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

2009 Fiscal Year Annual Research Report

• Project/Area Number: 18109011
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 野田 政樹 Tokyo Medical and Dental University, 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: 骨形成 / 細胞分化 / 機能制御 / アンジオテンシン / 骨髄 / 神経系 / 循環系

Research Abstract

骨形成のメカニズムにおいては骨芽細胞分化と増殖の機能制御を主要な制御対象としたが、これまで骨芽細胞における制御の分子として循環系の分子についての存在が明らかにされていなかったことから今年度の研究においてレニン、アンジオテンシン:システムが骨において機能するか否かを解析した。この結果まず骨芽細胞におけるアンジオテンシン受容体のAT1および受容体AT2の発現が確認された。更に骨髄におけるアンジオテンシンコンバーティングエンザイムの発現が見出された。組織学の検討によりAT1は骨芽細胞に発現すると共にAT2と共に破骨細胞においても発現しており、この点から骨芽細胞、破骨細胞の両者はAT1、AT2の両者を発現することが明らかとなった。次にAT2のブロッカーおよびAT1のブロッカーも作用を検討すると、全般的な骨増加が明らかとなった。このアンジオテンシン受容体AT2の2型(AT2)のブロッキングを行うと、骨形成量が増加した。更に吸収の面での低下にもAT2のブロッカーの作用が明らかとなった。このような阻害剤による実験のみでなく、AT2のノックアウトマウスを用いた解析からも骨量増加および骨梁幅の増加が明らかとなったことから、骨の量の決定においてはこれまでの骨特異的な成長因子やホルモンのみならず、神経系と共に作用する循環系の分子の存在が重要な働きを持つことが明らかとなった。これに加え、骨の低下をもたらす責任細胞である破骨細胞の分化においてはエピジェネティックな作用を起こす物質であるmicroRNAの機能が重要であることをダイサー(Dicer)の破骨細胞特異的ノックアウトによって明らかにした。以上の成果は本研究が目的とする骨芽細胞メカニズムとしてのニッチの分子制御と治療への応用基盤の展開研究に資するものであり、今後更に骨芽細胞破骨細胞における分子レベルの制御についても解析を行う基盤が得られた。

