The development of bone regeneration therapy based on the clarification of mechanism of BMP-2 induced bone formation and resorption

• Project/Area Number: 16H05524
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Prosthodontics/ Dental materials science and
• Research Institution: Okayama University
• Principal Investigator: Ono Mitsuaki 岡山大学, 医歯薬学総合研究科, 助教 (60613156)
• Co-Investigator(Kenkyū-buntansha): 窪木 拓男 岡山大学, 医歯薬学総合研究科, 教授 (00225195) ; 大島 正充 徳島大学, 大学院医歯薬学研究部(歯学域), 准教授 (00548307) ; 大野 彩 (木村彩) 岡山大学, 大学病院, 助教 (20584626) ; 大橋 俊孝 岡山大学, 医歯薬学総合研究科, 教授 (50194262) ; 渡辺 亮 京都大学, iPS細胞研究所, 特定拠点助教 (60506765) ; 秋山 謙太郎 岡山大学, 大学病院, 講師 (70423291)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 骨形成 / 骨吸収 / BMP-2 / 骨髄環境下 / 骨髄環境 / 骨再生 / 骨髄 / 骨 / 骨髄ニッチ

Outline of Final Research Achievements

Bone morphogenetic protein 2 (BMP-2) is widely known as a potent growth factor that promotes bone formation. However, in this experiment, we revealed that the effect of BMP-2 in inducing bone formation is remarkably repressed by marrow cells via direct cell-cell contact with osteoblasts; this opens new perspectives on the clarification of the side-effects associated with BMP-2 application.

Academic Significance and Societal Importance of the Research Achievements

これまでBMP-2は最も強力に骨形成を促進する因子として広く認識されてきたが，我々は骨髄内においてBMP-2は骨形成を抑制することを明らかにした．これは，骨髄内には骨髄外とは異なった骨代謝機構が存在することを強く示唆しており，このメカニズムを解き明かすことは，大理石病や線維骨異形成症など難治性骨代謝疾患のみならず，血液・免疫疾患の新たな理解，治療法に画期的な影響を与えると考える．

