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加藤 賢治カトウ ケンジ

所属部署医学研究科整形外科学分野
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Last Updated :2020/06/02

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論文

  • Short Link N promotes disc repair in a rabbit model of disc degeneration., Mwale F, Masuda K, Grant MP, Epure LM, Kato K, Miyazaki S, Cheng K, Yamada J, Bae WC, Muehleman C, Roughley PJ, Antoniou J, Arthritis research & therapy, 20, (1) ,   2018年08月, 査読有り
  • ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model., Miyazaki S, Diwan AD, Kato K, Cheng K, Bae WC, Sun Y, Yamada J, Muehleman C, Lenz ME, Inoue N, Sah RL, Kawakami M, Masuda K, European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 27, (4) 739 - 751,   2018年04月, 査読有り
  • Advantages of an on-the-screwhead crosslink connector for atlantoaxial fixation using the Goel/Harms technique., Mizutani J, Inada A, Kato K, Kondo A, Kainuma S, Fujita K, Yagi K, Shimamura Y, Fukuoka M, Shibamoto Y, Wada I, Otsuka T, Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 50, 183 - 189,   2018年04月, 査読有り
  • Progenitor cell fate, SOXC and WNT., Bhattaram P, Kato K, Lefebvre V, Oncotarget, 6, (28) 24596 - 24597,   2015年09月, 査読有り
  • SOXC Transcription Factors Induce Cartilage Growth Plate Formation in Mouse Embryos by Promoting Noncanonical WNT Signaling., Kato K, Bhattaram P, Penzo-Méndez A, Gadi A, Lefebvre V, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 30, (9) 1560 - 1571,   2015年09月, 査読有り
  • SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis, Pallavi Bhattaram, Alfredo Penzo-Mendez, Kenji Kato, Kaustav Bandyopadhyay, Abhilash Gadi, Makoto M. Taketo, Veronique Lefebvre, JOURNAL OF CELL BIOLOGY, 207, (5) 657 - 671,   2014年12月, 査読有り, Canonical WNT signaling stabilizes beta-catenin to determine cell fate in many processes from development onwards. One of its main roles in skeletogenesis is to antagonize the chondrogenic transcription factor SOX9. We here identify the SOXC proteins as potent amplifiers of this pathway. The SOXC genes, i.e., Sox4, Sox11, and Sox12, are coexpressed in skeletogenic mesenchyme, including presumptive joints and perichondrium, but not in cartilage. Their inactivation in mouse embryo limb bud caused massive cartilage fusions, as joint and perichondrium cells underwent chondrogenesis. SOXC proteins govern these cells cell autonomously. They replace SOX9 in the adenomatous polyposis coli-Axin destruction complex and therein inhibit phosphorylation of beta-catenin by GSK3. This inhibition, a crucial, limiting step in canonical WNT signaling, thus becomes a constitutive event. The resulting SOXC/canonical WNT-mediated synergistic stabilization of beta-catenin contributes to efficient repression of Sox9 in presumptive joint and perichondrium cells and thereby ensures proper delineation and articulation of skeletal primordia. This synergy may determine cell fate in many processes besides skeletogenesis.
