Optimization of the bone regeneration system using small molecules and examination of its molecular mechanisms

• Project/Area Number: 23390460
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: The University of Tokyo
• Principal Investigator: TSUYOSHI Takato 東京大学, 医学部附属病院, 教授 (90171454)
• Co-Investigator(Kenkyū-buntansha): SAIJO Hideto 東京大学, 医学部附属病院, 講師 (80372390) ; OGASAWARA Toru 東京大学, 医学部附属病院, 講師 (20359623) ; MORI Yoshiyuki 東京大学, 医学部附属病院, 准教授 (70251296) ; TEI Yuichi 東京大学, 工学系研究科, 教授 (30345053)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2011: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 骨再生 / 低分子化合物

Research Abstract

This study is aimed to obtain basic knowledge on the bone regenerative therapy in which the shape and amount of regenerated bones are controlled by osteogenic small molecules. Optimization of osteogenic small molecule-based bone formation revealed that several small molecules efficiently induced osteoblast differentiation. Mechanistic studies proposed that their modes of action were the cell fate specification into an osteoblast lineage and the subsequent osteoblast maturation. Local administration of the molecules into bone defect models achieved bone regeneration in animals. Thus, these findings will lead to the development of small molecule-based bone regenerative therapies.

Research Products

• [Journal Article] Implantation of tetrapod-shaped granular artificial bones or β-tricalcium phosphate granules in a canine large bone-defect model (2014)
  • Author(s): Choi S, Liu I, Yamamoto K, Honnami M, Sakai T, Ohba S, Echigo R, Suzuki S, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: J Vet Med Sci Volume: 76(2) Pages: 229-235
  • Peer Reviewed
• [Journal Article] Cranioplasty with custom-made artificial bone after resection of multilobular bone tumor in a dog (2014)
  • Author(s): Choi S, Honnami M, Liu I, Yamamoto K, Ohba S, Echigo R, Suzuki S, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: J Vet Clin Volume: 31(1) Pages: 46-50
  • Peer Reviewed
• [Journal Article] Bone Regeneration by the Combined Use of Tetrapod-Shaped Calcium Phosphate Granules with Basic Fibroblast Growth Factor-Binding Ion Complex Gel in Canine Segmental Radial Defects (2014)
  • Author(s): Honnami M, Choi S, Liu IL, Kamimura W, Taguchi T, Hojo H, Shimohata N, Ohba S, Koyama H, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: Journal of Veterinary Medical Science Volume: 76 Issue: 7 Pages: 955-961
  • DOI: 10.1292/jvms.14-0027
  • NAID: 130003391309
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed
• [Journal Article] Implantation of Tetrapod-Shaped Granular Artificial Bones or β-Tricalcium Phosphate Granules in a Canine Large Bone-Defect Model (2014)
  • Author(s): Choi S, Liu I, Yamamoto K, Honnami M, Sakai T, Ohba S, Echigo R, Suzuki S, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: Journal of Veterinary Medical Science Volume: 76 Issue: 2 Pages: 229-235
  • DOI: 10.1292/jvms.13-0054
  • NAID: 130003382365
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed
• [Journal Article] Cranioplasty with custom-made artificial bone after resection of multilobular bone tumor in a dog. (2014)
  • Author(s): Choi S, Honnami M, Liu I, Yamamoto K, Ohba S, Echigo R, Suzuki S, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: J Vet Clin Volume: 31 Pages: 46-50
  • Peer Reviewed
• [Journal Article] Repair of rabbit segmental femoral defects by using a combination of tetrapod-shaped granular artificial bones and basic fibroblast growth factor-binding ion complex gel (2013)
