Development of new therapeutic drugs for inflammatory bone destruction by the CIAM compound, a new TNF receptor antagonist.

• Project/Area Number: 19390471
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OHYA Keiichi Tokyo Medical and Dental University, 医歯学総合研究科, 教授 (10126211)
• Co-Investigator(Kenkyū-buntansha): AOKI Kazuhiro 東京医科歯科大学, 医歯学総合研究科, 准教授 (40272603) ; TAKAHASHI Mariko 東京医科歯科大学, 歯学部, 技術職員 (90334440) ; 自見 英治郎 九州歯科大学, 歯学部・教授, 教授 (40276598)
• Co-Investigator(Renkei-kenkyūsha): JIMI Eijiro 九州歯科大学, 歯学部, 教授 (40276598)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2009: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2008: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2007: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
• Keywords: TNF受容体 / 骨吸収 / RANK / RANKL / 破骨細胞 / NF-κB / 骨吸収阻害 / 低Ca食飼育食マウス / NF-kB

Research Abstract

The cavity-induced allosteric modification (CIAM) compound binds to the cavity located near by the specific loop of the ligand binding site of the TNF receptor and thus inhibits the function of TNF. This study was undertaken to clarify the possibility in which the CIAM compound inhibits the proliferation of the osteoclasts and decreases bone resorption. The CIAM compound inhibited the osteoclast formation and finally increased bone formation. In addition, the compound inhibited the decrease of bone formation which accompanied with the inflammation. These results indicated that the CIAM compound is a new candidate drug both for the inhibitor of bone resorption and for the stimulator of bone formation induced by the inflammatory reactions.

Research Products

• [Journal Article] The Pivotal role of the alternative NF-κB pathway in maintenance of basal bone homeostasis and osteoclastogenesis. Published on 14^<th> December, 2009 (2010)
  • Author(s): Soysa N, Alles N, Weih D, Lovas A, Mian H, Shimokawa H, Yasuda H, Weih F, Jimi E, Ohya K, Aoki K.
  • Journal Title: J Bone Miner Res. (印刷中)
  • Peer Reviewed
• [Journal Article] Processing of the NF-β2 Precursor, p100, to p52 is Critical for RANKL-Induced Osteoclast Differentiation. published on 14^<th> December, 2009 (2010)
  • Author(s): Maruyama T, Fukushima H, Nakao K, Shin M, Yasuda H, Weih F, Doi T, Aoki K, Alles N, Ohya K, Hosokawa R, Jimi E.
  • Journal Title: J Bone Miner Res. (印刷中)
  • Peer Reviewed
• [Journal Article] Three-dimensional characterization of osteoclast bone-resorbing activity in the resorption lacunae (2009)
  • Author(s): Soysa N, Alles N, Aoki K, Ohya K
  • Journal Title: J Med & Dent Sci Vol. 56(2) Pages: 107-112
  • NAID: 130005420250
• [Journal Article] LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model (2009)
  • Author(s): Tomomatsu N, Aoki K, Alles N, Soysa N, Hussain A, Nakachi H, Kita S, Shimokawa H, Ohya K, Amagasa T
  • Journal Title: J Bone Miner Res Vol. 24(10) Pages: 1770-1781
• [Journal Article] Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss (2009)
  • Author(s): Alles N, Soysa N, Hussain A, Tomomatsu N, Saito H, Baron R, Morimoto N, Aoki K, Akiyoshi K, Ohya K
  • Journal Title: Eur J Pharm Sci Vol. 37 Pages: 83-88
• [Journal Article] The Pivotal role of the alternative NF-κB pathway in maintenance of basal bone homeostasis and osteoclastogenesis (2009)
  • Author(s): Soysa N, Alles N, Weih D, Lovas A, Mian H, Shimokawa H, Yasuda H, Weih F, Jimi E, Ohya K, Aoki K
  • Journal Title: J Bone Miner Res, Published on 14^<th> December
• [Journal Article] Processing of the NF-β2 Precursor, p100, to p52 is Critical for RANKL-Induced Osteoclast Differentiation (2009)
  • Author(s): Maruyama T, Fukushima H, Nakao K, Shin M, Yasuda H, Weih F, Doi T, Aoki K, Alles N, Ohya K, Hosokawa R, Jimi E
  • Journal Title: J Bone Miner Res published on 14^<th> December
• [Journal Article] Three-dimensional characterization of osteoclast bone-resorbing activity in the resorption lacunae. (2009)
  • Author(s): Soysa N, Alles N, Aoki K, Ohya K.
  • Journal Title: J Med & Dent Sci. Vol.56(2) Pages: 107-112
  • NAID: 130005420250
  • Peer Reviewed
• [Journal Article] LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model (2009)
  • Author(s): Tomomatsu N, Aoki K, Alles N, Soysa N, Hussain A, Nakachi H, Kita S, Shimokawa H, Ohya K, Amagasa T.