  • Minimally invasive tension band wiring technique for olecranon fractures., Takada N, Kato K, Fukuta M, Wada I, Otsuka T, Techniques in hand & upper extremity surgery, 17, (4) 199 - 201,   2013年12月, 査読有り
  • Unphosphorylated heat shock protein 27 suppresses fibroblast growth factor‑2‑stimulated vascular endothelial growth factor release in osteoblasts., Kondo A, Tokuda H, Matsushima-Nishiwaki R, Kato K, Kuroyanagi G, Mizutani J, Fukuoka M, Wada I, Kozawa O, Otsuka T, Molecular medicine reports, 8, (2) 691 - 695,   2013年08月, 査読有り
  • AMP-activated protein kinase regulates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts., Kondo A, Otsuka T, Kato K, Matsushima-Nishiwaki R, Kuroyanagi G, Mizutani J, Tokuda H, Kozawa O, International journal of molecular medicine, 31, (6) 1457 - 1462,   2013年06月, 査読有り
  • Rho-kinase negatively regulates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts, Akira Kondo, Haruhiko Tokuda, Kenji Kato, Rie Matsushima-Nishiwaki, Gen Kuroyanagi, Jun Mizutani, Osamu Kozawa, Takanobu Otsuka, BIOCHIMIE, 95, (4) 719 - 724,   2013年04月, 査読有り, Evidence is accumulating that Rho-associated kinase (Rho-kinase) plays important roles not only in vascular smooth muscle cell contraction, but also in a variety of cellular functions, including bone metabolism. In the present study, we investigated the involvement of Rho-kinase in the osteocalcin synthesis induced by triiodothyronine (T-3) in osteoblast-like MC3T3-E1 cells. T-3 time-dependently induced phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase. Y27632, a specific inhibitor of Rho-kinase, attenuated the MYPT-1 phosphorylation induced by T-3. T-3-stimulated osteocalcin release was significantly enhanced by Y27632. Fasudil, another Rho-kinase inhibitor, amplified the osteocalcin release induced by T-3. T-3-stimulated osteocalcin release was significantly augmented in Rho-knockdown cells with Rho A-siRNA. Y27632 and fasudil also increased the mRNA expression level of osteocalcin induced by T-3. These results strongly suggest that T-3 stimulates the activation of Rho-kinase in osteoblasts, which functions as a negative regulator of T-3-stimulated osteocalcin synthesis. (C) 2012 Elsevier Masson SAS. All rights reserved.
  • Significant correlation between the acceleration of platelet aggregation and phosphorylation of HSP27 at Ser-78 in diabetic patients, Haruhiko Tokuda, Kenji Kato, Senji Kasahara, Rie Matsushima-Nishiwaki, Takahiko Mizuno, Seiko Sakakibara, Osamu Kozawa, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 30, (6) 1387 - 1395,   2012年12月, 査読有り, To clarify the mechanism underlying a high risk of thrombotic complications in diabetic patients, we investigated the relationship between HSP27 phosphorylation and the platelet activation induced by adenosine diphosphate (ADP) in diabetic patients. Platelet-rich plasma was prepared from the blood of type 2 diabetes mellitus (DM) patients. By measuring the dose response of platelet aggregation to ADP, an individual ED50 was determined. Based on the normal range identified in non-DM controls, the subjects were divided into a hyper-aggregate (Group 1) and a normo- or hypo-aggregate group (Group 2). The protein phosphorylation was analyzed by western blotting. The release of PDGF-AB and sCD40 ligand (sCD40L) was measured by ELISA. In both groups, ADP induced HSP27 phosphorylation at Ser-78 and Ser-82. The phosphorylation at Ser-78 and the release of both PDGF-AB and sCD40L induced by a low dose of ADP (1 mu M) in Group 1 were significantly higher than these values in Group 2. There was a significant relationship between the ADP-induced HSP27 phosphorylation level at Ser-78 and the ADP ED50 value of platelet aggregation. The ADP (1 mu M)-induced phosphorylation of HSP at Ser-78 observed in the platelets from Group 1 was inhibited by PD98059 or SB203580. The use of aspirin ameliorated the accelerated microaggregation of platelets in Group 1, and the low-dose ADP-induced phosphorylation of HSP27 at Ser-78 was no longer observed. These results strongly suggest that the phosphorylation of HSP27 at Ser-78 is correlated with the acceleration of platelet aggregation induced by ADP in type 2 DM patients.
