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骨・骨髄損傷後の血管新生から組織再生までの遺伝子発現と制御

Research Project

Project/Area Number 12137210
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionUniversity of Occupational and Environmental Health, Japan

Principal Investigator

中村 利孝  産業医科大学, 医学部, 教授 (50082235)

Co-Investigator(Kenkyū-buntansha) 酒井 昭典  産業医科大学, 医学部, 助教授 (90248576)
成澤 研一郎  産業医科大学, 医学部, 講師 (20269062)
内田 宗志  産業医科大学, 医学部, 助手 (60330990)
鶴上 浩  産業医科大学, 医学部, 講師 (70299618)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥52,100,000 (Direct Cost: ¥52,100,000)
Fiscal Year 2004: ¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2003: ¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2002: ¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2001: ¥13,300,000 (Direct Cost: ¥13,300,000)
Keywords骨・骨髄損傷 / 海綿骨 / 皮質骨 / ビスフォスフォネート / cbfa-1 / osterix / osteocalcin / RANKL / PECAM-1 / CD31 / 骨髄細胞 / 血管内皮細胞 / 骨芽細胞 / CFU-f / アルカリフォスファターゼ / 非荷重 / 骨損傷 / 血管内皮細胞成長因子 / flt-1 / 骨再生 / 骨髄 / 組織形態計測 / 力学強度 / HIF / 血管芽細胞 / VEGF / Flk-1 / Flt-1 / 骨髄損傷 / 血管新生 / HIFファミリー
Research Abstract

我々は、骨・骨髄損傷後の組織修復過程において、骨形成と血管形成因子との関連を明らかにする目的で研究を行ってきた。今年度は、ビスフォスフォネート(BP)投与により骨代謝回転が低下した(骨芽細胞分化能が低下した)状態で、骨・骨髄損傷を生じた場合、その修復過程が遅延するか否か、その機序について明らかにする目的で実験を行った。
7週齢の雄性C57BL/6Nマウスを、1週間の予備飼育後、8週齢からBP (YM529の0.1mg/kgを毎週1回静注)を投与開始した。10週齢で大腿骨骨幹部の骨・骨髄にドリルで穴を開けた。修復部組織の組織形態計測およびrealtime PCRで遺伝子発現を調べた。
骨・骨髄損傷後14日までの骨髄修復期においては、骨髄内仮骨の形成は、BP投与による影響を受けなかったが、14日以降の皮質骨の再構築期においては、BP投与群では層板骨(lamellar bone)構造が多成されず、修復が遅延した。損傷前は、BP投与により、ALP陽性CFU-fの形成は低下し、骨芽細胞分化は抑制されていた。しかし、損傷後3日、cbfa-1、osterixの発現は、BP投与群と非投与群に差がなくなった。しかし、osteocalcinの発現は低下しており、RANKLの発現は亢進していた。BPにより低下していた骨芽細胞分化能は、損傷後は非投与群と同じように急激に促進されたが、骨芽細胞の最終分化段階は依然抑制された状態であった。
マウス骨・骨髄損傷後の修復過程において、ビスフォスフォネート投与は、1)骨髄内仮骨の形成に影響を与えないこと、2)骨髄内仮骨の吸収を遅延させること、3)皮質骨の再構築(層板骨構造形成)を遅延させること、を明らかにした。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (27 results)

All 2004 Other

All Journal Article (6 results) Publications (21 results)

  • [Journal Article] Prostaglandin E_2 receptor (EP4) selective agonist (ONO-4819, CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats.2004

    • Author(s)
      Tanaka M, Sakai A, Nakamura T, et al.
    • Journal Title

      Bone 34・6

      Pages: 940-948

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Regulation of mineral-to-matrix ratio of lumbar trabecular bone in ovariectomized rats treated with risedronate in combination with or without vitamin K2.2004

    • Author(s)
      Ohtomo H, Sakai A, Nakamura T, et al.
    • Journal Title

      Journal of Bone and Mineral Metabolism 22・5

      Pages: 404-414

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Skeletal unloading alleviates the anabolic action of intermittent parathyroid hormone (1-34) in mouse tibia in association with inhibition of PTH-induced increase in c-fos RNA in bone marrow cells.2004

    • Author(s)
      Tanaka S, Sakai A, Nakamura T, et al.
    • Journal Title

      Journal of Bone and Mineral Research 19・11

      Pages: 1813-1820

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Human parathyroid hormone (1-34) increases mass and structure of the cortical shell, with resultant increase in lumbar bone strength, in ovariectomized rats.2004

    • Author(s)
      Arita S, Sakai A, Nakamura T, et al.
    • Journal Title

      Journal of Bone and Mineral Metabolism 22・6

      Pages: 530-540

    • NAID

      10014316617

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Bisphosphonate (YM529) delays the repair of cortical bone defect after drill-hole injury by reducing terminal differentiation of osteoblasts in the mouse femur.