  • Journal Title: J Bone Miner Res. Vol.24(10) Pages: 1770-1781
  • Peer Reviewed
• [Journal Article] Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss. (2009)
  • Author(s): Alles N, Soysa N, Hussain A, Tomomatsu N, Saito H, Baron R, Morimoto N, Aoki K, Akiyoshi K, Ohya K.
  • Journal Title: Eur J Pharm Sci. Vol.37 Pages: 83-88
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Aoki K
  • Journal Title: Applications and the Future of Peptide Drugs for Inflammatory Bone Resorption(J Oral Biosci, Vol.51 (3)) Pages: 119-133
• [Journal Article] Cathepsin K-Dependent Toll-Like Receptor 9 Signaling Revealed in Experimental Arthritis (2008)
  • Author(s): Asagiri M, Hirai T, Kunigami T, Kamano S, Gober H-J, Okamoto K, Nishikawa K, Latz E, Golenbock D. T, Aoki K, Ohya K, Imai Y, Morishita Y, Miyazono K, Kato S, Saftig P, Takayanagi H
  • Journal Title: Science Vol. 319 Pages: 624-627
• [Journal Article] Lipopolysaccharide-induced bone resorption is increased in TNF type 2 receptor-deficient mice in vivo (2008)
  • Author(s): Mian MD, Saito H, Alles N, Shimokawa H, Aoki K, Ohya K
  • Journal Title: J Bone Miner Metab Vol. 26 Pages: 469-477
  • NAID: 10024459458
• [Journal Article] Inhibition of the classical NF-κB oathway prevents osteoclast bone-resorbing activity (2008)
  • Author(s): Soysa N, Alles N, Shimokawa H, Jimi E, Aoki K, Ohya K
  • Journal Title: J Bone Miner Metab Vol. 27(2) Pages: 131-139
• [Journal Article] Cathepsin K-Dependent Toll-Like Receptor 9 Signaling Revealed in Experimental Arthritis. (2008)
  • Author(s): Asagiri M, Hirai T, Kunigami T, Kamano S, Gober H-J. Okamoto K, Nishikawa K, Latz E, Golenbock D. T, Aoki K, Ohya K, Imai Y, Morishita Y, Miyazono K, Rato S, Saftig P, Takayanagi H.
  • Journal Title: Science Vol. 319 Pages: 624-627
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-induced bone resorption is increased in TNF type 2 receptor-deficient mice in vivo. (2008)
  • Author(s): Mian MD, Saito H, Alles N, Shimokawa H, Aoki K, Ohya K.
  • Journal Title: J Bone Miner Metab Vol. 26 Pages: 469-477
  • NAID: 10024459458
  • Peer Reviewed
• [Journal Article] Inhibition of the classical NF-kB pathway prevents osteoclast bone-resorbing activity (2008)
  • Author(s): Soysa N, Alles N, Shimokawa H, Jimi E, Aoki K, Ohya K.
  • Journal Title: J Bone Miner Metab 27(2) Pages: 131-139
  • Peer Reviewed
• [Journal Article] A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis (2007)
  • Author(s): Saito H, Kojima T, Takahashi M, Horne WC, Baron R, Amagasa T, Ohya K, Aoki K
  • Journal Title: Arthritis Rheum 56 Pages: 1164-1174
• [Journal Article] A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis. (2007)
  • Author(s): Saito H, Kojima T, Takahashi M, Horne WC, Baron R, Amagasa T, Ohya K, Aoki K.
