの応用

    十川千春, 江口傑徳, 石毛真行, 河合穂高, 奥舎有加, 中野敬介, 十川紀夫, 小崎健一, 岡元邦彰

    2019.12.15 

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    Event date： 2019.12.15

    Presentation type：Oral presentation (general)  

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  • Keap1遺伝子欠損はNrf2の活性化を介して破骨細胞分化を抑制する

    坂井詠子, 福間裕, 西下一久, 岡元邦彰, 筑波隆幸

    第40回日本分子生物学会年会／第90回日本生化学会大会  2017.12 

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    Event date： 2017.12.6 - 2017.12.9

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  • 口腔扁平上皮癌由来エクソソームニ含まれるプロテオームの特性

    小野喜章, 江口傑徳, 十川千春, 村上純, 藤原敏史, 笠井智成, 妹尾昌治, 佐々木朗, 小崎健一, 岡元邦彰

    第40回日本分子生物学会年会／第90回日本生化学会大会  2017.12 

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  • Transcription factor Sp1 regulates the expression of the murine cathepsin E gene in gastric adenosarcoma cells

    第83回日本薬理学会年会  2010 

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  • Transcription factor Sp1 regulates the expression of the murine cathepsin E gene in gastric adenosarcoma cells

    2010 

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  • 鉄代謝を介した新規の破骨細胞分化機構

    第51回歯科基礎医学会学術大会  2009 

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  • 破骨細胞分化における鉄代謝とミトコンドリアストレスの重要性

    第３３回日本鉄バイオサイエンス学会学術集会  2009 

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  • カテプシンE欠損によるオートファジー低下とそれに伴うミトコンドリア機能低下と酸化ストレスの増大

    第14回日本病態プロテアーゼ学会  2009 

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  • IMPAIRMENT OF AUTOPHAGY ACCOMPANIED BY INCREASED ABERRANT MITOCHONDRIA AND OXIDATIVE STRESS IN CATHEPSIN E DEFICIENT MACROPHAGES

    2009 

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  • カテプシンE欠損マクロファージにおけるオートファジーの低下とそれに伴うミトコンドリア機能異常と酸化ストレスの上昇

    第51回歯科基礎医学会学術大会  2009 

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  • IMPAIRMENT OF AUTOPHAGY ACCOMPANIED BY INCREASED ABERRANT MITOCHONDRIA AND OXIDATIVE STRESS IN CATHEPSIN E DEFICIENT MACROPHAGES

    5th International Symposium on Autophagy  2009 

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  • RANKL誘導性破骨細胞分化における鉄結合蛋白の関与

    第50回歯科基礎医学会学術大会  2008 

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  • カテプシンE欠損はマクロファージの膜蛋白質輸送異常とミトコンドリア機能異常を起こす

    第31回日本分子生物学会／第81回日本生化学会合同大会  2008 

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  • カテプシンＥ欠損による遊走能および細胞接着能の低下

    第50回歯科基礎医学会学術大会  2008 

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  • カテプシンＥ遺伝子発現に関する転写因子Sp1

    第31回日本分子生物学会／第81回日本生化学会合同大会  2008 

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  • カテプシンＥ欠損マウスにおける高脂血症および脂肪肝の誘導

    第50回歯科基礎医学会学術大会  2008 

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  • カテプシンＥ遺伝子発現に関与する転写因子Sp1

    第50回歯科基礎医学会学術大会  2008 

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  • CONTROL OF THE ENDOSOME/LYSOSOME SYSTEM OF MACROPHAGES BY CATHEPSIN E

    5TH General Meeting of the International Proteolysis Society  2007 

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  • 赤血球におけるカテプシンＥの役割

    第49回歯科基礎医学会学術大会  2007 

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  • P. gingivalis感染とインスリン抵抗性に関する実験的解析

    第49回歯科基礎医学会学術大会  2007 

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  • ASSOCIATION OF CATHEPSIN E WITH HOST DEFFENCE AGAINST TUMOR CELLS

    5TH General Meeting of the International Proteolysis Society  2007 

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  • 成熟破骨細胞の延命と脂質ラフト形成におけるリセドロネートおよびD-PDMPの作用

    第49回歯科基礎医学会学術大会  2007 

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  • Cathepsin E mediates membrane trafficking in macrophages

    第80回日本薬理学会  2007 

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  • カテプシンＥ欠損によるミトコンドリア機能異常と酸化ストレス亢進

    第49回歯科基礎医学会学術大会  2007 

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  • ベルベリンによる破骨細胞生存の抑制機構の解明

    第49回歯科基礎医学会学術大会  2007 

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  • Cathepsin E mediates membrane trafficking in macrophages

    2007 

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  • CONTROL OF THE ENDOSOME/LYSOSOME SYSTEM OF MACROPHAGES BY CATHEPSIN E

    2007 

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  • ASSOCIATION OF CATHEPSIN E WITH HOST DEFFENCE AGAINST TUMOR CELLS

    2007 

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  • Suppression of carcinogenesis and tumor growth by cathepsin E

    20th IUBMB International Congress of Biochemistry and Molecular Biology  2006 

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  • Involvement of glycosphingolipids in LPS mediated survival of mature osteoclasts

    第７９回日本薬理学会総会  2006 

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  • A possible mechanism for cathepsin E-mediated tumor supression

    Satellite Meeting for the 20th IUBMB International Congress and 11th FAOBMB Congress  2006 

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  • Berberine inhibits RANKL, TNFa, LPS and PGN-induced mature osteoclasts survival

    第７９回日本薬理学会総会  2006 

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  • Porphyromonas gingivalisの血球凝集および接着性におけるHGP44の役割とＣ末端ペプチドの阻害効果

    第48回歯科基礎医学会学術大会  2006 

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  • P. gingivalis感染の生活習慣病増悪機序について

    第48回歯科基礎医学会学術大会  2006 

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  • マウスカテプシンＥ遺伝子発現におけるSp1の関与

    日本分子生物学会2006フォーラム  2006 

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  • カテプシンＥ欠損マクロファージにおける膜タンパク質の輸送異常

    第48回歯科基礎医学会学術大会  2006 

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  • ベルベリンによる破骨細胞形成抑制の分子機構

    第５８回日本薬理学会西南部会  2005 

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  • カテプシンＥ欠損が及ぼすマクロファージの機能異常

    第５８回日本薬理学会西南部会  2005 

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  • Berberine Inhibits RANKL, TNF-a, LPS and Peptidoglycan (PGN)-induced Fusion of Osteoclasts

    日中医学会  2005 

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  • スフィンゴ糖脂質による破骨細胞内LPSシグナル伝達の制御

    第４７回歯科基礎医学会学術大会  2005 

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  • ベルベリンの破骨細胞形成抑制作用のメカニズム検討

    第４７回歯科基礎医学会学術大会  2005 

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  • Aberrant antigen processing in cathepsin E-deficient dendritic cells

    第７８回日本生化学会  2005 

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    Presentation type：Poster presentation  

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  • 破骨細胞におけるスフィンゴ糖脂質の役割

    第４７回歯科基礎医学会学術大会  2005 

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  • Cathepsin E is important for endo/lysosomal systems in macrophages against a bacterial infection.