  • Author(s): Honnami M, Choi S, Liu I, Kamimura W, Taguchi T, Hojo H, Shimohata N, Ohba S, Koyama H, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: Biomaterials Volume: 34(36) Pages: 9056-9062
  • Peer Reviewed
• [Journal Article] Bone healing by sterilizable calcium phosphate tetrapods eluting osteogenic molecules (2013)
  • Author(s): Maeda Y, Hojo H, Shimohata N, Choi S, Yamamoto K, Takato T, Chung UI, Ohba S
  • Journal Title: Biomaterials Volume: 34(22) Pages: 5530-5537
  • Peer Reviewed
• [Journal Article] Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium (2013)
  • Author(s): Hojo H, Ohba S, Taniguchi K, Shirai M, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Mishina Y, Yamada M, Konno T, Takato T, Kawaguchi H, Kambara H, Chung UI
  • Journal Title: J Biol Chem Volume: 288(14) Pages: 9924-9932
  • Peer Reviewed
• [Journal Article] Bone healing by sterilizable calcium phosphate tetrapods eluting osteoge nic molecules. (2013)
  • Author(s): Maeda Y, Hojo H, et al.
  • Journal Title: Biomaterials Volume: 34 Issue: 22 Pages: 5530-5537
  • DOI: 10.1016/j.biomaterials.2013.03.089
  • Peer Reviewed
• [Journal Article] Hedgehog-Gli activators direct osteo-chondrogenic function of bone morp hogenetic protein toward osteogenesis in the perichondrium. (2013)
  • Author(s): Hojo H, et al.
  • Journal Title: J Biol Chem Volume: 288 Issue: 14 Pages: 9924-9932
  • DOI: 10.1074/jbc.m112.409342
  • Peer Reviewed
• [Journal Article] Repair of rabbit segmental femoral defects by using a combination of tetrapod-shaped granular artificial bones and basic fibroblast growth factor-binding ion complex gel. (2013)
  • Author(s): Honnami M, Choi S, Liu I, Kamimura W, Taguchi T, Hojo H, Shimohata N, Ohba S, Koyama H, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: Biomaterials Volume: 34 Issue: 36 Pages: 9056-9062
  • DOI: 10.1016/j.biomaterials.2013.08.014
  • Peer Reviewed
• [Journal Article] Nanog promotes osteogenic differentiation of the mouse mesenchymal cell line C3H10T1/2 by modulating bone morphogenetic protein(BMP) signaling. (2013)
  • Author(s): Ogasawara T, Ohba S, Yano F, Kawaguchi H, Chung UI, Saito T, Yonehara Y, Nakatsuka T, Mori Y, Takato T, and Hoshi K
  • Journal Title: J Cell Physiol Volume: (in press) Issue: 1 Pages: 163-71
  • DOI: 10.1002/jcp.24116
  • Peer Reviewed
• [Journal Article] Gli1 protein participates in the hedgehog-mediated specification of the osteoblast lineage during endochondral ossification (2012)
  • Author(s): Hojo H, Ohba S, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Takato T, Kawaguchi H, Chung UI
  • Journal Title: J Biol Chem Volume: 287(21) Pages: 17860-69
  • Peer Reviewed
• [Journal Article] Bioactive factors for tissue regeneration : State of Art (2012)
  • Author(s): Ohba S, Hojo H, Chung UI
  • Journal Title: Muscles Ligaments Tendons J Volume: 2(3) Pages: 193-203
  • Peer Reviewed
• [Journal Article] Current progress on tissue engineering of bone and cartilage (2012)
  • Author(s): Ohba S, Hojo H, Chung UI
  • Journal Title: Endocrinol Metab Volume: 27(1) Pages: 1-11
  • Peer Reviewed
• [Journal Article] Gli1 protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral ossification (2012)
  • Author(s): Hojo H, 他
  • Journal Title: J Biol Chem Volume: 287 Issue: 21 Pages: 17860-17869
  • DOI: 10.1074/jbc.m112.347716
  • Peer Reviewed
• [Journal Article] Application of floating cells for improved harvest in human chondrocyte culture (2012)
  • Author(s): Kazumichi Yonenaga
  • Journal Title: Biomedical Research Volume: 33 Issue: 5 Pages: 281-289
  • DOI: 10.2220/biomedres.33.281
  • NAID: 130004903831
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed
