Faculty Profiles - OKAMURA Hirohiko

Papers - OKAMURA Hirohiko

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O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study Reviewed

Yao Weng, Ziyi Wang, Yoko Fukuhara, Airi Tanai, Mika Ikegame, Daisuke Yamada, Takeshi Takarada, Takashi Izawa, Satoru Hayano, Kaya Yoshida, Hiroshi Kamioka, Hirohiko Okamura

BioFactors 2021.8

The role of extracellular vesicles throughout normal pregnancy and in relation to oral bacteria Reviewed

Journal of Oral Biosciences 63 ( 1 ) 14 - 22 2021.3

The role of extracellular vesicles throughout normal pregnancy and in relation to oral bacteria. Reviewed

Tanai A, Okamura H.

Journal of Oral Biosciences 63 ( 1 ) 14 - 22 2021.1

O-GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics-oriented study. Reviewed

Weng Y, Wang Z, Fukuhara Y, Tanai A, Ikegame M, Yamada D, Takarada T, Izawa T, Hayano S, Yoshida K, Kamioka H, Okamura H.

BioFactors 2021

The inhibitory role of Rab11b in osteoclastogenesis through triggering lysosome-induced degradation of c-Fms and RANK surface receptors. Reviewed

Tran MT, Okusha Y, Feng Y, Morimatsu M, Wei P, Sogawa C, Eguchi T, Kadowaki T, Sakai E, Okamura H, Naruse K, Tsukuba T, Okamoto K.

International Journal of Molecular Sciences 21 ( 24 ) 9352 2020.12

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

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

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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Loading history changes the morphology and compressive force-induced expression of receptor activator of nuclear factor kappa B ligand/osteoprotegerin in MLO-Y4 osteocytes. Reviewed

Wang Z, Weng Y, Ishihara Y, Odagaki N, Ei Hsu Hlaing E, Izawa T, Okamura H, Kamioka H.

Peer J 8 e10244 2020.11

Loading history changes the morphology and compressive force-induced expression of receptor activator of nuclear factor kappa B ligand/osteoprotegerin in MLO-Y4 osteocytes Reviewed

Ziyi Wang, Yao Weng, Yoshihito Ishihara, Naoya Odagaki, Ei Ei Hsu Hlaing, Takashi Izawa, Hirohiko Okamura, Hiroshi Kamioka

PeerJ 8 e10244 - e10244 2020.11

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

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

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

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

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

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DOI： 10.7717/peerj.10244

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Other Link： https://peerj.com/articles/10244.xml

N-(3-oxododecanoyl)-homoserine lactone regulates osteoblast apoptosis and differentiation by mediating intracellular calcium. Reviewed International coauthorship

Guo J, Wang Z, Weng Y, Yuan H, Yoshida K, Ikegame M, Uchibe K, Kamioka H, Ochiai K, Okamura H, Qiu L.

Cellular Signaling 75 1097450 2020.11

Outer membrane vesicles derived from porphylomonas gingivalis induced cell death with disruption of tight junctions in human lung epithelial cells. Reviewed International coauthorship

He Y, Shiotsu N, Uchida-Fukuhara Y, Guo J, Weng Y, Ikegame M, Wang Z, Ono K, Kamioka H, Torii Y, Sasaki A, Yoshida K, Okamura H.

Archives of Oral Biology 118 104841 2020.10

Outer membrane vesicles derived from Porphyromonas gingivalis induced cell death with disruption of tight junctions in human lung epithelial cells. Reviewed International journal