    第７８回日本薬理学会総会  2005 

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  • Alterration of substance P levels in various regions of mouse brain caused by cathepsin E-deficiency

    日本薬理学会総会  2005 

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  • Porphyromonas gingivalisの産生するシステインプロテアーゼ(Kgp)の活性中心の決定

    第４７回歯科基礎医学会学術大会  2005 

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    Presentation type：Poster presentation  

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  • Glycosphingolipids regulate osteoclastgenesis mediated by lipopolysaccharide

    第７８回日本薬理学会総会  2005 

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Works

  • 破骨細胞におけるカテプシンＥの役割と創薬にむけた基質分子の探究

    2009
    -
    2011

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  • 骨疾患における創薬のターゲットとなりうるプロテアーゼの作用機序の解明

    2007
    -
    2009

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  • 歯周病原性細菌の産生するプロテアーゼの膜輸送システムの解明

    2005

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Awards

  • 日本生化学会ＪＢ論文賞

    2004  

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    Country：Japan

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Research Projects

  • 膜ダイナミクスをターゲットとしたがん骨転移ニッチモデルと病態制御機構の開発

    Grant number：24K13239  2024.04 - 2027.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    岡元 邦彰

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

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  • Roles of cancer extracellular vesicles in hijacking macrophages and metastatic niche formation

    Grant number：23H03310  2023.04 - 2026.03

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

    江口 傑徳, 河合 穂高, 高橋 賢, 冨樫 庸介, 岡元 邦彰

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    Grant amount：\18720000 （ Direct expense: \14400000 、 Indirect expense：\4320000 ）

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  • Roles of cancer extracellular vesicles in hijacking macrophages and metastatic niche formation

    Grant number：23K28000  2023.04 - 2026.03

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

    江口 傑徳, 高橋 賢, 河合 穂高, 岡元 邦彰, 冨樫 庸介, 武部 克希

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    Grant amount：\18720000 （ Direct expense: \14400000 、 Indirect expense：\4320000 ）

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  • 三次元腫瘍オルガノイド評価系により見出された新規癌転移抑制化合物の創薬展開

    Grant number：20K09904  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    十川 千春, 岡元 邦彰, 江口 傑徳, 河合 穂高, 青山 絵理子

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    Grant amount：\4420000 （ Direct expense: \3400000 、 Indirect expense：\1020000 ）

    癌の悪性化、転移および再発を制御するには、分子機序の解明と有効な抗腫瘍薬の開発が不可欠である。近年、癌の悪性化には癌細胞を取りまく腫瘍微小環境が影響するといわれ、癌細胞のみならず腫瘍微小環境を制御する因子も標的分子の候補に入れた検討が必要である。本研究課題では、三次元腫瘍オルガノイド形成とMMP9発現をモニタリングすることによる、独自の多元薬物評価系によって見出したヒット化合物をもとに、新規癌転移抑制薬開発に向けた創薬展開を行うことを目的とする。
    令和3年度は、これまで得られたヒット化合物のさらなるブラッシュアップのため、腫瘍微小環境に対する薬剤の効果を評価可能な高次アッセイ系の構築を引き続き行った。エクソソームをはじめとする細胞外小胞（Extracellular Vesicles: EV）は腫瘍微小環境制御に関わるとされるが、免疫系細胞が分泌するEVの腫瘍細胞に対する影響について、昨年度確立した蛍光または発光モニタリングシステムを応用することにより検討した。マクロファージ様に分化させたTHP-1細胞から分泌されたEVをサイズ排除クロマトグラフィーを用いて粒子径により分画し、CD9陽性の大型EV（80-300 nm）とCD63/HSP90陽性小型EV(20-200 nm)を得た。蛍光標識したこれらのEVは口腔癌細胞HSC-3に効率的に取り込まれ、口腔癌細胞の生存率を大幅に低下させることが明らかとなった。
    以上のことから、マクロファージ様細胞におけるEVの分泌を促進する薬剤は抗がん作用を発揮する可能性が高く、腫瘍微小環境に対する薬剤の効果を検討する上で重要であると考えられた。

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  • MZF1-Driven Cancer Stem-Like Resistance Against Cell Stress

    Grant number：17K11642  2017.04 - 2021.03

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

    Eguchi Takanori

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

    Refractory cancers are highly resistant to cellular stress. In this study, we demonstrated: 1) 3D cell aggregative structures of 66 cancer cell types, 2) cancer stem-like properties of metastatic prostate cancer cell-derived organoid, 3) stress-responsive production of extracellular heat shock protein (eHSP) and exosome, 4) reciprocal regulatory mechanism of CDC37 gene by oncogenic transcription factor MZF1 and tumor-suppressing transcription factor SCAND1, 5) “stresssome” including eHSP90 and damaged membrane vesicles, 6) eHSPs as prognostic markers in exosomes in metastatic oral carcinoma, 7) roles of metastatic cancer-derived exosomes in cancer progression and microenvironment such as M2-type macrophages, and 8) a triple knockdown method as a novel therapeutic strategy targeting refractory metastatic cancers.

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  • Drug repositioning using the gene promoter activity-based anticancer drug screening system

    Grant number：17K11643  2017.04 - 2021.03

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

    Sogawa Chiharu

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    In the present study, we aimed to develop a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability. High expression and genetic amplification of matrix metalloproteinase 9 (MMP9) were found in rapid metastatic colon cancer cases. Furthermore, the properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors. We screened the pharmacologically active compounds using an original tumoroid-based multiplex phenotypic screening system with an MMP9 promoter-driven fluorescence reporter to evaluate tumoroid formation and progression. The anti-Parkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also inhibited the tumor growth, circulating tumor cell number, and rate of metastasis in a tumor allograft model in mice.