  • Journal Title: Arthritis and rheumatism 56 Pages: 1164-1174
  • Peer Reviewed
• [Presentation] The control release of TNF-α is necessary to mimic the LPS-induced bone resorption on calvaria (2009)
  • Author(s): Nagano K, Aoki K, Mian H, Alles N, Akiyoshi K, Ohya K
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Lack of precursor p100 of NFκB2 causes osteopenia in mice (2009)
  • Author(s): Soysa N, Alles N, Aoki K, Ohya K
  • Organizer: The 29^<th> Japanese Society for Bone Morphometry (第29回骨形態計測学会)
  • Place of Presentation: 大阪
• [Presentation] 炎症時の抜歯後骨新生は、NBDペプチドにより亢進される-LPS投与抜歯窩骨新生モデルを用いた検討- (2009)
  • Author(s): 中地浩之, 友松伸允, 天笠光雄, 大谷啓一
  • Organizer: 第29回日本歯科薬物療法学会
  • Place of Presentation: 大阪
• [Presentation] LPS投与による抜歯後の骨新生は、TNF-α依存的に抑制される (2009)
  • Author(s): 中地浩之, 青木和広, 友松伸允, 永野健一, Neil Alles, Niroshani Soysa, 下川仁彌太, 天笠光雄, 大谷啓一
  • Organizer: 第27回日本骨代謝学会学術集会
  • Place of Presentation: 大阪
• [Presentation] TNF-α誘導の骨吸収に対するTNFR2の役割 (2009)
  • Author(s): 永野健一, 青木和広, Neil Alles, 大谷啓一
  • Organizer: 第51回歯科基礎医学会学術大会ならびに総会
  • Place of Presentation: 新潟
• [Presentation] NF-κB非古典的経路における破骨細胞分化調節機構 (2009)
  • Author(s): 福島秀文, 進正史, 丸山俊正, 青木和広, 大谷啓一, 細川隆司, 自見英治郎
  • Organizer: 第51回歯科基礎医学会学術大会ならびに総会
  • Place of Presentation: 新潟
• [Presentation] Inhibition of IKK-β blocks osteoclast formation and activity (2009)
  • Author(s): Ohya K, Soysa N, Alles N, Aoki K
  • Organizer: 1^<st> meeting of the IADR APR
  • Place of Presentation: 武漢 (中国)
• [Presentation] Lack of precursor p100 of NFκB2 causes osteopenia in mice. (2009)
  • Author(s): Soysa N, Alles N, Aoki K, Ohya K.
  • Organizer: The 29^<th> Japanese Society for Bone Morphometry(第29回骨形態計測学会)
  • Place of Presentation: 大阪
• [Presentation] LPS投与による抜歯後の骨新生は、TNF-α依存的に抑制される. (2009)
  • Author(s): 中地浩之、青木和広、友松伸允、永野健一、Neil Alles、Niroshani Soysa、下川仁彌太、天笠光雄、大谷啓一
  • Organizer: 第27回日本骨代謝学会学術集会
  • Place of Presentation: 大阪
• [Presentation] TNF-α誘導の骨吸収に対するTNFR2の役割. (2009)
  • Author(s): 永野健一、青木和広、Neil Alles、大谷啓一
  • Organizer: 第51回歯科基礎医学会学術大会ならびに総会
  • Place of Presentation: 新潟
• [Presentation] NF-kB非古典的経路における破骨細胞分化調節機構. (2009)
  • Author(s): 福島秀文、進正史、丸山俊正、青木和広、大谷啓一、細川隆司、自見英治郎
  • Organizer: 第51回歯科基礎医学会学術大会ならびに総会
  • Place of Presentation: 新潟
• [Presentation] Inhibition of IKK-β blocks osteoclast formation and activity. (2009)
  • Author(s): Ohya K, Soysa N, Alles N, Aoki K.
  • Organizer: 1^<st> meeting of the IADR APR.
  • Place of Presentation: 武漢(中国)
• [Presentation] The control release of TNF-α is necessary to mimic the LPS-induced bone resorption on calvaria. (2009)
  • Author(s): Nagano K, Aoki K, Mian H, Alles N, Shimokawa H, Morimoto N, Akiyoshi K, Ohya K.
  • Organizer: 第82回日本薬理学会年会.
  • Place of Presentation: 横浜
• [Presentation] NIK MUTATION IN ALY/ALY MICE CAUSES OSTEOPETROSIS AND REDUCE RANKL INDUCED OSTEOCLASTOGENESIS (2008)
  • Author(s): Soysa N, Alles N, Mian MD, Yasuda H, Jimi E, Shimokawa H, Aoki K, Ohya K
  • Organizer: 2^<nd> International Conference on Osteoimmunology : Interactions of the Immune and Skeletal Systems
  • Place of Presentation: Rhodes (Greece)
• [Presentation] Defective Alternative Pathway of NF-κB Causes Mild Osteopetrosis in Mice (2008)
  • Author(s): Soysa N, Alles N, Aoki K, Shimokawa H, Jimi E, Ohya K
  • Organizer: 86^<th> General Session & Exhibition of the IADR
  • Place of Presentation: Toronto
• [Presentation] LPS-induced Inhibition of Osteogenesis is TNF-α Dependent (2008)
  • Author(s): Tomomatsu N, Aoki K, Hussain MA, Alles N, Shimokawa H, Amagasa T, Ohya K
  • Organizer: 30^<th> ASBMR Annual Meeting
  • Place of Presentation: Montreal
• [Presentation] 破骨細胞機能抑制ペプチドによる臨床応用の可能性 (2008)
  • Author(s): 青木和広, Alles N, Soysa N, 自見英治郎, 下川仁彌太, 大谷啓一
  • Organizer: 第50回歯科基礎医学会学術大会・総会
  • Place of Presentation: 東京
• [Presentation] TNF-α-induced bone resorption model using CHP nanogel in mice (2008)
  • Author(s): Nagano K, Aoki K, Mian A. H, Alles N, Shimoda A, Morimoto N, Akiyoshi K, Ohya K
  • Organizer: Japanese Association for Dental Research 56^<th> Annual Meeting
  • Place of Presentation: 名古屋
• [Presentation] NIK MUTATION IN ALY/ALY MICE CAUSES OSTEOPETROSIS AND REDUCE RANKL INDUCED OSTEOCLASTOGENESIS. (2008)
  • Author(s): Soysa N, Alles N, Mian MD, Yasuda H, Jimi E, Shimokawa H, Aoki K, Ohya K.
