骨形成メカニズムとしてのニッチの分子的解明と治療への応用基盤の先端ナノサイエンス

2010 Fiscal Year Annual Research Report

• Project/Area Number: 18109011
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 野田 政樹 東京医科歯科大学, 難治疾患研究所, 教授 (50231725)
• Co-Investigator(Kenkyū-buntansha): 江面 陽一 東京医科歯科大学, 難治疾患研究所, 准教授 (50333456) ; 早田 匡芳 東京医科歯科大学, 難治疾患研究所, 助教 (40420252)
• Keywords: ナノゲル / プロスタグランディン / 骨芽細胞 / BMP / EP4A / 分化 / 細胞増殖

Research Abstract

本年は、自然修復が不可能な骨欠損を促進する新規のデリバリーシステムとしてコレステロールプルランを用いたナノゲルの検討を行うと共に、現在、BMPの骨修復に際しては、特に霊長類においては多量を要する問題がある事から、新たな非蛋白性の骨形成促進因子を用いてBMP量を低減可能な新たなコンパウンド療法の検討を行った。すなわち、頭頂骨における自然修復が不可能な骨欠損に対し、コレステロールプルランに一分子あたり、一分子のBMP2を取り込むと共に、円盤状の成形を行い骨形成の明らかな促進因子であるプロスタグランディンの4つのサブタイプの受容体のうち、EP4に特異的なアゴニストである化合物を用い、低用量のBMPと同時にナノゲルに取り込む事によりBMPの骨形成の活性を強化する事に成功した。本研究においては、BMPとEP4アゴニストとの共存により、頭頂骨の形態が、無傷の反対側の頭頂骨と同じ形態に形成され、骨再構築において形態系形成シグナルの存在が推察された。さらに、BMPによるこの作用は、スマッドのリン酸化を検出する免疫染色に基づく検討により、BMPのシグナルの増強である事が示された。加えて、BMP応答配列を持つルシフェラーゼアッセイにより、BMPとEP4の相互作用が転写性の制御に基づく事が示され、その結果としての骨芽細胞としての分化の指標である、アルカリフォスファターゼの活性を指標とした検討により、BMPとEP4Aの相互作用が最終的には、骨芽細胞分化を制御する事が明らかとなった。さらに、デリバリーシステムとしての、ナノゲルの担体は、周囲における細胞増殖を亢進させ、その後に分化形質としてのコラーゲン等の細胞外基質の分泌と石灰化により、骨の形成は、ナノゲルにより正常の形態を再構築する事が見出された。以上の結果は、本研究の目的とする新たな骨再構築における、ナノサイエンスの応用の成果が確立されたものである。