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  • Discovery of a novel gene regulating membrane trafficking of immune cells and elucidation of its pathology

    Grant number：17H04379  2017.04 - 2020.03

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

    TSUKUBA Takayuki

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    Grant amount：\16900000 （ Direct expense: \13000000 、 Indirect expense：\3900000 ）

    Our previous study identified the gene Rab44, which is increased during osteoclast differentiation. In this study, the function of Rab44 especially in immune cells was elucidated. First, as a molecular mechanism, we found that Rab44 deficiency increases calcium influx from lysosomes. Subsequent examination of tissue distribution revealed that Rab44 was expressed at high levels in bone marrow cells and at low levels in other tissues. Furthermore, we generated Rab44-deficient mice, and we compared wild and Rab44-defieint mice when anaphylactic reaction was induced. As a result, the anaphylactic reactions of Rab44-defieint mice were reduced by about half compared with wild-type mice. These results indicate that Rab44 regulates allergic reaction.

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  • フラボノイドをベースにした抗がん作用をもつサプリメントの開発

    2016.04 - 2019.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • Molecular mechanism of bone destruction in rheumatoid arthritis based on CD147

    Grant number：16K08567  2016.04 - 2019.03

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

    NISHIOKU TSUYOSHI

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

    We examined the hypothesis that CD147, which is upregulated in rheumatoid arthritis, enhances actin ring formation via podosome. In osteoclastogenisis, CD147 expression was significantly increased and localized to the cell membrane. We confirmed podosome marker expression and actin ring formation in osteoclasts, and CD147 co-localized with actin ring. We examined the expression of MT1-MMP, which is involved in the sealing by actin ring, and increased expression was observed in osteoclasts. However, the interaction between CD147 and MT1-MMT could not be confirmed. It has been shown that CD147, which is upregulated in osteoclasts, may be involved in podosome formation.

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  • Elucidation of Keap1/Nrf2-mediated control system of bone metabolism and application to in silico drug discovery

    Grant number：16K11480  2016.04 - 2019.03

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

    SAKAI Eiko

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    Grant amount：\4810000 （ Direct expense: \3700000 、 Indirect expense：\1110000 ）

    We revealed that Nrf2 activation, which reduces oxidative stress, not only suppresses osteoclast differentiation, but also inhibits osteoblast differentiation. However, contrary to expectation, no remarkable abnormality of the skeleton was observed.Furthermore, we constructed Keap1/Nrf2 double knockout mice to determine whether the cause of marked suppression of osteoclast differentiation in Keap1 deficiency is due to constitutive activation of Nrf2.
    As a result, it was revealed that the constitutive activation of Nrf2 raises the expression of MafB, a NFATc1 inhibitor molecule, and negatively regulates osteoclast differentiation.On the other hand, among 1360 kinds of synthetic compounds and marine microorganism-derived components, those having an osteoclast differentiation inhibitory effect at very low concentrations, or those activating Nrf2 were found.Administration of candidate compounds to pathological model mice and analysis of pathological conditions were conducted.

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  • 破骨細胞におけるリソソーム分泌機構の制御因子の同定と分子メカニズムの解析

    Grant number：16K11510  2016.04 - 2018.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    西下 一久, 筑波 隆幸, 岡元 邦彰, 坂井 詠子

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    Grant amount：\4810000 （ Direct expense: \3700000 、 Indirect expense：\1110000 ）

    １）マクロファージ及び破骨細胞Rab27A結合タンパク質の同定
    Rabタンパク質は通常、種々のエフェクタータンパク質と相互作用して働く。そのために結合タンパク質の同定は、rabタンパク質を理解するうえで必要不可欠である。さらに破骨細胞では、リソソームを分泌するという特徴があるにもかかわらず、破骨細胞におけるRab結合タンパク質はこれまで同定されていない。そこでマクロファージ及び破骨細胞におけるRab27A結合タンパク質を同定する方法として以下の方法を試みた。
    ①酵母ツーハイブリッドシステムを用いて相互作用する分子を分子生物学的に同定する方法。この方法は２つの対象タンパク質間の直接相互作用を試験するための、高感度な方法である。相互作用パートナーは、その後選択された酵母コロニーで対応するプラスミドをシークエンシングすることによって得ることができる。しかしこの方法では同定できなかった。
    ②Rab27A過剰発現細胞を用いて、Rab27Aプルダウンアッセイを行い、結合タンパク質をプロテオーム解析により同定する方法。恒常的に活性型であるドミナント・アクティブ型、恒常的に不活性型であるドミナント・ネガティブ型を発現させて、結合タンパク質の違いがあるかどうかを解析した。
    ③結合タンパク質がRab27Aのどの部位に結合するかを調べるために、部位特異的遺伝子変異体を用いて結合部位の同定を試みた。さらにこの実験系を用いて、結合するタンパク質を免疫沈降やプロテオーム解析により同定した。

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  • Analyses using bioimaging of invasion and colonization mechanisms by periodontal bacteria in the liver

    Grant number：16K15790  2016.04 - 2018.03

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

    TSUKUBA Takayuki

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    Grant amount：\3510000 （ Direct expense: \2700000 、 Indirect expense：\810000 ）

    Invasion of periodontal bacteria from the oral cavity into the blood circulation causes several systemic diseases. Recently, infection with P. gingivalis was reported to accelerate the development and progression of non-alcoholic fatty liver disease. However, the detailed mechanisms remain unknown. In this study, using bioimaging analysis, we observed invasion and colonization of the periodontal bacteria in the culture hepatocytes. As a result, we found that periodontitis bacteria were present mainly in autophagosomes and lysosomes. It was also found that the presence of lipid droplets within the cells increases the survival rate at the early stage of the infection of the same fungus, and that lipid droplets influence autolysosome formation of bacterial exclusion.

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  • Examination of new medicine for bone metabolism by investigation of potential natural drugs in China

    Grant number：15H05298  2015.04 - 2018.03

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

    TSUKUBA Takayuki

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    Grant amount：\15990000 （ Direct expense: \12300000 、 Indirect expense：\3690000 ）

    Osteoporosis is accompanied by an increase in the population of elderly people, the number of patients in Japan has been rapidly increasing. Since bisphosphonates, currently used osteoporosis drugs, have extremely strong side effects such as necrosis of the jaw, development of drugs with low toxicity is urgent. The purpose of this research is to find bone metabolism drugs with less toxicity from natural medicines in China and Jilin Province, which is a treasure house of natural products and is known as a longevity village. As a result of various analyzes, it was revealed that Rutaecarpine and Dihydroartemisinin are less toxic and have strong osteoclast inhibitory effects. Furthermore, the detailed molecular mechanisms were also analyzed.