  • Organizer: 2^<nd> International Conference on Osteoimmunology : Interactions of the Immune and Skeletal Systems
  • Place of Presentation: Rhodes (Greece)
• [Presentation] Defective Alternative Pathway of NF-κB Causes Mild Osteopetrosis in Mice. (2008)
  • Author(s): Soysa N, Alles N, Aoki K, Shimokawa H, Jimi E, Ohya K.
  • Organizer: 86^<th> General Session &Exhibition of the IADR
  • Place of Presentation: Toronto
• [Presentation] LPS-induced Inhibition of Osteogenesis is TNF-α Dependent. (2008)
  • Author(s): Totaoniatsu N, Aoki K, HussainMA, Alles N, Shimokawa H, Amagasa T, Ohya K.
  • Organizer: 30^<th> ASBMR Annual Meeting
  • Place of Presentation: Montreal
• [Presentation] TNF-α-induced bone resorption model using CHP nanogel in mice. (2008)
  • Author(s): Nagano K, Aoki K, Mian A. H, Alles N, Shimoda A, Morimoto N, Akiyoshi K, Ohya K.
  • Organizer: Japanese Association for Dental Research 56^<th> Annual Meeting
  • Place of Presentation: 名古屋
• [Presentation] 機械的非荷重による骨量減少におけるNF-κB シグナルの役割 (2007)
  • Author(s): 自見英治郎, 青木和広, 仲村一郎, 大谷啓一
  • Organizer: 第25回日本骨代謝学会学術集会25th Annual Meeting of the Japanese Society for Bone and Mineral Research
  • Place of Presentation: 大阪
• [Presentation] 骨の最新情報―骨疾患治療薬の現状と未来 (2007)
  • Author(s): 大谷啓一
  • Organizer: The 10^<th> Special Meeting of Innovational Advanced Implant Association
  • Place of Presentation: 東京
• [Presentation] 機械的非荷重による骨量減少におけるNF-κβシグナルの役割. (2007)
  • Author(s): 自見英治郎, 青木和広, 仲村一郎, 大谷啓一.
  • Organizer: 第25回日本骨代謝学会学術集会25th Annual Meeting of the Japanese Society for Bone and Mineral Research.
  • Place of Presentation: 大阪
• [Presentation] 骨の最新情報-骨疾患治療薬の現状と未来. (2007)
  • Author(s): 大谷啓一.
  • Organizer: The 10th Special Meeting of Innovational Advanced Implant Association.
  • Place of Presentation: 東京
• [Book] Applications and the Future of Peptide Drugs for Inflammatory Bone Resorption (2009)
  • Author(s): Aoki K
  • Publisher: J Oral Biosci
• [Book] ビスフォスフォネート製剤の現状 (2008)
  • Author(s): 大谷啓一
  • Publisher: DENTAL DIAMOND
• [Book] ビスフォスフォネート系薬剤との正しい付き合い方 (2008)
  • Author(s): 大谷啓一, 新井豊, 斎藤健一
  • Publisher: DENTAL DIAMOND
• [Book] ビスフォスフォネート製剤の現状 (2008)
  • Author(s): 大谷啓一
  • Publisher: DENTAL DIAMOND Vol. 33(475)
• [Book] ビスフォスフォネート系薬剤との正しい付き合い方 (2008)
  • Author(s): 大谷啓一, 新井豊, 斎藤健一
  • Publisher: DENTAL DIAMOND Vol. 33 (475)
• [Book] 腫瘍壊死因子中和療法の新しい展開―WP9QYペプチドによる治療の可能性― (2007)
  • Author(s): 青木和広, 大谷啓一
  • Publisher: 日本歯科評論 (The Nippon Dental Review)
• [Book] 腫瘍壊死因子中和療法の新しい展開-WP9QYペプチドによる治療の可能性- 日本歯科評論(The Nippon Dental Review)Vol.67(7) (2007)
  • Author(s): 青木和広, 大谷啓一.
  • Publisher: 株式会社ヒョーロンパブリッシャーズ