  • AMP-activated protein kinase inhibitor decreases prostaglandin F2α-stimulated interleukin-6 synthesis through p38 MAP kinase in osteoblasts., Kondo A, Otsuka T, Kato K, Natsume H, Kuroyanagi G, Mizutani J, Ito Y, Matsushima-Nishiwaki R, Kozawa O, Tokuda H, International journal of molecular medicine, 30, (6) 1487 - 1492,   2012年12月, 査読有り
  • AMPK limits IL-1-stimulated IL-6 synthesis in osteoblasts: involvement of IκB/NF-κB pathway., Kato K, Tokuda H, Matsushima-Nishiwaki R, Natsume H, Kondo A, Ito Y, Kozawa O, Otsuka T, Cellular signalling, 24, (8) 1706 - 1712,   2012年08月, 査読有り
  • Involvement of AMP-activated protein kinase in TGF-β-stimulated VEGF synthesis in osteoblasts., Mizutani J, Tokuda H, Matsushima-Nishiwaki R, Kato K, Kondo A, Natsume H, Kozawa O, Otsuka T, International journal of molecular medicine, 29, (4) 550 - 556,   2012年04月, 査読有り
  • AMP-activated protein kinase regulates PDGF-BB-stimulated interleukin-6 synthesis in osteoblasts: Involvement of mitogen-activated protein kinases, Kenji Kato, Takanobu Otsuka, Akira Kondo, Rie Matsushima-Nishiwaki, Hideo Natsume, Osamu Kozawa, Haruhiko Tokuda, LIFE SCIENCES, 90, (1-2) 71 - 76,   2012年01月, 査読有り, Aim: We have previously reported that platelet-derived growth factor (PDGF)-BB stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells, and that the activation of p44/p42 mitogen-activated protein (MAP) kinase, p38MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is implicated in the IL-6 synthesis. In the present study,we investigated the involvement of AMP-activated protein kinase (AMPK), a regulator of energy metabolism, in the PDGF-BB-stimulated IL-6 synthesis in MC3T3-E1cells. Main methods: The levels of IL-6 were measured by ELISA. The phosphorylation of each protein kinases was analyzed by Western blotting. The mRNA levels of IL-6 were determined by real-time RT-PCR. Key findings: PDGF-BB time-dependently induced the phosphorylation of AMPK Compound C. an inhibitor of AMPK, which reduced PDGF-BB-induced acetyl-CoA carboxylase phosphorylation, dose-dependently suppressed the PDGF-BB-stimulated IL-6 release. In addition, the PDGF-BB-stimulated IL-6 release in human osteoblasts was also inhibited by compound C. The mRNA expression of IL-6 induced by PDGF-BB was markedly reduced by compound C. The PDGF-BB-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK was inhibited by compound C. Significance: These results strongly suggest that AMPK positively regulates PDGF-BB-stimulated IL-6 synthesis via the MAP kinases in osteoblasts. (C) 2011 Elsevier Inc. All rights reserved.
  • Role of HSP27 in tumor necrosis factor-α-stimulated interleukin-6 synthesis in osteoblasts., Kato K, Tokuda H, Mizutani J, Adachi S, Matsushima-Nishiwaki R, Natsume H, Kozawa O, Otsuka T, International journal of molecular medicine, 28, (5) 887 - 893,   2011年11月, 査読有り
  • Rho-kinase regulates thrombin-stimulated interleukin-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts, Kenji Kato, Takanobu Otsuka, Rie Matsushima-Nishiwaki, Hideo Natsume, Osamu Kozawa, Haruhiko Tokuda, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 28, (4) 653 - 658,   2011年10月, 査読有り, We have previously reported that thrombin stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the mechanism of thrombin in the thrombin-stimulated IL-6 synthesis and the involvement of Rho-kinase in MC3T3-E1 cells. Thrombin time-dependently induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and myosin phosphatase targeting subunit-1 (MYPT-1), a Rho-kinase substrate. While SP600125, an inhibitor of SAPK/JNK, failed to reduce IL-6 synthesis, PD98059, a specific inhibitor of MEK, and SB203580 and BIRB0796, potent inhibitors of p38 MAP kinase, suppressed the IL-6 synthesis induced by thrombin. Y27632, a specific Rho-kinase inhibitor, significantly reduced thrombin-stimulated IL-6 synthesis as well as the MYPT-1 phosphorylation. Fasudil, another inhibitor of Rho-kinase, suppressed thrombin-stimulated IL-6 synthesis. Y27632 and fasudil failed to affect thrombin-induced phosphorylation of p44/p42 MAP kinase. Y27632 as well as fasudil attenuated thrombin-induced phosphorylation of p38 MAP kinase. These results strongly suggest that Rho-kinase regulates thrombin-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.