Research Products

• [Journal Article] Nanogel-based scaffold delivery of prostaglandin E(2) receptor-specificagonist in combination with a low dose of growth factor heals critical-size bone defects in mice. (2011)
  • Author(s): Kamolratanakul P, Hayata T, Ezura Y, Kawamata A, Hayashi C, Yamamoto Y, Hemmi H, Nagao M, Hanyu R, Notomi T, Nakamoto T, Amagasa T, Akiyoshi K, Noda M
  • Journal Title: Arthritis Rheum Volume: 63(4) Pages: 1021-1033
  • Peer Reviewed
• [Journal Article] Per-1 is a specific clock gene regulated by parathyroid hormone (PTH)signaling in osteoblasts and is functional for the transcriptional eventsinduced by PTH. (2011)
  • Author(s): Hanyu R, Hayata T, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Knonenbery H, Kaneko K, Kurosawa H, Ezura Y, Noda M
  • Journal Title: Journal of Cellular Biochemistry Volume: 112 Pages: 433-438
  • Peer Reviewed
• [Journal Article] Schnurri-2 deficiency counteracts against bone loss induced by ovariectomy. (2010)
  • Author(s): Nagao M, Saita, Y, Hanyu, R, Hemmi H, Notomi T Hayata T, Nakamoto T, Kaneko K, Kurosawa H, Ishii S, Ezura Y, Noda M.
  • Journal Title: Journal of Cellular Physiology Volume: 226 Pages: 573-578
  • Peer Reviewed
• [Journal Article] Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. (2010)
  • Author(s): Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, Kato S, Miyasaka N, Ezura Y, Noda M
  • Journal Title: Journal of Cellular Biochemistry Volume: 109 Pages: 866-875
  • Peer Reviewed
• [Journal Article] Cbl-b Enhances Runx2 Protein Stability and Augments OsteocalcinPromoter Activity in Osteoblastic Cell Lines. (2010)
  • Author(s): Ampornaramveth Salingcarnboriboon R, Pavasant P, Noda M
  • Journal Title: Journal of Cellular Physiology Volume: 224 Pages: 743-747
  • Peer Reviewed
• [Journal Article] Nemo-like kinase (NLK) expression in osteoblastic cells and suppression ofosteoblastic differentiation. (2010)
  • Author(s): Nifuji A, Ideno H, Ohyama Y, Takanabe R, Araki R, Abe M, Noda M, Shibuya H
  • Journal Title: Experimental Cell Research Volume: 316 Pages: 1127-1136
  • Peer Reviewed
• [Presentation] Anabolic action of PTH signaling on bone activated expression of a clockgene, Per-1 (2011)
  • Author(s): Ryo Hanyu, Masashi Nagao, Yoshitomo Saita, Hisashi Kurosawa, Kauzo, Kaneko, Masaki Noda.
  • Organizer: 第1回国際スポートロジー学会学術集会
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-03-05
• [Presentation] CIZは悪性黒色腫細胞の転移に促進的に働くCIZ : Cas-Interacting-Zincfinger protein accelrates metastasis of malignant melanoma (2010)
  • Author(s): 佐久間朋美、中元哲也、宮井健太郎、辺見弘明、天笠光雄、早田匡芳、江面陽一、野田政樹
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 兵庫、日本
  • Year and Date: 20101207-20101210
• [Presentation] Amagasa T Ovariectomy induced bone loss was prevented by the deficiencyof jund which determines osteoblastic activity and basal levels of bone mass. (2010)
  • Author(s): Kawamata A, Yokoyama H, Izu Y, Hayata T, Erwin F.Wanger, Nakashima K, Ezura Y, Noda M
  • Organizer: The 9^<th> Asian Congress on Oral and MaxillofacialSurgery
  • Place of Presentation: Kuala Lumpur, Malaysia
  • Year and Date: 20101125-20101128
• [Presentation] Schnurri2 Deficiency Increases all of 1, 25(OH)2D3, Renal 25-hydroxyvitaminD 1-α Hdroxylase, PTH, FGF23, Serum Calcium and Phosphate in Association with Hypercalcificationin in Joints. (2010)
  • Author(s): Nagao M, Ezura Y, Saita Y, MiyaiK, Hanyu R, Nakamoto T, Hemm H, Hayata T, Notomi T, Ishii S, Kato S, Fukumoto S, Kurosawa H, Kaneko K, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Osteopontin Plays a Pivotal Role Sympathetic Control of Bone Mass. (2010)
  • Author(s): Nagao M, Ezura Y, Saita Y, Nakamoto T, Hayata T, Izu Y, Hanyu R, Hemmi H, Notomi T, Rittling S, Kurosawa H, KanekoK, Denhardt D, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Unloading-induced Suppression of B-lymphogenesis and Expansion of Peripheral Monocyte/macrophage Lineage Cells is Preserved in the Mice Deficient for Osteopontin. (2010)
  • Author(s): Ezura Y, Nagata J, Hemmi H, Nagao M, Notomi T, Hayata T, Nakamoto T, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Adregergic Receptor Regulates Anabolic Action of Constitutively Active Form of PTH/PTHrP Receptor Signaling. (2010)
  • Author(s): Hanyu R, Karsenty G, Hayata T, Nakamoto T, Notomi T, Kronenberg H, Saita Y, Hemmi H, Nagao M, Noda M, Ezura Y, Takeda S
  • Organizer: The 32^<nd> Annual Meeting of American Society forBone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Cnot3, a Novel Critical Regulator of a mRNA Stability, is Involved in the Maintenance of the Bone Mass and the Bone Structure in Senile Osteoprosis Model. (2010)