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  • Development of detection systems for polyphenols that inhibit osteoclast formation and its applications

    Grant number：26670906  2014.04 - 2016.03

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

    TSUKUBA Takayuki, OKAMOTO Kuniaki, SAKAI Eiko

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

    Control of decreased expression levels of hemeoxygenase-1 (HO-1) is essential for the development of osteoclast formation. Addition of oxidants inducing HO-1 is thought to inhibit the osteoclast formation. One of the candidates is polyphenols in foods. However, numerous polyphenols remain to be identified. In this study, we constructed rapid and simple systems for detecting polyphenols that inhibit osteoclast formation. By the methods, we will analyze the identified polyphenols. Consequently, the drugs or supplements that prevent bone absorption by osteoclasts will be developed in future.

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  • Analysis of new functions of an intracellular protease in epithelial cancers

    Grant number：25462920  2013.04 - 2016.03

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

    FUKUMA Yutaka, TSUKUBA Takayuki, OKAMOTO Kuniaki, NISHISHITA Kazuhisa, SAKAI Eiko

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

    There are many studies reported relationship between cancer and proteases. For a long time, proteases have been recognized as bad factors for cancer progression. However, we discovered that cathepsin E prevents cancer progression as a good factor. In this study, we found that cathepsin E deficiency developed mammary tumors, and identified the altered genes and proteins in the cathepsin E-deficient mammary cells. As a result, Wnt5a was significantly impaired in the deficient mammary cells. Therefore, cathepsin E deficiency may cause abnormal Wnt/β-catenin signaling, thereby resulting in cancer development.

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  • Elucidation of molecular mechanisms of Nrf2-mediated osteoclastogenesis and search of natural products as molecular targets

    Grant number：25462892  2013.04 - 2016.03

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

    SAKAI Eiko, TSUKUBA Takayuki, OKAMOTO Kuniaki, NISHISHITA Kazuhisa

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    Grant amount：\5070000 （ Direct expense: \3900000 、 Indirect expense：\1170000 ）

    This study investigated the role of Keap1/Nrf2 axis in the differentiation of osteoclast using wild-type, Keap1-deficient, and Nrf2-deficient mice. Keap1-deficient osteoclast precursors showed defects in osteoclastogenesis through the inhibition of phosphorylation of ERK, P38 MAPK, and JNK. Furthermore, the protein expression of NFATc1 was significantly downregulated. In contrast, Nrf2-deficient osteoclast precursors underwent enhanced osteoclastogenesis through the activation of ERK, p38 MAPK, and JNK signaling. Moreover, nuclear translocation of NFATc1 and c-Fos was increased in Nrf2-deficient osteoclast precursors. However, microcomputed tomographic analyses and histological analyses of femurs with hematoxylin-eosin staining showed no significant defects among these mice. Furthermore, we compared the inhibitory effects of cafestol and kahweol, or sanguiin H-6 and its degradation product, ellagic acid on osteoclast differentiation.

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  • Elucidation of the mechanism of systemic diseases by a periodontal pathogen in the intracellular transport

    Grant number：25293383  2013.04 - 2016.03

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

    TSUKUBA Takayuki, NAKAYAMA Koji, OKAMOTO Kuniaki, NISHISHITA Kazushisa, SAKAI Eiko

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

    Recent studies have shown that infection with Porphyromonas gingivalis, a major periodontal pathogen, hastens the progression of non-alcoholic fatty liver disease (NAFLD). However, the intracellular fate of P. gingivalis in hepatocytes remains unknown. Here, using oleic-acid-induced HepG2 cells as an in vitro model for NAFLD, we found that lipid droplets increased the existence of P. gingivalis in the cells at an early phase of infection. Confocal microscopic analysis revealed that lipid droplets affected the formation of autolysosomes in infected cells. Thus, lipid droplets affect the elimination of P. gingivalis in HepG2 cells by altering the autophagy-lysosome system.

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  • ステロイドによって誘発される膜タンパク質の細胞生物学的解析

    2012.04 - 2015.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • Phylogenetic and biochemical approach for identifying the chronic proinflammatory proteins accumulated in protease-deficient species and individuals

    Grant number：24592836  2012.04 - 2015.03

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

    NISHISHITA Kazuhisa, SAKAI Eiko, OKAMOTO Kuniaki, TSUKUBA Takayuki, FUKUMA Yutaka, SUGAWARA Megumi

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    Grant amount：\5330000 （ Direct expense: \4100000 、 Indirect expense：\1230000 ）

    We investigated the evolution and gene organization of the aspartic proteases, including cathepsin D, cathepsin E, pepsins, renin and napsins. Cathepsin E gene appears to be absent in Ruminants and Platypus. Human napsin B has been annotated as a pseudogene because it lacks an in-frame stop codon. napsin B orthologs are primarily distributed in primates, while napsin A orthologs are the only napsin genes in other species. Napsin B was duplicated from napsin A during the early stages of primate evolution, and the subsequent loss of napsin B function reflected ongoing human-specific napsin B pseudogenization.
    Cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress in macrophage. The impaired adipose tissue development in high fat diet-fed cathepsin E-deficient mice was probably due to reduced infiltration of macrophages and may lead to hepatomegaly accompanied by hepatic steatosis and hypercholesterolemia.

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  • Mechanistic analysis of periodontal bacteria attached on cardiovascular tissues by live-imaging

    Grant number：24659840  2012.04 - 2014.03

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

    TSUKUBA Takayuki, OKAMOTO Kuniaki, SAKAI Eiko

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    Grant amount：\3770000 （ Direct expense: \2900000 、 Indirect expense：\870000 ）

    We analyzed a fate of Porphyromonas gingivalis, a periodontal pathogen, with human aortic endothelial cells by live-imaging. We detected the bacteria within the cells for 6-8 hs, but failed to find them for 18-24 hs, indicating that the bacteria is probably transported to the lysosomes.
    Futhermore, we performed live-imaging of P. gingivalis using mice. We found that the bacteria attached on blood vessels of bifurcation area and thin vessels. In ApoE-deficient mice, which is a model for arterial sclerosis, the attachment rate of the bacteria was increased. These results indicate that cholesterol in the blood probably interacts with P. gingivalis during endocytosis.

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  • 破骨細胞に関するカテプシンＥの役割と創薬にむけた探求

    2011.04 - 2012.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • Pathological analysis of epithelial cells in periodontitis

    Grant number：22592086  2010 - 2012

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

    FUKUMA Yutaka, TSUKUBA Takayuki, OKAMOTO Kuniaki, NISHISHITA Kazuhisa, SAKAI Eiko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    Periodontitis is a bacterial infectious disease that destroys gingival epithelial cells, and develops inflammation of immune-related cells. However, pathological studies on epithelial cells in periodontitis have been less frequently performed compared to those of immune-related cells. In this study, we focused on lysosomal abnormalities, because gene mutants of lysosomal proteins such as cathepsin C and Lyst causes severe periodontal diseases in human．Therefore, we analyzed epithelial cells in cathepsin C deficient mice and Lyst mutant mice (beige mouse) infected by Porphyromonas gingivalis, a major periodontal pathogen, in order to clear the physiological and pathological roles of epithelial cells in periodontitis.