  • Wnt3a upregulates transforming growth factor-β-stimulated VEGF synthesis in osteoblasts., Natsume H, Tokuda H, Matsushima-Nishiwaki R, Kato K, Yamakawa K, Otsuka T, Kozawa O, Cell biochemistry and function, 29, (5) 371 - 377,   2011年07月, 査読有り
  • Enhancement of basic fibroblast growth factor-stimulated VEGF synthesis by Wnt3a in osteoblasts, Haruhiko Tokuda, Seiji Adachi, Rie Matsushima-Nishiwaki, Kenji Kato, Hideo Natsume, Takanobu Otsuka, Osamu Kozawa, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 27, (6) 859 - 864,   2011年06月, 査読有り, It is currently recognized that the Writ signaling pathway regulates bone mass. We have previously reported that the basic fibroblast growth factor (FGF-2) stimulates the synthesis of the vascular endothelial growth factor (VEGF) at least in part via the p44/p42 mitogen-activated protein (MAP) kinase and the stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) in osteoblast-like MC3T3-El cells. In the present study, we investigated the effect of Wnt3a on FGF-2-stimulated VEGF synthesis in MC3T3-E1 cells. Writ 3a significantly augmented the FGF-2-stimulated VEGF release in a dose-dependent manner in the range between 1 and 30 ng/ml. Lithium chloride and SB216763, inhibitors of glycogen synthase kinase 3 beta (GSK3 beta), enhanced the FGF-2-stimulated VEGF release. Wnt3a did not affect the phosphorylation of the p44/p42 MAP kinase, SAPK/JNK, Akt, p38 MAP kinase or the p70 S6 kinase induced by FGF-2. Wnt3a and SB216763 increased the levels of VEGF mRNA expression induced by FGF-2. These results strongly suggest that Wnt3a enhances VEGF synthesis stimulated by FGF-2 via activation of the canonical Wnt/beta-catenin pathway in osteoblasts.
  • cAMP regulates ADP-induced HSP27 phosphorylation in human platelets, Yukiko Enomoto, Seiji Adachi, Tomoaki Doi, Hideo Natsume, Kenji Kato, Rie Matsushima-Nishiwaki, Shigeru Akamatsu, Haruhiko Tokuda, Shinichi Yoshimura, Takanobu Otsuka, Shinji Ogura, Osamu Kozawa, Toru Iwama, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 27, (5) 695 - 700,   2011年05月, 査読有り, Elevation of cAMP in platelets is recognized to play a suppressive role in platelet functions. We have previously shown that adenosine diphosphate (ADP)-induced phosphorylation of heat shock protein 27 (HSP27) via p38 mitogen-activated protein (MAP) kinase is correlated with platelet-derived growth factor (PDGF)-AB secretion and soluble CD40 ligand (sCD40L) release. In the present study, we investigated the relationship between cAMP and HSP27 phosphorylation in platelet function. 8-Bromoadenosine-3',5'-cyclic monophosphate (8-bromo-cAMP), a plasma membrane-permeable cAMP analogue, or cilostazol, an inhibitor of cAMP phosphodiesterase, markedly attenuated the ADP-induced phosphorylation levels of p38 MAP kinase. In addition, the ADP-induced H5P27 phosphorylation was suppressed by 8-bromo-cAMP or cilostazol. 8-Bromo-cAMP, forskolin and cilostazol remarkably reduced the ADP-stimulated PDGF-AB secretion and sCD40L release. These results strongly suggest that cAMP regulates ADP-stimulated platelet activation due to inhibition of HSP27 phosphorylation via p38 MAP kinase.