Research Products

• [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 109 Pages: 866-75
  • Peer Reviewed
• [Journal Article] Cbl-b Enhances Runx2 Protein Stability and Augments Osteocalcin Promoter Activity in Osteoblastic Cell Lines (2010)
  • Author(s): Ampornaramveth Salingcarnboriboon, R., Pavasant, P., Noda, M.
  • Journal Title: Journal of Cellular Physiology (in press)
  • Peer Reviewed
• [Journal Article] Nemo-like kinase(NLK)expression in osteoblastic cells and suppression of osteoblastic 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 316 Pages: 1127-1136
  • Peer Reviewed
• [Journal Article] Angiotensin II type 2 receptor blockade increases bone mass. (2009)
  • Author(s): Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, Inagami T, Ezura Y, Noda M
  • Journal Title: Journal of Biological Chemistry 284 Pages: 4857-64
  • Peer Reviewed
• [Journal Article] Methylation status of CpG-islands in the promoter regions of signature genes during chondrogenesis of human synovium-derived mesenchymal stem cells. (2009)
  • Author(s): Ezura Y, Koga H, Muneta T, Sekiya I, Noda M
  • Journal Title: Arthritis & Rheumatism 60 Pages: 1416-1426
  • Peer Reviewed
• [Journal Article] Osteoblastic Bone Formation Is Induced by Using Nanogel-Crosslinking Hydrogel as Novel Scaffold for Bone Growth Factor (2009)
  • Author(s): Hayashi C, Hasegawa U, Saita Y, Hemmi H, Hayata T, Nakashima K, Ezura Y, Amagasa T, Akiyoshi K, Noda M
  • Journal Title: Journal of Cellular Physiology 220 Pages: 1-7
  • Peer Reviewed
• [Journal Article] ANA deficiency enhances BMP-induced ectopic bone formation via transcriptional events. (2009)
  • Author(s): Miyai K, Yoneda M, Hasegawa U, Toida S, Izu Y, Hemmi H, Hayata T, Ezura Y, Mizutani S, Miyazono K, Akiyoshi K, Yamamoto T, Noda M
  • Journal Title: Journal of Biological Chemistry 284 Pages: 10593-600
  • Peer Reviewed
• [Journal Article] Combinatory effects of androgen receptor deficiency and hind limb unloading on bone (2009)
  • Author(s): Saita Y, Takashi Nakamura, Fumitaka Mizoguchi, Kazuhisa Nakashima, Tadayoshi Hayata, Yoichi Ezura, Hisashi Kurosawa, Shigeaki Kato, Masaki Noda
  • Journal Title: Thime ejournals 41 Pages: 822-8
  • Peer Reviewed
• [Presentation] The hypermethylated high-density CpG-region(-1112/-888)of the stromal cell-derived factor 1(SDF1)is demethylated in the synovium derived mesenchymal stem cells during chondrogenesis. (2009)
  • Author(s): Ezura Y, Sekiya I, Muneta T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Dullard, a novel phosphatase, that dephosphorylates and degrades BMP receptors, suppresses signaling in osteoblasts. (2009)
  • Author(s): Hayata T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] The identification and characterization of a new Trem-like molecule. (2009)
  • Author(s): Hemmi H, Idoyaga J, Suda K, Noda M, Steinman R.M.
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Anabolic Action of PTH/PTHrP Receptor Signaling in Bone i Suppressed by a Nucleocytoplasmic Shuttling Protein CIZ. (2009)
  • Author(s): Nakamoto T, Ono N, Hanyu R, Sakuma T, Hayata T, Ezura Y, Schipani E, Kronenberg HM, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Pacemaker channel HCN1 affects osteoclast function in vitro and bone remodeling in vivo. (2009)
  • Author(s): Notomi T, Tanaka S, Amano H, Nakamura T, Noda M, Skerry TM, Kuno M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Sympathetic nervous tone modulates constitutively active parathyroid hormone receptor signaling in vivo. (2009)
  • Author(s): Hanyu R, Takeda S, Notomi T, Hemmi H, Hayata T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Schnurri-2(SHN-2)deficiency counteracts against bone loss induced by ovariectomy. (2009)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hemmi H, Notomi T, Nakamoto T, Hayata T, Ezura Y, Kurosawa H, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Nanogel scaffold delivery of Prostaglandin E2 Receptor(EP4)specific agonist in combination with BMP repairs microstructure of bone produced in the defect via potentiation of transcription activity of smad response element (2009)
  • Author(s): Kamolratanakul P, Kawamata A, Yamamoto Y, Hayata T, Ezura Y, Akiyoshi K, Amagasa T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Deficiency of Ciz, Cas Interactive Zinc Finger Protein, suppresses tumor invasion into bone. (2009)
  • Author(s): Sakuma T, Nakamoto T, Hayata T, Miyai K, Amagasa T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] PTH signaling and Osteopontin deficiency coordinately enhance progenitor niche for the cells to support tooth development. (2009)
  • Author(s): Morishita M, Ono N, Hanyu R, Kamolratanakul P, Nagao M, Hemmi H, Hayata T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Cbl-b enhanced Runx2 function on osteocalcin promoter activity in osteoblastic cell line. (2009)
  • Author(s): Ampornaramveth, R, Pavasant, Noda, M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Bone biology in PTH signaling (2009)
  • Author(s): 野田政樹
  • Organizer: OGEKM Autumn Symposium 2009
  • Place of Presentation: Wien, Austria
  • Year and Date: 2009-11-21
• [Presentation] 骨形成の制御機構 (2009)
  • Author(s): 野田政樹
  • Organizer: 第20回栃木県骨・カルシウム代謝研究会
  • Place of Presentation: 栃木、日本
  • Year and Date: 2009-06-19
• [Presentation] 骨の形成とその調節機構 (2009)
  • Author(s): 野田政樹
  • Organizer: 第29回日本骨形態計測学会
  • Place of Presentation: 大阪、日本
  • Year and Date: 2009-05-29
• [Presentation] 骨と骨の分子破壊と再構築のフロンティア (2009)
  • Author(s): 野田政樹
  • Organizer: 第63回日本口腔科学会
  • Place of Presentation: 静岡、日本
  • Year and Date: 2009-04-17