Archives of oral biology 118 104841 - 104841 2020.10

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

OBJECTIVE: Porphyromonas gingivalis (P. gingivalis) is a major bacterium responsible for the progression of periodontitis. P. gingivalis produces small vesicles called outer membrane vesicles (OMVs) containing virulence factors. Increasing evidence suggests a close relationship between periodontitis and respiratory system diseases, such as aspiration pneumonia. However, little is known about whether P. gingivalis OMVs give rise to the impediment of lung epithelial cells. We investigated the effect of the OMVs on cell viability and tight junctions of lung epithelial cells. DESIGN: Human lung epithelial A549 cells were treated with P. gingivalis OMVs. Cell viability was evaluated, and cell morphology was examined using scanning electron and phase contrast microscopies. To detect apoptosis induced by P. gingivalis OMVs, activation of caspase-3 and poly ADP-ribose polymerase (PARP) cleavage was examined by using Western blotting. Immunocytochemistry was performed to stain tight junction proteins. RESULTS: P. gingivalis OMVs decreased cell viability in A549 cells in a dose- and time-dependent manner. Microscopic analysis revealed that the OMVs induced morphological changes leading to irregular cell membrane structures. The OMVs caused cell shrinkage, membrane blebbing, and cytoplasmic expulsion in a dose-dependent manner. Western blot analysis showed the OMVs induced caspase-3 activation and PARP cleavage. Treatment with the OMVs disrupted the intact distributions of tight junction proteins. CONCLUSIONS: These results indicate that P. gingivalis OMVs induced cell death by destroying the barrier system in lung epithelial cells. Our present study raises the possibility that P. gingivalis OMVs is an important factor in the engagement of periodontitis with respiratory system diseases.

DOI： 10.1016/j.archoralbio.2020.104841

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N-(3-oxododecanoyl)-homoserine lactone regulates osteoblast apoptosis and differentiation by mediating intracellular calcium. Reviewed International journal

Jiajie Guo, Ziyi Wang, Yao Weng, Haoze Yuan, Kaya Yoshida, Mika Ikegame, Kenta Uchibe, Hiroshi Kamioka, Kazuhiko Ochiai, Hirohiko Okamura, Lihong Qiu

Cellular signalling 75 109740 - 109740 2020.8

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

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

DOI： 10.1016/j.cellsig.2020.109740

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

Seyama M, Yoshida K, Yoshida K, Fujiwara N, Ono K, Eguchi T, Kawai H, Guo J, Weng Y, Haoze Y, Uchibe K, Ikegame M, Sasaki A, Nagatsuka H, Okamoto K, Okamura H, Ozaki K.

Biochimica Biophysica Acta-Molecular Basis of Disease 1866 ( 6 ) 165731 2020.6

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

Publishing type：Research paper (scientific journal)

© 2020 Elsevier B.V. Outer membrane vesicles (OMVs) are nanosized particles derived from the outer membrane of gram-negative bacteria. Oral bacterium Porphyromonas gingivalis (Pg) is known to be a major pathogen of periodontitis that contributes to the progression of periodontal disease by releasing OMVs. The effect of Pg OMVs on systemic diseases is still unknown. To verify whether Pg OMVs affect the progress of diabetes mellitus, we analyzed the cargo proteins of vesicles and evaluated their effect on hepatic glucose metabolism. Here, we show that Pg OMVs were equipped with Pg-derived proteases gingipains and translocated to the liver in mice. In these mice, the hepatic glycogen synthesis in response to insulin was decreased, and thus high blood glucose levels were maintained. Pg OMVs also attenuated the insulin-induced Akt/glycogen synthase kinase-3 β (GSK-3β) signaling in a gingipain-dependent fashion in hepatic HepG2 cells. These results suggest that the delivery of gingipains mediated by Pg OMV elicits changes in glucose metabolisms in the liver and contributes to the progression of diabetes mellitus.

DOI： 10.1016/j.bbadis.2020.165731

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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.

Ono K, Sogawa C, Kawai H, Tran HK, Taha EA, Lu Y, Oo MW, Okusha Y, Okamura H, Ibaragi S, Takigawa M, Kozaki K, Nagatsuka H, Sasaki A, Okamoto K, Calderwood SK, Eguchi T.

Journal of Extracellular Vesicles 9 ( 1 ) 1769373 2020.5

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor Reviewed International coauthorship

Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki KI, Calderwood SK, Takigawa M, Okamoto K.

Cancers (Basel) 12 ( 4 ) E881 2020.4

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 ) 881 - 881 2020.4

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

Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.

DOI： 10.3390/cancers12040881

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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

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

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

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.

DOI： 10.20944/preprints202002.0281.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

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

Quorum-sensing molecule N-(3-Oxododecanoyl)-L-Homoserine lactone: An all-rounder in mammalian cell modification. Invited Reviewed International coauthorship

Guo J, Yoshida K, Ikegame M, Okamura H.

Journal of Oral Biosciences 62 ( 1 ) 16 - 29 2020.1

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Papers - OKAMURA Hirohiko