  • Regulation by Heat Shock Protein 27 of Osteocalcin Synthesis in Osteoblasts, Kenji Kato, Seiji Adachi, Rie Matsushima-Nishiwaki, Chiho Minamitani, Hideo Natsume, Yasuo Katagiri, Yoshinobu Hirose, Jun Mizutani, Haruhiko Tokuda, Osamu Kozawa, Takanobu Otsuka, ENDOCRINOLOGY, 152, (5) 1872 - 1882,   2011年05月, 査読有り, We have previously reported that various stimuli, including sphingosine 1-phosphate, are able to induce heat shock protein (HSP) 27 in osteoblast-like MC3T3-E1 cells. However, the precise role of HSP27 in bone metabolism has not been satisfactory clarified. In this study, we investigated the effect of HSP27 on osteocalcin synthesis induced by bone morphogenetic protein (BMP)-4 or T(3) in these cells. In MC3T3-E1 cells, pretreatment with sphingosine 1-phosphate, sodium arsenite, or heat stress caused the attenuation of osteocalcin synthesis induced by BMP-4 or T(3) with concurrent HSP27 induction. To further investigate the effect of HSP27, we established stable HSP27-transfected cells. The osteocalcin synthesis was significantly reduced in the stable HSP27-transfected MC3T3-E1 cells and normal human osteoblasts compared with empty-vector transfected cells. On the other hand, anisomycin, a p38 MAPK activator, caused the phosphorylation of HSP27 in both sphingosine 1-phosphate-stimulated untransfected MC3T3-E1 cells and HSP27-transfected MC3T3-E1 cells. An immunofluorescence microscopy study showed that the phosphorylated HSP27 induced by anisomycin concentrated perinuclearly in these cells, in which it colocalized with the endoplasmic reticulum. We also established stable mutant-HSP27-transfected cells. Osteocalcin synthesis induced by either BMP-4 or T3 was markedly suppressed in the nonphosphorylatable HSP27-overexpressing MC3T3-E1 cells compared with the phosphomimic HSP27-overexpressing cells. In contrast, the matrix mineralization was more obvious in nonphosphorylatable HSP27-overexpressing cells than that in phosphomimic HSP27-overexpressing cells. Taken together, these results strongly suggest that unphosphorylated HSP27 has an inhibitory effect on osteocalcin synthesis, but has a stimulatory effect on mineralization, in osteoblasts. (Endocrinology 152: 1872-1882, 2011)
  • Role of heat shock protein 27 in transforming growth factor-β-stimulated vascular endothelial growth factor release in osteoblasts., Kato K, Tokuda H, Adachi S, Matsushima-Nishiwaki R, Yamauchi J, Natsume H, Minamitani C, Mizutani J, Otsuka T, Kozawa O, International journal of molecular medicine, 27, (3) 423 - 428,   2011年03月, 査読有り
  • (-)-Epigallocatechin gallate inhibits thyroid hormone-stimulated osteocalcin synthesis in osteoblasts, Kenji Kato, Takanobu Otsuka, Seiji Adachi, Rie Matsushima-Nishiwaki, Hideo Natsume, Osamu Kozawa, Haruhiko Tokuda, MOLECULAR MEDICINE REPORTS, 4, (2) 297 - 300,   2011年03月, 査読有り, It is recognized that catechin possesses beneficial properties for bone metabolism. We previously revealed that triiodothyronine (T(3))-activated p38 mitogen-activated protein (MAP) kinase, but not p44/p42 MAP kinase, is involved in the synthesis of osteocalcin in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of (-)-epigallocatechin gallate (EGCG), the predominant green tea polyphenol, on the synthesis of osteocalcin in MC3T3-E1 cells. EGCG significantly suppressed T(3)-stimulated osteocalcin synthesis. The inhibitory effect of EGCG was dose-dependent in the range of 3 to 30 mu M. On the other hand, T(3)-induced phosphorylation of p38 MAP kinase was not affected by EGCG. EGCG profoundly inhibited T(3)-stimulated transcriptional activity. These results strongly suggest that EGCG suppresses T(3)-stimulated osteocalcin synthesis upstream of the transcriptional level in osteoblast-like MC3T3-E1 cells.