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  • Elucidation of molecular mechanisms of osteoclastogenesis by iron

    Grant number：22592069  2010 - 2012

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

    SAKAI Eiko, TSUKUBA Takayuki, OKAMOTO Kuniaki, NISHISHITA Kazuhisa

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    We reported that RANKL-induced suppression of heme oxygenase-1 (HO-1), a heme-degrading enzyme, promoted caspase3 activation and HMGB1 release during osteoclastogenesis. Induction of HO-1 by tBHQ or polyphenol such as kahweol and fisetin inhibited osteoclastogenesis respectively. Since transcriptional induction of HO-1 is up-regulated by Nrf2, we studied the effect of Nrf2 on osteoclastogenesis. Studies with Nrf2 KO mice bone marrow macrophages showed enhanced formation of osteoclasts compared with wild type mice bone marrow macrophages.

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  • 骨疾患における創薬のターゲットとなりうるプロテアーゼの作用機序の解明

    2009.04 - 2011.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • The role of cathepsin E in osteoclast and the research for substrate molecule binding with cathepsin E

    Grant number：21592369  2009 - 2011

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

    OKAMOTO Kuniaki, TSUKUBA Takayuki, NISHISHITA Kazuhisa, SAKAI Eiko

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

    An axis of RANK(Receptor Activator of NF-kB)/ RANKL(RANK Ligand), OPG(Osteoprotegerin) and Macrophage colony stimulating factor(M-CSF)/ c-fms is one of the most important signal pathways in differentiation and activation of osteoclast. In previous study, we reported that number of osteoclast significantly decreased in cathepsin E(CE) knockout mice. In this time, real time PCR analyses showed that mRNA expression levels of M-CSF, c-fms, RANK, c-fos and osteoclast specific marker, cathepsin K and TRAP tended to decrease in CE KO mice, although no statistical differences were recognized. Moreover, mRNA of fusion-related protein such as DC-STAMP and OC-STAMP also decreased. Therefore, we examined mRNA profile with wild(C57BL/ 6) and CE KO mice using DNA microarray. Then, lots of factors related with oxidative stress significantly increased in CE KO mice compared with wild type mice. Furthermore, hydrogen peroxide also increased in CE KO mice after adding RANKL. Studies of autophagy related molecules such as p62, LC3 and ubiquitin showed that they migrated toward non soluble fraction from soluble fraction. These results suggest that CE deficiency causes impairment of autophagy, a degradation system for aggregated proteins and damaged organelles, and increase of oxidative stress. Finally, number of osteoclast significantly decrease in CE KO mice.

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  • Role(s) of pepstatin A-sensitive aspartic proteinases in osteoclast differentiation

    Grant number：20592175  2008 - 2010

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

    NISHISHITA Kazuhisa, TSUKUBA Takayuki, OKAMOTO Kuniaki, SAKAI Eiko

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

    We investigated the roles of aspartic proteinase family in mouse in vitro osteoclast differentiation model. Osteoclastogenesis in bone marrow macrophage culture from cathepsin E-knockout mice were significantly suppressed, probably through elevating the RANKL-induced caspase 3 activation. We also studied the comparative genetic and biochemical analyses of napsins. Napsin A is endogenously expressed in mouse bone marrow cells and recombinant proteins possess pepstatin-A sensitive activities against several synthetic aspartic proteinase substrates.

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  • 歯周病原性細菌の産生するプロテアーゼの膜輸送システムの解明

    2007.04 - 2009.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • Elucidation of autophagy in development of periodontitis and its application of therapy

    Grant number：21390496  2007 - 2011

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

    TSUKUBA Takayuki, OKAMOTO Kuniaki, NISHISHITA Kazuhisa, SAKAI Eiko

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    Grant amount：\18720000 （ Direct expense: \14400000 、 Indirect expense：\4320000 ）

    Various genetic disorders in severe periodontitis are caused by abnormalities of lysosomal-related genes. However, the detailed mechanisms are still unknown. Recently, we have assumed that autophagy is involved in elimination of Porphyromonas gingivalis, a major periodontal pathogen, after infection. In this study, we have elucidated the detailed mechanisms of autophagy in periodontitis, an important issue of dental science, in order to provide clues to the molecular basis of new methods for prevention, diagnosis, and therapy in oral sciences.

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  • Basic studies for drug discovery using adhesin domain protein and interdomain regional peptide of Porphyromonas gingivalis

    Grant number：19592151  2007 - 2008

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

    SAKAI Eiko

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

    歯周病原細菌Porphyromonas gingivalisのrgp A遺伝子産物であるHGP44のN末端アミノ酸を欠失させた変異蛋白を作成し、赤血球凝集活性を調べた。N末端20アミノ酸を欠失すると血球凝集活性が消失したため、この領域が活性中心である可能性が考えられた。シアル酸のはずれた糖蛋白と結合しやすく、また赤血球凝集の強さが動物種によって異なることからGalBl-4GlcNAcの糖鎖を介して糖蛋白と結合している可能性が示唆された。

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  • 歯周病原性細菌におけるタンパク質発現機構の確立

    2005.04 - 2007.03

    日本学術振興会科学研究費補助金  基盤研究 (C)（一般） 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • 歯周病に関わる因子における細胞生物学的研究

    2004.04 - 2005.03

    長崎大学  教育改善推進費 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • FUNCTIONAL REGULATION OF OSTEOCLAST BY GLYCOSPHINGOLIPID

    Grant number：16591860  2004 - 2005

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

    SAKAI Eiko, KATO Yuzo, OKAMOTO Kuniaki, FUKUMOTO Satoshi

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    Grant amount：\3500000 （ Direct expense: \3500000 ）