  • Author(s): Watanabe C, Morita M, Ezura Y, Nakamoto T, Hayata T, Hemmi H, Notomi T, Moriyama K, Yamamoto T, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] PTH Anabolic Action is Influenced by the Deficiency of TRPV4 in Bone. (2010)
  • Author(s): Kamolratanakul P, Ezura Y, Mizoguchi F, Hayata T, Hemmi H, Notomi T, Amagasa T, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Identification of Novel Molecule for Melanoma Malignancy- Role of CIZ. (2010)
  • Author(s): Miyai K, Noda M, Hayata T, Sakuma T, Ezura Y
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Dullard, a Novel BMP Inhibitor, Targets Smadl to Suppress BMP-dependent Transcription in Mammalian Osteoblastic Cells. (2010)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Deficiency of Dok-1 and Dok-2, Ras- Erk Pathway Inhibitors, Enhances BoneLoss in Postmenopausal Osteoprosis Model of Mice. (2010)
  • Author(s): Miyajima D, Kawamata A, Inoue A, Ezura Y, Nakamoto T, Hayata T, Notomi T, Amagasa T, Yamanashi Y, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Nck1, a Molecular Adaptor Prerequisite for Cell Motility, is Stimulated by Bone Morphogenetic Protein and Contributes to Maintain Bone Mass. (2010)
  • Author(s): Hanyu R, Nakamoto T, Miyai K, Nagao M, Aryal A.C S, Noda M, Ezura Y, Hayata T, Notomi T, Hemmi H, Pawson T
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] TRPV4(Transient Receptor Potential Vanilloid 4), a Mechanosensor for Bone. Is Required for the Maintenance of Bone Mineral. Density of MandibleExposed to Occlusal Force. (2010)
  • Author(s): Suzuki T, Notomi T, Ezura Y, Nakamoto T, Hayata T, Hemmi H, Mizuno A, Suzuki M, Mizoguchi F, Izumi Y, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] CIZ Expression is Enhanced by Inflammatory Stimulation and Transcriptionally Regulates the RANKL Promoter. (2010)
  • Author(s): Nakamoto T, Motoyoshi T, Hada T, Sakuma T, Hayata T, Ezura Y, Kitazawa R, Kitazawa S, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] Genetic Conversiion of Osteoclast Precursor to be Responsive to Light-controlled Cation Channel Activation Enhances Differentiation Upon Modulation of their Membrane Potential. (2010)
  • Author(s): Notomi T, Kuno M, Ezura Y, Noda M
  • Organizer: The 32^<nd> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Toronoto, Canada
  • Year and Date: 20101015-20101019
• [Presentation] マウスSchcurri2欠失は腎25-hydroxyvitamin D 1-alpha hydroxylaseの発現高値と高カルシウム・リン積を呈して間接周囲の異所性石灰化をもたらす (2010)
  • Author(s): 長尾雅史、斎田良知、羽生亮、辺見弘明、納富拓也、早田匡芳、中元哲也、金子和夫、黒澤尚、江面陽一、野田政樹
  • Organizer: 第25回日本整形外科学会
  • Place of Presentation: 京都、日本
  • Year and Date: 20101014-20101015
• [Presentation] 副甲状腺ホルモンによる全身性骨量増加作用は交換神経系シグナルを必要とする (2010)
  • Author(s): 羽生亮、斎田良知、長尾雅史、辺見弘明、納富拓也、早田匡芳、中元哲也、江面陽一、竹田修、金子和夫、黒澤尚、野田政樹
  • Organizer: 第25回日本整形外科学会
  • Place of Presentation: 京都、日本
  • Year and Date: 20101014-20101015
• [Presentation] IL-1βはマウス軟骨細胞においてCIZの発現を促進するIL-1β induces CIZ expression in mouse chondrocytes (2010)
  • Author(s): 元吉貴之、中元哲也、江面陽一、早田匡芳、納富拓也、長尾雅史、羽生亮、佐久間朋美、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京、日本
  • Year and Date: 20100721-20100723
• [Presentation] CizによるRANKLのプロモーター制御機構の解析Transcriptional regulation of RANKL promoter by CIZ protein (2010)
  • Author(s): 羽田佑、中元哲也、佐久間朋美、長尾雅史、早田匡芳、江面陽一、北澤理子、北澤荘平、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京、日本
  • Year and Date: 20100721-20100723
• [Presentation] 転写因子CIZの欠損は、関節炎進展を抑制する (2010)
  • Author(s): 中元哲也、羽田佑、元吉貴之、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京、日本
  • Year and Date: 20100721-20100723
• [Presentation] Bone Formation and Extracellular Signaling (2010)
  • Author(s): 野田政樹
  • Organizer: The American Society for Cell Biology 50th Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2010-12-11
• [Presentation] 非荷重と骨量制御のメカニズム (2010)
  • Author(s): 野田政樹
  • Organizer: 社団法人 日本酪農乳業協会 第25回国際学術フォーラム
  • Place of Presentation: 東京、日本
  • Year and Date: 2010-12-04
• [Presentation] Molecular mechanism under lying regulation of bone metabolism (2010)
  • Author(s): 野田政樹
  • Organizer: The 70^<th> Anniversary Celebration 2010 Faculty of Dentistry Chulalongkorn University
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2010-08-11
• [Presentation] 骨粗霧症治療薬・最新の進化 (2010)
  • Author(s): 野田政樹
  • Organizer: 第23回日本臨床整形外科学会学術集会
  • Place of Presentation: 神奈川、日本
  • Year and Date: 2010-07-18
• [Presentation] 骨粗嶺症の基礎 (2010)
  • Author(s): 野田政樹
  • Organizer: 第83回日本整形外科学会学術総会
  • Place of Presentation: 東京、日本
  • Year and Date: 2010-05-29
• [Book] Mechanosensing Biology (2011)
  • Author(s): Masaki Noda
  • Total Pages: 219
  • Publisher: Springer