  • Wnt3a regulates tumor necrosis factor-α-stimulated interleukin-6 release in osteoblasts., Natsume H, Tokuda H, Adachi S, Matsushima-Nishiwaki R, Kato K, Minamitani C, Otsuka T, Kozawa O, Molecular and cellular endocrinology, 331, (1) 66 - 72,   2011年01月, 査読有り
  • Antithrombin III reduces collagen-stimulated granule secretion of PDGF-AB and the release of soluble CD40 ligand from human platelets, Tomoaki Doi, Seiji Adachi, Rie Matsushima-Nishiwaki, Hisaaki Kato, Yukiko Enomoto, Hideo Natsume, Kenji Kato, Jun Mizutani, Takanobu Otsuka, Haruhiko Tokuda, Shigeru Akamatsu, Toru Iwama, Osamu Kozawa, Shinji Ogura, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 26, (3) 387 - 392,   2010年09月, 査読有り, Although antithrombin-III (AT-Ill), an anticoagulant, has been shown to affect human platelet functions, the direct effect of AT-III on platelets is still unknown. We recently reported that the collagen-induced phosphorylation of the heat shock protein 27 (HSP27) via the p44/p42 mitogen-activated protein (MAP) kinase is sufficient for granule secretion and the release of soluble CD40 ligand (sCD40L) from platelets but not platelet aggregation. In the present study, we investigated whether AT-III affects the collagen-induced secretion of the platelet-derived growth factor (PDGF)-AB and sCD40L release. AT-Ill inhibited collagen-stimulated platelet aggregation. The collagen-induced secretion of PDGF-AB was significantly suppressed by AT-III. AT-III also reduced sCD40L release. AT-III markedly attenuated the collagen-induced phosphorylated levels of p44/p42 MAP kinase. In addition, AT-HI suppressed collagen-induced HSP27 phosphorylation. These results strongly suggest that AT-III reduced collagen-stimulated platelet granule secretion due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase.
  • AMP-activated protein kinase positively regulates FGF-2-stimulated VEGF synthesis in osteoblasts, Kenji Kato, Haruhiko Tokuda, Seiji Adachi, Rie Matsushima-Nishiwaki, Hideo Natsume, Kengo Yamakawa, Yumi Gu, Takanobu Otsuka, Osamu Kozawa, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 400, (1) 123 - 127,   2010年09月, 査読有り, AMP-activated protein kinase (AMPK) is recognized as a regulator of energy homeostasis. We have previously reported that basic fibroblast growth factor (FGF-2) stimulates vascular endothelial growth factor (VEGF) release through the activation of p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of AMPK in FGF-2-stimulated VEGF release in these cells. FGF-2 time-dependently induced the phosphorylation of AMPK alpha-subunit (Thr-172). Compound C, an AMPK inhibitor, which suppressed the FGF-2-induced phosphorylation of AMPK, significantly inhibited the VEGF release stimulated by FGF-2. The AMPK inhibitor also reduced the mRNA expression of VEGF induced by FGF-2. The FGF-2-induced phosphorylation of both p44/p42 MAP kinase and SAPK/JNK was attenuated by compound C. These results strongly suggest that AMPK positively regulates the FGF-2-stimulated VEGF synthesis via p44/p42 MAP kinase and SAPK/JNK in osteoblasts. (C) 2010 Elsevier Inc. All rights reserved.