    The lipid raft, is enriched in cholesterol and glycosphingolipids (GSLs), has been implicated as a functional microenviroment that regulates cellular signaling for various biological processes. Osteoclasts are monocyte/macrophage lineage multinucleated cells that play a critical role in bone resorption. Lipopolysaccharide (LPS), a major constituent of Gram-negative bacteria, has been suggested to be a survival factor of mature osteoclasts via Toll-like receptor 4. To clarify the role of GSLs in LPS mediated osteoclast survival, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glucosylceramide synthase inhibitor. Mature osteoclast survival by LPS was dramatically inhibited by D-PDMP in a dose dependent manner. Raft fraction of osteoclast was determined by the localization of ganglioside GM1 and flotillin-1 as raft markers. Raft fractionation of Triton X-100 extracts revealed that TLR4, MyD88, IRAK 1/4 and TRAF6 were recruited in raft fractions following LPS stimulation. These proteins were eliminated from raft fractions to non-raft fraction by D-PDMP treatment, however, by the addition of GM1 into culture medium, elimination of signaling molecules was canceled, and signaling molecules including TLR4, IRAK4, and TRAF6 were recruited in raft fraction again. Although the nuclear translocation of NF-κB promoted by LPS was inhibited by D-PDMP treatment, exogenous GSLs recovered the activation of NF-κB, and also osteocalst survival, suggesting the involvement of GSLs in LPS mediated osteoclast survival. GSLs have crucial roles for innate immune responses in mature osteoclast.

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  • 歯周病原性細菌におけるタンパク質の新規膜透過システムの解明

    Grant number：16659516  2004 - 2005

    日本学術振興会  科学研究費助成事業  萌芽研究

    加藤 有三, 岡元 邦彰, 西下 一久

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    Grant amount：\2800000 （ Direct expense: \2800000 ）

    歯周病原性細菌Porphyromonas gingivalis(P.g.)の産生する2つのシステインプロテアーゼRgpとKgpは歯周疾患の発症および進行に重要な役割をしていると考えられている。これら2つの酵素はプロテアーゼドメインと血球凝集素ドメインの2つの機能ドメインをもつ構造上類似した酵素である。我々は、前回P.g.内でのKgpの発現法を確立し、Kgpの活性中心は248番目と249番目のシステインが重要であることを明らかとした。今回はまず、非常に大きなC末端血球凝集素ドメインの役割を解析するために、C末端ドメインの長さの異なるプラスミドを作製した。野生型におけるKgpのC末端血球凝集素ドメインは3つのサブドメインに分けられるため、これらプラスミドを欠損変異体に発現させるKgpの長さはそれぞれのサブドメインを参考にした。昨年度のKgpの発現法をもとにP.g.内で安定に維持できるプラスミドpYKP028のKpnI部位に目的の長さのKgp遺伝子を挿入し、まず、大腸菌SM10λpirへ導入した。大腸菌での選別はアンピシリンで行った。これを接合伝達によりKgp欠損変異体へ導入した。ここでの選別はテトラサイクリンを用いた。現在、これらの変異体を解析中であるが、これらの変異体の中で、全遺伝子を含むプラスミドを導入した変異体は活性が非常に弱かった。もしかすると、C末端領域が非常に大きいため、発現効率が下がった可能性も考えられる。今後は、さらに構造解析を進め、血球凝集素ドメインのKgp輸送における役割、およびにプロドメインの役割についても解析を加えていきたい。

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  • 歯周病原性細菌の産生するプロテアーゼの高次構造と輸送機構に関する研究

    2003.04 - 2005.03

    日本学術振興会科学研究費補助金  基盤研究奨励研究Ａ 

    岡元 邦彰

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    Authorship：Principal investigator  Grant type：Competitive

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  • Study of the correlation bone in osteoclast resorption with atopic disease

    Grant number：15390563  2003 - 2005

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

    KATO Yuzo, OKAMOTO Kuniaki, NISHISHITA Kazuhisa, SHIBATA Mitsue, SAKAI Eiko

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    Grant amount：\14900000 （ Direct expense: \14900000 ）

    Receptor activator of nuclear factor kB (RANK) ligand (RANKL), expressed by osteoblastic cells, plays a pivotal role in osteoclastogenesis as well as in osteoclast activation and survival. After RANKL binds to its receptor, RANK, several tumor necrosis factor receptor-associated factors (TRAFs) bind directly to the cytoplasmic domain of RANK. The interaction between TRAF and RANK appears to be responsible for initiating the activation of most of the RANK-mediated signaling pathways such as NF-kB, Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3K) and calcium signaling pathways. RANK occupancy mobilizes intracellular calcium, a requisite for calcineurin-mediated nuclear factor activated T cells (NFAT) activation. NFAT binds to its DNA response element via a ternary complex with AP-1 proteins, including Fos/Jun, to transactivate target genes including tartrate-resistant acid phosphatase (TRAP). Thus NF-kB, AP-1 and NFAT play essential roles in osteoclast differentiation, fusion and activation. In this study, non-toxic concentrations of pepstatin A suppressed the osteoclastogenesis in a dose-dependent manner, especially in an early stage of osteoclast formation. The concentration of pepstatin A required for the suppression of osteoclast formation was higher than that for the complete inhibition of the aspartic proteinase activity in intact cells. Namely, the inhibition of osteoclastgenesis by pepstatin A was independent of the activity for cathepsin D. A cell signaling analyses indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkB, Akt and p38 showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cell c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression, and such actions are not due to the inhibition of the cathepsin D activity.

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  • FUNCTION OF ANNEXIN FAMILY PROTEINS IN OSTEOCLAST DIFFERENTIATION AND ACTIVATION

    Grant number：14571765  2002 - 2003

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

    SAKAI Eiko, SHIBATA Mitsue, OKAMOTO Kuniaki, KATO Yuzo

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    Grant amount：\3000000 （ Direct expense: \3000000 ）

    To investigate the, molecular events involved in osteoclastogenesis induced by macrophage-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), we analyze gene expression using cDNA microarray techniques. Significant induction of a number of mRNAs including annexins 2,4,5were observed during, osteoclast differentiation. We confirmed protein expression of annexins 2,4,5 by immunostaining techniques using specific antibody for each. All of them were expressed in differentiated osteoclasts. Annexin expressions were enhanced by M-CSF without RANKL, suggesting annexins are not necessary for osteoclastgenesis. It has been known that annexins are distributed in lipid raft in some cells. Previous studies show that many signaling molecules localize in microdomains of the plasma membrane, lipid rafts. A number of subsequent studies indicate that glycosphingolipid and cholesterol enriched membrane fraction are clustered with receptors and signal transducing molecules to form lipid rafts and can be recovered as low density, triton X-100 insoluble membrane fractions. We found that RANK, c-Src, TRAF2, and TRAF6, but not c-fins, integrin a_v, or annexins were localized in lipid rafts. Depletion of endogenous glycosphingolipids by 2.5 to 10mM of D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glucosylceramide synthase inhibitor, led to depletion of endogenous glycosphingolipids, treatment-induced suppression of osteoclastgenesis, and elimination of RANK and c-Src from lipid rafts. Further, exogenous glycosphingolipids induced the translocation of RANK and c-Src to rafts, indicating that glycosphingolipids in general are required for the association of RANK and c-Src with rafts. Thus, the lipid raft structure plays important roles in RANK signaling events in osteoclasts. Although the function of annexin is still unclear, it may participate intracellular vesicle transport out side of lipid rafts of differentiated osteoclasts.