    • Author(s)
      Nagashima M, Sakai A, Nakamura T, et al.
    • Journal Title

      Bone (in press)

      Pages: 2005-2005

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reduced expression of platelet endothelial cell adhesion molecule-1 in bone marrow cells in mice after skeletal unloading.

    • Author(s)
      Sakuma-Zenke M, Sakai A, Nakamura T, et al.
    • Journal Title

      Journal of Bone and Mineral Research (in press)

      Pages: 2005-2005

    • Related Report
      2004 Annual Research Report
  • [Publications] Okazaki R, Sakai A, Nakamura T, et al.: "Apoptosis and p53 expression in chondrocytes relate to degeneration in articulacartilage of immobilized knee joints."Journal of Rheumatology. 30・3. 559-566 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohichi Y, Narusawa K, Nakamura T, et al.: "Lack of association between osteophyte and disc degeneration in postmenopausa Japanese women with back pain."Bone. 32・4. 405-411 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uchida S, Sakai A, Nakamura T, et al.: "Vascular endothelial growth factor is expressed along with its receptors durin the healing process of bone and bone marrow after drill-hole injury in rats."Bone. 32・5. 491-501 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masuyama R, Sakai A, Nakamura T, et al.: "Dietary calcium and phosphorus ratio regulates bone mineralization and turnove in vitamin D receptor knockout mice by affecting intestinal calcium and phosphorus absorption."Journal of Bone and Mineral Research. 18・7. 1217-1226 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mori T, Sakai A, Nakamura T, et al.: "Climbing exercise increases bone mass and trabecular bone turnover through transient regulation of marrow osteogenic and osteoclastogenic potentials in mice."Journal of Bone and Mineral Research. 18・11. 2002-2009 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka M, Sakai A, Nakamura T, et al.: "Prostaglandin E_2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bon repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats."Bone. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Watanuki M, Sakai A, Nakamura T, et al.: "Role of inducible oxide synthase in skeletal adaptation to acute increases in mechanical loading"J Bone Miner Res. 17・6. 1015-1025 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Notomi T, Nakamura T, et al.: "Effects of tower climbing exercise on bone mass, strength, and turnover in orchidectomized growing rats"J Appl Physiol. 93・3. 1152-1158 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Notomi T, Nakamura T, et al.: "Tower climbing exercise started 3 months after ovariectomy recovers of bone strenth of the femur and lumbar vertebrae in aged osteopenic rats"J Bone Miner Res. 18・1. 140-149 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okazaki R, Sakai A, Nakamura T, et al.: "Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints"J Rheum. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohishi Y, Narusawa K, Nakamura T, et al.: "Lack of association between osteophyte and disc degeneration in postmenopausal Japanese women with back pain"Bone. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchida S, Sakai A, Nakamura T, et al.: "Vascular endothelial growth factor is expressed along with its receptors during the healing process of bone and bone marrow after drill-hole injury in rats"Bone. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito M, Nakamura T, et al.: "Effects of lifetime volleyball exercise on bone mineral densities in lumbar spine, calcaneus and tibia for pre-, peri and postmenopausal women"Osteoporosis International. 12. 104-111 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ikeda S, Nakamura T, et al.: "Effect of trabecular bone contour on ultimate strength of lumbar vertebra after bilateral ovariectomy in rats"Bone. 28・6. 625-633 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okazaki R, Sakai A, Nakamura T, et al.: "Sequential changes in transforming growth factor (TGF)-β1 receptors in chondrocytes after immobilization of rabbit knees"Journal of Bone and Mineral Metabolism. 19・5. 228-235 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakai A, Nakamura T, et al.: "1α-Hydroxyvitamin D3 suppresses trabecular bone resorption by inhibiting osteoclastogenic potential in bone marrow cells after ovariectomy in mice"Journal of Bone and Mineral Metabolism. 19・5. 277-286 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakai A, Okazaki R, Nakamura T, et al.: "Disruption of the p53 gene results in preserved trabecular bone mass and bone formation after mechanical unloading"Journal of Bone and Mineral Research. 17. 119-127 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uchida S,Nakamura T et al.,: "Transient Expression of activin beta A mRNA on Osteoprogenitor Cells in Rat Bone Regeneration After Drill-Hole Injury"Bone. Vol27.No.1. 81-90 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masuyama R,Turukami H,Nakamura T et al.,: "Dietary Phosphorus restriction reverse the impaired bone mineralization in vitamin D receptor knockout mice"Endocrinology. Vol142.No.1. 494-497 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Notomi T,Nakamura T et al.,: "A comparison of resistance and aerobic training for mass, strength and turnover of bone in growing rats"Eur J Appl Physiol. 83. 469-474 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Notomi T,Nakamura T: "Effects of Tower Climbing Exercise on Bone Mass, Strength, and Turnover in Growing Rats."Journal of Bone and Mineral Research. Vol16.No.1. 166-174 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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