  • Rho-kinase regulates prostaglandin D-2-stimulated heat shock protein 27 induction in osteoblasts, Kenji Kato, Haruhiko Tokuda, Hideo Natsume, Seiji Adachi, Rie Matsushima-Nishiwaki, Chiho Minamitani, Jun Mizutani, Osamu Kozawa, Takanobu Otsuka, EXPERIMENTAL AND THERAPEUTIC MEDICINE, 1, (4) 579 - 583,   2010年07月, 査読有り, We previously reported that prostaglandin D-2 (PGD(2)) stimulates heat shock protein 27 (HSP27) induction through p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In addition, we recently showed that PGD(2) activates Rho-kinase, resulting in the regulation of interleukin-6 synthesis via activation of p38 MAP kinase but not p44/p42 MAP kinase in these cells. In the present study, in order to investigate whether Rho-kinase is involved in the PGD(2)-stimulated HSP27 induction in MC3T3-E1 cells, we examined the effects of Rho-kinase inhibitors on H5P27 induction. Y27632 and fasudil, Rho-kinase inhibitors, markedly suppressed the HSP27 induction stimulated by PGD(2) in a dose-dependent manner without affecting levels of HSP70 in the presence of PGD(2). Immunofluorescence microscopy studies also revealed that Y27632 and fasudil markedly suppressed the induction of H5P27. Y27632 and fasudil attenuated the PGD(2)-induced phosphorylation levels of S.APK/JNK. In conclusion, Rho-kinase inhibitors regulate PGD(2)-stimulated.HSP27 induction via activation of both SAPK/JNK and p38 MAP kinase in osteoblasts.
  • Synergistic effect of vasoactive intestinal peptides on TNF-alpha-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation, Hideo Natsume, Haruhiko Tokuda, Jun Mizutani, Seiji Adachi, Rie Matsushima-Nishiwaki, Chiho Minamitani, Kenji Kato, Osamu Kozawa, Takanobu Otsuka, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 25, (5) 813 - 817,   2010年05月, 査読有り, We previously showed that tumor necrosis factor-alpha (TNF-alpha) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of vasoactive intestinal peptide (VIP) on TNF-alpha-induced IL-6 synthesis in these cells. VIP, which by itself slightly stimulated IL-6 synthesis, synergistically enhanced the TNF-alpha-induced IL-6 synthesis in MC3T3-E1 cells. The synergistic effect of VIP on the TNF-a-induced IL-6 synthesis was concentration-dependent in the range between I and 70 nM. We previously reported that VIP stimulated cAMP production in MC3T3-E1 cells. Forskolin, a direct activator of adenylyl cyclase, or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP), a plasma membrane-permeable cAMP analogue, markedly enhanced the TNF-alpha-induced IL-6 synthesis as well as VIP. VIP markedly up-regulated the TNF-alpha-induced p44/p42 MAP kinase phosphorylation. The Akt phosphorylation stimulated by TNF-alpha was only slightly affected by VIP. PD98059, a specific inhibitor of MEK1/2, significantly suppressed the enhancement of TNF-alpha-induced IL-6 synthesis by VIP. The synergistic effect of a combination of VIP and TNF-alpha on the phosphorylation of p44/p42 MAP kinase was diminished by H-89, an inhibitor of cAMP-dependent protein kinase. These results strongly suggest that VIP synergistically enhances TNF-alpha-stimulated IL-6 synthesis via up-regulating p44/p42 MAP kinase through the adenylyl cyclase-cAMP system in osteoblasts.
  • Rho-kinase limits FGF-2-stimulated VEGF release in osteoblasts, Hideo Natsume, Haruhiko Tokuda, Seiji Adachi, Shinji Takai, Rie Matsushima-Nishiwaki, Kenji Kato, Chiho Minamitani, Shunpei Niida, Jun Mizutani, Osamu Kozawa, Takanobu Otsuka, BONE, 46, (4) 1068 - 1074,   2010年04月, 査読有り, We previously reported that basic fibroblast growth factor (FGF-2) stimulates the release of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates the VEGF release in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether Rho-kinase is involved in FGF-2-stimulated VEGF release in MC3T3-E1 cells. FGF-2 induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase. Y27632, a specific inhibitor of Rho-kinase, which attenuated the MYPT-1 phosphorylation, significantly enhanced the FGF-2-stimulated VEGF release. Fasudil, another Rho-kinase inhibitor, also amplified the VEGF release. FGF-2 significantly stimulated VEGF accumulation and fasudil enhanced FGF-2-stimulated VEGF accumulation also in whole cell lysates. Neither Y27632 nor fasudil affected the phosphorylation levels of p44/p42 MAP kinase or p38 MAP kinase. Y27632 and fasudil markedly strengthened the FGF-2-induced phosphorylation of SAPK/JNK. Y27632 as well as fasudil enhanced FGF-2-stimulated VEGF release and Y27632 enhanced the FGF-2-induced phosphorylation levels of SAPK/JNK also in human osteoblasts. These results strongly suggest that Rho-kinase negatively regulates FGF-2-stimulated VEGF release in osteoblasts. (C) 2010 Elsevier Inc. All rights reserved.