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  • 歯周病原性細菌における新規の膜結合型タンパク質の遺伝学的探求とその精製の試み

    Grant number：14657479  2002 - 2003

    日本学術振興会  科学研究費助成事業  萌芽研究

    加藤 有三, 柴田 光枝, 岡元 邦彰

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    Grant amount：\2700000 （ Direct expense: \2700000 ）

    歯周病原性細菌Porphyromonas gingivalis(P.g.)の産生する2つのシステインプロテアーゼRgpとKgpはプロテアーゼドメインと血球凝集素ドメインの2つの機能ドメインを持つ構造上類似した酵素である。プロテアーゼドメインの内膜から外膜への膜輸送機構にC末端側の血球凝集素ドメインが関与しているかどうかを調べるため、2つの酵素の内の一つKgpをKgp欠損変異体で発現させた。まず、Pg内で安定に存在するプラスミドpYKP028にKgp遺伝子を挿入し、Kgp欠損変異体KDP129へ導入した。このプラスミドにはテトラサイクリンの薬剤耐性遺伝子が含まれており、これにより変異体の選別を行った。発現の確認は合成基質を用いたKgp活性測定と抗体を用いたウエスタンブロット解析で行った。プロテアーゼの正確なC末端側が決定されていないため、分子量から換算したプロテアーゼドメインを導入した結果、その活性および発現は認められなかった。これが正確なC末端側ではなかったためかどうかは現在のところ不明であるが、血球凝集素ドメインの一部を含むコンストラクトではKgp活性および発現が認められたことから、プロテアーゼの発現に血球凝集素ドメインが必要である可能性が示唆された。この変異体はKgp欠損変異体が失った性質、すなわち黒色色素産生能などの回復も認められ、野生型とほぽ同等の性質を持つものと思われる。さらに、血球凝集素ドメインのどの部位が必須か等の解析を行う予定である。

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  • ESTABLISHMENT OF A CLINICAL TREATMENT SYSTEM FOR PERIODONTAL DISEASE

    Grant number：13357016  2001 - 2004

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

    YAMAMOTO Kenji, TSUKUBA Takayuki, KADOWAKI Tomoko, OKAMOTO Kuniaki

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    Grant amount：\50440000 （ Direct expense: \38800000 、 Indirect expense：\11640000 ）

    Periodontal disease is a common inflammatory oral disease characterized by acute progressive lesions of periodontal tissues, excessive leukocyte infiltration, and occurrence of a characteristic microflora. Porphyromonas gingivalis is a Gam-negative anaerobic bacterium that is implicated as a major etiologic agent of some types of periodontitis. This bacterium produces a unique type of cysteine proteinases referred to as gingipains in both cell associated and secretory forms. Gingipains consist of arginine-specific cysteine proteinases (Arg-gingipains, Rgp) and lysine-specific cysteine proteinase (Lys-gingipain, Kgp). The cell-associated gingipains comprise the majority (80%) of Rgp and Kgp activities and thus believed to be responsible for the virulence of the bacterium. Accordingly, the characterization and subsequent control of the cell-associated gingipain complex are thought to be the most important promising therapeutic approaches for periodontitis and related systemic disorders including atherosclerosis. Furthermore, we have shown previously with various P.gingivalis mutants deficient in Rgp- and Kgp-encoding genes that both enzymes play critical roles in most of the virulence of the bacterium and thus indicated that potent inhibitors of gingipains should be useful tools to assess the contribution of their proteolytic activities to the virulence of the bacterium and to facilitate the development if new therapeutic approaches to periodontal diseases. In this research project, thus, we have purified and characterized a major form of cell-associated gingipain complex from the bacterium. The complex comprised the catalytic domains and hemagglutinin domains of both rgpA and kgp gene products. Moreover, lipopolysaccharide (LPS) and phospholipids were associated with the complex. The complex significantly degraded human type I collagen and elastin and strongly disrupted viability of human gingival fibroblasts and umbilical vein endothelial cells with an efficiency which was higher than that of the monomeric gingipains. Importantly, the native complex produced only a small amount of nitrogen dioxide, TNF-□ and IL-6 by macrophages, whereas the heat-denatured complex resulted in increased production, indicating that the functional domains of LPS are structurally masked by the complex proteins. The results indicate the importance of the complex in evasion of host defense mechanisms as well as host tissue breakdown. Furthermore, we designed and synthesized a series of peptides analogues able to inhibit either Rgp or Kgp on the basis of the cleavage site specificity of histatins by each enzyme. Among this series of compounds, we found that KYT-1 and KYT-36 had the most potent and selective inhibitory activities of Rgp and Kgp, respectively. We have also demonstrated that these inhibitors are useful in assessing to what extent the proteolytic activities of Rgp and Kgp contribute to biological activities of P.gingivalis, and indicated that they should facilitate the development of new approaches to periodontal diseases.

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  • The role of proteinase in osteoclast formation and activation

    2001

    Grant-in-Aid for Scientific Research 

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    Grant type：Competitive

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  • 破骨細胞形成・活性化におけるプロテアーゼの役割

    2001

    科学研究費補助金 

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    Grant type：Competitive

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  • 神経系におけるオートファジー・リソソームシステム

    Grant number：12146203  2000 - 2004

    日本学術振興会  科学研究費助成事業  特定領域研究

    山本 健二, 筑波 隆幸, 筑波 知子, 岡元 邦彰, 中西 博

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    Grant amount：\31600000 （ Direct expense: \31600000 ）

