Faculty Profiles - OKAMOTO Kuniaki

Papers - OKAMOTO Kuniaki

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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

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

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

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

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.

File： 62. Iwatake (Exp Cell Res).pdf

DOI： 10.1016/j.yexcr.2017.08.025

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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

Language：English Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-kappa B ligand (RANKL)-mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitro via attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-gamma coactivator 1 beta and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.

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

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

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

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

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

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

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

The dental resin monomers 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are released from the resin matrix due to unpolymerized monomers; once released, they influence various biological functions and the viability of cells in the oral environment. Although HEMA and TEGDMA have various effects on cells, including inflammation, inhibition of cell proliferation or differentiation, and apoptosis, the effects of these monomers on osteoclasts remain unknown. In this study, we investigated the effects of HEMA and TEGDMA on osteoclast differentiation of bone marrow-derived macrophages or murine monocytic cell line RAW-D. Both HEMA and TEGDMA inhibited osteoclast formation and their bone-resorbing activity at non-cytotoxic concentrations. Moreover, HEMA and TEGDMA decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of osteoclast differentiation, and of osteoclast markers that are transcriptionally regulated by NFATc1, including Src and cathepsin K. Regarding their effects on signaling pathways involved in osteoclast differentiation, HEMA impaired the phosphorylation of extracellular signal-regulated kinase and Jun N-terminal kinase, whereas TEGDMA attenuated the phosphorylation of Akt and Jun N-terminal kinase. Thus, HEMA and TEGDMA inhibit osteoclast differentiation through different signaling pathways. This is the first report on the effects of the monomers HEMA and TEGDMA on osteoclasts. Copyright (C) 2017 John Wiley & Sons, Ltd.

File： 58. Inamitsu(J Appl Toxicol.pdf

DOI： 10.1002/jat.3429

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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

Authorship：Last author Language：English Publisher：ELSEVIER SCIENCE BV

© 2017 Japanese Association for Oral Biology Background Lysosomes are intracellular acidic organelles that contain approximately 50 hydrolases and 25 species of integral membrane proteins. Although lysosome-like specific compartments, termed lysosome-related organelles (LROs), are found in osteoclasts, their functions in these cells and lysosomal functions in osteoblasts remain to be elucidated. Highlight Recently, we found that expression of RAB27A is markedly increased during osteoclastic differentiation. RAB27A deficiency causes multinucleation and giant cell formation, characterized by abnormal transport of cell surface receptors and LROs into osteoclasts. Furthermore, we have shown that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, regulates osteoblastic differentiation. Overexpression of TFEB in preosteoblastic MC3T3-E1 cells enhances osteoblastic differentiation via decreased expression of activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). These results indicate that the expression of ATF4 and CHOP is essential for differentiation into osteoblasts. Conclusion RAB27A participates in bone resorption by LROs in osteoclasts. In addition, lysosomal biogenesis modulated by TFEB is necessary for osteoblastic differentiation.

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

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

ObjectiveCathepsin K was initially discovered as an osteoclast-specific cysteine proteinase, but the enzyme is also expressed in various cancers including oral squamous cell carcinomas. This study aimed to clarify the function of cathepsin K in oral squamous cell carcinomas.
Materials and MethodsExpression levels of cathepsin K were examined in six types of cell carcinomas. Carcinomas overexpressing cathepsin K were constructed. Effects of cathepsin K overexpression and treatment with odanacatib, a specific cathepsin K inhibitor, on cell invasion, migration and adhesion were analysed.
ResultsDifferent levels of cathepsin K were expressed in carcinomas. Cathepsin K was predominantly localised in lysosomes. Cathepsin K overexpression impaired the proliferation of carcinomas. Invasion analysis showed that cathepsin K overexpression enhanced invasion and migration of carcinomas, whereas inhibition of cathepsin K by odanacatib caused the opposite effects in carcinomas. Cathepsin K overexpression also increased cell adhesion and slightly increased surface expression of the adhesion receptor CD29/integrin (1).
ConclusionsThe enhanced invasion of carcinomas resulting from cathepsin K overexpression is probably due to the increased cell migration and adhesion. Thus, cathepsin K is implicated not only in protein degradation but also in invasion, migration and adhesion of oral squamous cell carcinomas.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG

Background: Osteoclasts are multinucleated bone-resorbing cells that differentiate in response to receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL). Enhanced osteoclastogenesis contributes to bone diseases, such as osteoporosis and rheumatoid arthritis. Rubus parvifolius L. is traditionally used as an herbal medicine for rheumatism; however, its detailed chemical composition and the molecular mechanisms responsible for its biological action have not been elucidated.
Purpose: To investigate the mechanisms by which R. parvifolius L. extract and its major constituent sanguiin H-6, inhibit osteoclastogenesis and bone resorption.
Methods: Cell proliferation, cell differentiation, and bone resorption were detected in vitro. Inhibition of signaling pathways, marker protein expression, and protein nuclear translocation were evaluated by western blot analysis. Tumor necrosis factor-alpha (TNF-alpha)-mediated osteoclastogenesis was examined in vivo.
Results: R. parvifolius L. extract inhibited the bone-resorption activity of osteoclasts. In addition, sanguiin H-6 markedly inhibited RANKL-induced osteoclast differentiation and bone resorption, reduced reactive oxygen species production, and inhibited the phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and p38 mitogen-activated protein kinase. Sanguiin H-6 also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), cathepsin K, and c-Src. Moreover, sanguiin H-6 inhibited the nuclear translocation of NFATc1, c-Fos, and NF-kappa B in vitro, as well as TNF-alpha-mediated osteoclastogenesis in vivo.
Conclusions: Our data revealed that R. parvifolius L. has anti-bone resorption activity and suggest that its constituent, sanguiin H-6, can potentially be used for the prevention and treatment of bone diseases associated with excessive osteoclast formation and subsequent bone destruction. (C) 2016 Elsevier GmbH. All rights reserved.

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

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

Osteoblasts are bone-forming cells that produce large amounts of collagen type I and various bone matrix proteins. Although osteoblast differentiation is highly regulated by various factors, it remains unknown whether lysosomes are directly involved in osteoblast differentiation. Here, we demonstrate the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, modulates osteoblast differentiation. The expression levels of TFEB as well as those of endosomal/lysosomal proteins were up-regulated during osteoblast differentiation using mouse osteoblastic MC3T3-E1 cells. By gene knockdown (KD) experiments with small interfering RNA (siRNA), TFEB depletion caused markedly reduced osteoblast differentiation as compared with the control cells. Conversely, overexpression (OE) of TFEB resulted in strikingly enhanced osteoblastogenesis compared to the control cells. By analysis of down-stream effector molecules, TFEB KD was found to cause marked up-regulation of activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP), both of which are essential factors for osteoblastogenesis. In contrast, TFEB OE promoted osteoblast differentiation through reduced expression of ATF4 and CHOP without differentiation agents. Given the importance of ATF4 and CHOP in osteoblastogenesis, it is clear that the TFEB-regulated signaling pathway for osteoblast differentiation is involved in ATF4/CHOP-dependent signaling pathway. (c) 2015 Wiley Periodicals, Inc.

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

DOI： 10.1002/jcp.25235

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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

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

Bone is constantly controlled by a balance between osteoblastic bone formation and osteoclastic bone resorption. Liquiritigenin is a plant-derived flavonoid and has various pharmacological effects, such as antioxidative, antitumor, and antiinflammatory effects. Here, we show that liquiritigenin has dual effects on the proliferation of bone cells, regarding the promotion of osteoblast differentiation and the inhibition of osteoclast differentiation. Liquiritigenin-treated murine osteoblastic MC3T3-E1 cells showed an increased alkaline phosphatase activity and enhanced phosphorylation of Smad1/5 compared with untreated cells. Moreover, liquiritigenin inhibited osteoclast differentiation, its bone-resorption activity through slightly decreased the phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and inhibitor of nuclear factor kappa B; however, the phosphorylation of Akt and p38 slightly increased in bone marrow-derived osteoclasts. The expression levels of the osteoclast marker proteins nuclear factor of activated T-cell cytoplasmic-1, Src, and cathepsin K diminished. These results suggest that liquiritigenin may be useful as a therapeutic and/or preventive agent for osteoporosis or inflammatory bone diseases. Copyright (C) 2015 John Wiley & Sons, Ltd.

File： 55. Uchino (Phytother res).pdf

DOI： 10.1002/ptr.5416

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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

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

Punicalagin is a bioactive polyphenol that is classified as an ellagitannin. Although punicalagin has been shown to have various pharmacological effects, such as anti-oxidative, anti-inflammatory, and anti-tumor effects, no studies have reported the effects of punicalagin on osteoclasts (OCLs). In this study, we investigated the effects of punicalagin on OCL differentiation by receptor activator of nuclear factor kappa-B ligand in the murine monocytic RAW-D cell line and bone marrow-derived macrophages (BMMs). Treatment with punicalagin significantly inhibited OCL formation from RAW-D cells and BMMs and prevented bone resorption of BMM-derived OCLs. Moreover, punicalagin impaired multinucleation and actin-ring formation in OCLs, and decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a master regulator of OCL differentiation, and concomitantly reduced the expression levels of Src and cathepsin K, which are transcriptionally regulated by NFATc1. The effects of punicalagin on intracellular signaling during the OCL differentiation of BMMs indicated that punicalagin-treated OCLs displayed markedly reduced phosphorylation of Jun N-terminal kinase and Akt, and partially impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and inhibitor of nuclear factor kappa-B alpha compared with untreated OCLs. Thus, punicalagin may affect bone metabolism by inhibiting OCL differentiation.