  • p70 S6 kinase limits tumor necrosis factor-alpha-induced interleukin-6 synthesis in osteoblast-like cells, Chiho Minamitani, Haruhiko Tokuda, Seiji Adachi, Rie Matsushima-Nishiwaki, Junichi Yamauchi, Kenji Kato, Hideo Natsume, Jun Mizutani, Osamu Kozawa, Takanobu Otsuka, MOLECULAR AND CELLULAR ENDOCRINOLOGY, 315, (1-2) 195 - 200,   2010年02月, 査読有り, Our previous study demonstrated that tumor necrosis factor-alpha (TNF-alpha) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p70 S6 kinase is involved in TNF-alpha-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-alpha time dependently induced the phosphorylation of p70 S6 kinase. Rapamycin, an inhibitor of p70 S6 kinase, which attenuated the phosphorylation of p70 S6 kinase induced by TNF-alpha, significantly amplified the TNF-alpha-stimulated IL-6 synthesis. TNF-alpha-induced phosphorylations of both p44/p42 MAP kinase and Akt were markedly enhanced by rapamycin. The amplification by rapamycin of TNF-alpha-induced IL-6 synthesis was reduced by PD98059, a specific inhibitor of MEK1/2, or Akt inhibitor. Rapamycin enhanced the IL-6 synthesis and the phosphorylation of Akt induced by TNF-alpha also in human osteoblasts. Taken together, these results strongly suggest that p70 S6 kinase limits the TNF-alpha-stimulated IL-6 synthesis at a point upstream from p44/p42 MAP kinase and Akt in osteoblast-like cells. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • Involvement of Rho-kinase in prostaglandin E-1-stimulated VEGF synthesis through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblast-like MC3T3-E1 cells, Seiji Adachi, Haruhiko Tokuda, Rie Matsushima-Nishiwaki, Kenji Kato, Hideo Natsume, Chiho Minamitani, Jun Mizutani, Takanobu Otsuka, Osamu Kozawa, PROSTAGLANDINS & OTHER LIPID MEDIATORS, 90, (1-2) 1 - 6,   2009年11月, 査読有り, We have previously shown that prostaglandin E-1 (PGE(1)) stimulates the synthesis of vascular endothelial growth factor (VEGF) through p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) but not p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of Rho-kinase in the PGE(1)-stimulated VEGF synthesis in these cells. PGE(1) induced within 3 min the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase. Y27632 and fasudil, specific inhibitors of Rho-kinase, which attenuated the MYPT-1 phosphorylation, significantly suppressed the PGE(1)-stimulated VEGF synthesis. Y27632 and fasudil markedly reduced the PGE(1)-induced phosphorylation of SAPK/JNK without affecting the phosphorylation levels of p38 MAP kinase or p44/p42 MAP kinase. These results strongly suggest that Rho-kinase functions at a point upstream of SAPK/JNK and regulates PGE(1)-stimulated VEGF synthesis in osteoblasts. (C) 2009 Elsevier Inc. All rights reserved.
  • Relationship between screw trajectory of C1 lateral mass screw and internal carotid artery., Murakami S, Mizutani J, Fukuoka M, Kato K, Sekiya I, Okamoto H, Abumi K, Otsuka T, Spine, 33, (24) 2581 - 2585,   2008年11月, 査読有り


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