    カテプシンEは抗原提示細胞やリンパ球、消化管上皮細胞等の免疫担当細胞に限局して存在していることから、生体防御系への関与が指摘されてきたが具体的な根拠は示されていない。そこで、本年度は、カテプシンEの生体防御系における役割を解明する目的で、カテプシンEノックアウトマウス(CatE-/-)由来のマクロファージの性状解析を行った。CatE^<-/->由来マクロファージでは、カテプシンDやBなどの可溶性リソソーム蛋白質の細胞外分泌が著明に亢進しているのに対し、それらとは生合成経路が異なるリソソーム膜糖蛋白質のLAMP-1,LAMP-2およびLGP85/LIMP-2に著明な蓄積が観察された。蛍光インディケーターを用いて酸性コンパートメントのpHを測定してみると、CatE-/-のpHは6.5となっており、正常細胞の5.3に比べて著しく上昇を示していた。これと関連して、endocytotic vesicle fusion eventsが障害されており、ファゴソーム膜蛋白質のNADPHオキシダーゼの活性増大が観察され、マクロファージが産生する活性酸素種の量も著明に増大していた。これと関連して、アネキシンIや酸化型ペロキシレドキシン6などの増加や還元型グルタチオンの減少などが観察され、CatE^<-/->由来マクロファージが強い酸化ストレスを受けていることが明らかにされた。カテプシンE欠損によるこうした変化はマクロファージのもつエンドリソソーム系の蛋白質分解能、殺菌能、細胞生存能などに著しい低下をもたらしていることが明らかにされ、カテプシンE欠損がマクロファージのもつ重要な種々の生理機能に著しい障害をもたらしているが示された。

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  • MOLECULAR BASIS OF PROTEINASE FUNCTION IN PROGRESSION OF PERIODONTAL DISEASES

    Grant number：11307042  1999 - 2001

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

    YAMAMOTO Kenji, OKAMOTO Kuniaki, TSUKUBA Tomoko, TSUKUB Takayuki

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    Grant amount：\36850000 （ Direct expense: \35200000 、 Indirect expense：\1650000 ）

    Periodontitis is an infectious diseases associated with a loss of connective tissue, resorption of alveolar bone, and formation of periodontal pockets. Porphyromonas gingivalis is one of the most important pathogens for the disease and produces two major cysteine proteinases, Arg-gingipain (Rgp) and Lys-gingipain (Kgp), in both secretory and cell-associated forms. Recent studies suggest that these enzymes are involved in the pathogenesis of periodontal disease through various mechanisms, such as direct destruction of periodontal tissue components, disruption of host defense mechanisms, processing of adhesion molecules and production of inflammatory mediators. In this study, we provide evidence that Rgp anf Kgp cooperatively function with respect to the disruption of periodontal connective tissue integrity induced by the bacterium, the adhesion of the bacterium to host tissue components, the proliferation and growth of the bacterium in periodontal pockets, the hemagglutination and colonization of the bacterium, and the disruption of cytokine responses and loss of viability of endothelial cells by the bacterium. On the other hand, we noticed that the lysosomal aspartic proteinase cathepsin D-deficient mice showed a progressive atrophy of the intestinal mucosa, a massive destruction of lymphoid organs, and a profound accumulation of ceroid lipofuscin, and developed a neurological phenotype resembling neuronal ceroid lipofusinosis. These results suggest that cathepsin D is essential for proteolysis of proteins regulating cell growth and tissue homeostasis. Cathepsin E is a homologous enzyme to cathepsin D. In contrast to cathepsin D, cathepsin E has a limited distribution and a cellular localization. In macrophages and microglia, we found that cathepsin E was responsible for the processing of exogenous antigens followed by the MHC class II-mediated antigen presentation. The present study provides evidence that proteinase inhibitors for Rgp and Kgp and factors regulating cathepsins D and E may provide a mean of preventing the onset and development of periodontal diseases.

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  • 遺伝子欠損変異体を用いた歯周病原性細菌の蛋白分解システムの解析

    Grant number：11771140  1999 - 2000

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    岡元 邦彰

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    Grant amount：\2200000 （ Direct expense: \2200000 ）

    筆者らは、昨年よりP.gingivalisの産生する2つのシステインプロテアーゼ(RgpとKgp)の完全欠損変異体を用いて様々な解析を行い、これらの酵素の役割について明らかとしてきた。本年は、それら欠損変異体に加えて、活性部位指向型の合成ペプチドインヒビターを用いて、RgpとKgpの宿主細胞における影響について解析を行った。合成ペプチドインヒビターはRgp特異的なインヒビター(KYT-1)とKgp特異的インヒビター(KYT-36)を、口腔内における宿主由来の細胞としては歯肉線維芽細胞(Gin-1)を用いて、P.gingivalis野生株と各欠損変異体の培養上清の歯肉線維芽細胞における影響を調べた。まず、P.gingivalis野生株の培養上清と歯肉線維芽細胞とを培養したところ、計時的に歯肉線維芽細が紡錘形から円形に形態変化をおこしやがて浮遊してきた。RgpあるいはKgpが歯肉線維芽細の接着を破壊したものと考えられたため、次に、各欠損変異体の培養上清で同様の実験を行ったところ、Rgpの欠損変異体とRgp.Kgpの両酵素の欠損変異体において細胞の浮遊率の減少が認められた。すなわち、Rgpにより細胞の浮遊が惹起されている可能性が高いことが明らかとされた。ここで先に述べた合成ペプチドインヒビターを用いて同じ実験を行ったところ、KYT-1において歯肉線維芽細胞の浮遊化が抑制され、P.gingivalis培養上清未処理の細胞と同様な像を呈した。このことにより歯肉線維芽細胞の浮遊化にはRgpが関与していることが考えられた。そこで、細胞接着における因子のうちでRgpのターゲットとなる物質を同定するためにP.gingivalis処理と未処理の歯肉線維芽細胞でSDS電気泳動後CBB染色を行った。すると、およそ200KDaの部位に著しい違いを認めたため、この部位のN末端アミノ酸配列を調べたところ、フィブロネクチンであることがわかった。そこで、フィブロネクチンの抗体を用いてウエスタンブロット解析を行ったところ、明らかにフィブロネクチンの分解が生じていた。また、フィブロネクチンと細胞を接着しているインテグリンについても抗体を用いて解析を行ったところ、インテグリンについても一部のサブユニットがRgpのターゲットとなっていることが明らかとされた。以上のことより、P.gingivalisの培養上清の歯肉線維芽細胞への影響は、細胞接着因子と細胞外マトリックスをP.gingivalisの産生するプロテアーゼが破壊することにより細胞を浮遊化させ、さらには細胞死へと導くものと考えられた。これには、プロテアーゼ欠損変異体と合成インヒビターの実験よりKgpよりRgpが主に関与しているものと思われた。

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  • Study on transport of aspartic proteinase

    1993

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  • 歯周病原性細菌の産生するプロテアーゼに関する研究

    1993

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  • アスパラギン酸プロテアーゼの輸送機構に関する研究

    1993

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  • Study on proteinase from periodontal pathogen

    1993

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Social Activities

  • 朝日医療大学校歯科衛生学科

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    2021.10

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    岡山大学  2018.8.30

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