File： 53. Iwatake (Mol Cell Biochem).pdf

DOI： 10.1007/s11010-015-2466-3

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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

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

Cobalt protoporphyrin (CoPP) is a metallo-protoporphyrin that works as a powerful inducer of heme oxigenase-1 (HO-1) in various tissues and cells. Our recent studies have demonstrated that induction of HO-1 by several reagents inhibited differentiation and activation of osteoclasts (OCLs), which are multinucleated bone resorbing cells. However, the effects of CoPP on osteoclastogenesis remain to be elucidated. In this study, we report that CoPP inhibits receptor activator of nuclear factor kappa B ligand (RANKL)-induced OCL formation in a dose dependent manner. Importantly, CoPP had little cytotoxicity, but rather enhanced cell proliferation of OCLs. CoPP suppressed the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) as well as those of OCLs markers such as Src and cathepsin K, which are transcriptionally regulated by NFATc1 in mature OCLs. Western blot analyses also showed that CoPP abolished RANKL-stimulated phosphorylation of several major signaling pathways such as I kappa B, Akt, ERK, JNK and p38 MAPKs in OCL precursor cells. Thus, our results show that CoPP represses osteoclastogenesis through blocking multiple signaling pathways.

File： 51. Yashima (Biometals).pdf

DOI： 10.1007/s10534-015-9861-9

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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

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

Bone homeostasis is regulated by a balance between osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-mediated bone formation. Thus, developing a compound that simultaneously inhibits OCL function and promotes OBL function would be useful as a new medical therapy for bone diseases. Here, we examined the effects of cafestol, a coffee diterpene, on the differentiation of OCLs and OBLs. Cafestol prevented OCL formation in a dose-dependent manner and suppressed the bone-resorbing activity of OCLs. Interestingly, the viability of OCLs treated with 10-50 mu M cafestol was significantly higher than that of untreated cells. At the molecular level, cafestol markedly decreased RANKL-induced phosphorylation of extracellular signal-regulated kinase (Erk) and inhibitor of nuclear factor kappa B alpha (IB). Compared to kahweol, another coffee-specific diterpene, the inhibitory effects of cafestol were milder on OCL differentiation, and cafestol and kahweol showed different characteristics in induction of the phase antioxidant enzymes and sensitivities in nuclear factor-erythroid 2-related factor 2 (Nrf2)-deficient BMMs. In addition to inhibiting OCLs, cafestol enhanced the differentiation of osteoblastic cells by increasing the mRNA levels of differentiation markers. Thus, cafestol inhibits OCL differentiation and promotes OBL differentiation, suggesting that cafestol may be a novel agent for bone diseases. (c) 2015 BioFactors, 41(4):222-231, 2015

File： 54. Fukuma (BioFactors).pdf

DOI： 10.1002/biof.1218

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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

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

Castalagin is a rare plant polyphenol that is classified as a hydrolyzable tannin. Although it has antioxidant, antitumorigenic, and leishmanicidal effects, the utility of castalagin against bone diseases remain to be elucidated. Here, we investigated the effects of castalagin on the differentiation of osteoclasts (OCLs), multinucleated bone-resorbing cells. After stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL), the formation of OCLs from bone marrow-derived macrophages was significantly inhibited by castalagin even at 1M. However, castalagin displayed little cytotoxicity at a higher concentration of 50M. The effects of castalagin on intracellular signaling during OCL differentiation showed that castalagin suppresses RANKL-stimulated phosphorylation of major signaling pathways including protein kinase B (Akt), extracellular signal-regulated kinase, Jun N-terminal kinase, p38 mitogen-activated protein kinases, and inhibitor of nuclear factor kappa B alpha. Moreover, following castalagin treatment, the protein levels of nuclear factor of activated T-cells, cytoplasmic 1, a master regulator for OCL differentiation, and NF-B were decreased. Thus, castalagin exerts inhibitory effects on osteoclastogenesis through blockage of a broad range of signaling pathways, but has low cytotoxicity. Copyright (c) 2015 John Wiley & Sons, Ltd.

File： 50. Iwatake (Phytother res).pdf

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

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

Rab27A regulates transport of lysosome-related organelles (LROs) and release of secretory granules in various types of cells. Here, we identified up-regulation of Rab27A during differentiation of osteoclasts (OCLs) from bone-marrow macrophages (BMMs), by DNA microarray analysis. Rab27A deficiency in OCLs, using small interfering RNA (siRNA) knockdown in RAW-D cell line or BMMs derived from ashen mice, which display genetic defects in Rab27A expression, induced multinucleated and giant cells. Upon stimulation with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL), essential cytokines for OCL differentiation, phosphorylation levels of extracellular signal-regulated kinase (Erk), proto-oncogene tyrosine-protein kinase (Src), and p-38 were slightly enhanced in ashen BMMs than in wild-type BMMs. The cell surface level of c-fms, an M-CSF receptor, was slightly higher in ashen BMMs than in wild-type BMMs, and down-regulation of RANK, a RANKL receptor, was delayed. In addition to receptors, OCLs derived from ashen mice exhibited aberrant actin ring formation, abnormal subcellular localization of lysosome-associated membrane protein (LAMP2) and cathepsin K (CTSK), and marked reduction in resorbing activity. Thus, these findings suggest that Rab27A regulates normal transport of cell surface receptors modulating multinucleation and LROs in OCLs.

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

DOI： 10.1038/srep09620

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