Research Products

• [Journal Article] Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment (2018)
  • Author(s): Nguyen Ha Thi、Ono Mitsuaki、Oida Yasutaka、Hara Emilio Satoshi、Komori Taishi、Akiyama Kentaro、Nguyen Ha Thi Thu、Aung Kyaw Thu、Pham Hai Thanh、Tosa Ikue、Takarada Takeshi、Matsuo Koichi、Mizoguchi Toshihide、Oohashi Toshitaka、Kuboki Takuo
  • Journal Title: Journal of Bone and Mineral Research Volume: 34 Issue: 2 Pages: 327-332
  • DOI: 10.1002/jbmr.3598
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Commensal Microbiota Enhance Both Osteoclast and Osteoblast Activities (2018)
  • Author(s): Uchida Yoko、Irie Koichiro、Fukuhara Daiki、Kataoka Kota、Hattori Takako、Ono Mitsuaki、Ekuni Daisuke、Kubota Satoshi、Morita Manabu
  • Journal Title: Molecules Volume: 23 Issue: 7 Pages: 1517-1517
  • DOI: 10.3390/molecules23071517
  • Peer Reviewed / Open Access
• [Journal Article] ost-produced ADAMTS4 inhibits early-stage tumor growth. (2018)
  • Author(s): Asano K, Edamatsu M, Hatipoglu OF, Inagaki J, Ono M, Ohtsuki T, Oohashi T, Hirohata S.
  • Journal Title: Acta Med Okayama. Volume: 72(3) Pages: 257-66
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-HMGB1 neutralizing antibody attenuates periodontal inflammation and bone resorption in a murine periodontitis model. (2018)
  • Author(s): Yoshihara-Hirata C, Yamashiro K, Yamamoto T, Aoyagi H, Ideguchi H, Kawamura M, Suzuki R, Ono M, Wake H, Nishibori M, Takashiba S.
  • Journal Title: Infect Immun. Volume: 86(5)
• [Journal Article] Type IV collagen α6 chain is a regulator of keratin 10 in keratinization of oral mucosal epithelium (2018)
  • Author(s): Komori T, Ono M, Hara ES, Ueda J, Nguyen HTT, Nguyen HT, Yonezawa T, Maeba T, Ono A, Takarada T, Momota R, Maekawa K, Kuboki T, Oohashi T
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2612-2612
  • DOI: 10.1038/s41598-018-21000-0
  • Peer Reviewed / Open Access
• [Journal Article] CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα. (2018)
  • Author(s): Ono M, Masaki A, Maeda A, Kilts TM, Hara ES, Komori T, Pham H, Kuboki T, Young MF.
  • Journal Title: Matrix Biol. Volume: 17 Pages: 30400-6
  • DOI: 10.1016/j.matbio.2018.01.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma. (2018)
  • Author(s): Morisawa A, Okui T, Shimo T, Ibaragi S, Okusha Y, Ono M, Nguyen TTH, Hassan NMM, Sasaki A.
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 989-999
  • DOI: 10.3892/ijo.2018.4242
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiological role of urothelial cancer-associated one long noncoding RNA in human skeletogenic cell differentiation (2017)
  • Author(s): Ishikawa T, Nishida T, Ono M, Takarada T, Nguyen HT, Kurihara S, Furumatsu T, Murase Y, Takigawa M, Oohashi T, Kamioka H, Kubota S
  • Journal Title: J Cell. Physiol. Volume: 233(6) Issue: 6 Pages: 4825-4840
  • DOI: 10.1002/jcp.26285
  • Peer Reviewed / Open Access
• [Presentation] Bone regeneration therapy using E-coli derived recombinant human BMP-2 and novel function of BMP-2 in marrow environment. (2018)
  • Author(s): Nguyen HT, Ono M
  • Organizer: The First International Symposium on Immunology and Tissue Regeneration in Okayama / 12th URA International Symposium.
  • Int'l Joint Research / Invited
• [Presentation] Novel function of BMP-2 to prohibit bone formation in marrow environment. (2018)
  • Author(s): Nguyen HT, Ono M, Oida Y, Hara ES, Komori T, Akiyama K, Nguyen HTT, Aung KT, Pham HT, Oohashi T, Kuboki T
  • Organizer: The American Society of Bone and Mineral Research.
  • Int'l Joint Research
• [Presentation] Analysis bacterial flora of infected shunt in dialysis patients and its relation to oral flora. (2018)
  • Author(s): Nguyen HTT, Ono M, Kimura-Ono A, Komori T, Koyama E, Oohashi T, Kuboki T
  • Organizer: The 66th Annual Meeting of Japanese Association for Dental Research.
• [Presentation] BMP antagonist inhibitor L51P regulates the chondrogenesis and osteoarthritis. (2017)
  • Author(s): Nguyen HT, Ono M, Komori T, Oohashi T, Kuboki T.
  • Organizer: The 65th Annual Meeting of JADR.
  • Int'l Joint Research
• [Presentation] Regulation of gingival keratinization by laminin332. (2017)
  • Author(s): Komori T, Ueda J, Ono M, Sonoyama W, Hara ES, Yoshioka Y, Maekawa K, Kuboki T．
  • Organizer: 95th General Session & Exhibition of the IADR.
• [Presentation] イヌ自家移植モデルにおける器官原基法を応用した歯の再生の試み． (2017)
  • Author(s): 大野充昭，大島正充， 園山 亘，小川美帆，笈田育尚，Emilio HS，新川重彦，中島 隆，辻 孝，窪木拓男．
  • Organizer: 第3回日本骨免疫学会．
• [Presentation] ヒト骨髄由来間葉系幹細胞および軟骨細胞の核内の染色体配置の解析の試み． (2017)
  • Author(s): 大野充昭，小盛大志，土佐郁恵，秋山謙太郎，大野 彩，窪木拓男，大橋俊孝．
  • Organizer: 公益社団法人日本補綴歯科学会第126回学術大会．
• [Presentation] 必須アミノ酸Tryptophanは骨髄由来間葉系幹細胞の幹細胞性を制御し骨形成を促進する． (2017)
  • Author(s): 大野充昭，Pham HT, 笈田育尚，小盛大志，土佐郁恵，大橋俊孝，秋山謙太郎，窪木拓男．
  • Organizer: 第47回公益社団法人日本口腔インプラント学会学術大会