• [Journal Article] BMP-2-embedded atelocollagen scaffold for tissue-engineered cartilage cultured in the medium containing insulin and Triiodothyronine-A new protocol for 3D in vitro culture of human chondrocytes (2012)
  • Author(s): Ko EC, et al.
  • Journal Title: Tissue Eng Part C Methods Volume: (掲載確定)(in press) Issue: 5 Pages: 374-86
  • DOI: 10.1089/ten.tec.2011.0217
  • Peer Reviewed
• [Journal Article] Evaluation of the implant type tissue-engineered cartilage by scanning acoustic microscopy (2012)
  • Author(s): Tanaka Y, et al.
  • Journal Title: J Biosci Bioeng Volume: (掲載確定)(in press) Issue: 2 Pages: 252-7
  • DOI: 10.1016/j.jbiosc.2011.10.011
  • Peer Reviewed
• [Journal Article] A novel method for designing and fabricating custom-made artificial bones (2011)
  • Author(s): Saijo H, Kanno Y, Mori Y, Suzuki S, Ohkubo K, Chikazu D, Yonehara Y, Chung UI, Takato T
  • Journal Title: Int J Oral Maxillofac Surg Volume: 40(9) Pages: 955-60
  • Peer Reviewed
• [Journal Article] Administration of the insulin into the scaffold atelocollagen for tissue-engineered cartilage (2011)
  • Author(s): Ko EC, Fujihara Y, Ogasawara T, Asawa Y, Nishizawa S, Nagata S, Takato T, Hoshi K
  • Journal Title: J Biomed Mater Res A Volume: 97(2) Issue: 2 Pages: 186-92
  • DOI: 10.1002/jbm.a.33046
  • Peer Reviewed
• [Journal Article] Tissue responses against tissue-engineered cartilage consisting of chondrocytes encapsulated within nonabsorbable hydrogel (2011)
  • Author(s): Kanazawa S, et al.
  • Journal Title: J Tissue Eng Regen Med Volume: 97(2) Issue: 1 Pages: 186-92
  • DOI: 10.1002/term.458
  • Peer Reviewed
• [Journal Article] PTHrP action on skeletal development : a key for the controlled growth of endochondral bones
  • Author(s): Ohba S, Chung UI
  • Journal Title: Clinc Rev Bone Miner Metab Volume: (in press)
  • Peer Reviewed
• [Journal Article] Bone regeneration by the combined use of tetrapod-shaped calcium phosphate granules with basic fibroblast growth factor-binding ion complex gel in canine segmental radial defects
  • Author(s): Honnami M, Choi S, Liu IL, KamimuraW, Taguchi T, Hojo H, Shimohata N, Ohba S, Koyama H, Nishimura R, Chung UI, Sasaki N, Mochizuki M
  • Journal Title: J Vet Med Sci Volume: (in press)
  • Peer Reviewed
• [Presentation] Bone healing by the combination of SAG and TH-loaded artificial bones (2013)
  • Author(s): Maeda Y, Ohba S, Hojo H, Shimohata N, Yano F, Yamamoto K, Takato T, Chung UI
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society and The Japanese Society for Bone and Mineral Research
  • Place of Presentation: Kobe, Japan (Travel Award)
• [Presentation] in situ Tissue Engineering 型カスタムメイド人工骨の骨癒合状態のCT による評価 (2013)
  • Author(s): 菅野勇樹, 西條英人 , 鄭雄一, 森良之, 高戸毅
  • Organizer: 第58回日本口腔外科学会総会・学術大会
  • Place of Presentation: 福岡
• [Presentation] ラット歯周炎モデルの確立と骨形成性低分子化合物による歯槽骨再生療法の検討 (2013)
  • Author(s): 波田野典子, 大庭伸介, 鄭雄一, 高戸毅
  • Organizer: 第67回日本口腔科学会総会
  • Place of Presentation: 栃木
• [Presentation] 低分子化合物による歯槽骨再生療法の検討とラット歯周炎モデルの確立 (2013)
  • Author(s): 波田野典子, 大庭伸介, 鄭雄一, 高戸毅
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 神奈川
• [Presentation] ヘッジホッグシグナル活性化剤とヘリオキサンチン誘導体を搭載した骨形成性薬剤徐放型人工骨の開発 (2013)
  • Author(s): 前田祐二郎, 大庭伸介, 北條宏徳, 高戸毅, 鄭雄一
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 神奈川
• [Presentation] Bone healing by the combination of SAG- and TH-loaded artificial bones. (2013)
  • Author(s): Maeda Y, Ohba S, Hojo H, Shimohata N, Yano F, Yamamoto K, Takato T, Chung UI
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society and The Japanese Society for Bone and Mineral Research
  • Place of Presentation: 神戸（神戸コンベンションセンター・神戸ポートピアホテル）
• [Presentation] Runx1 and Runx3 are downstream effectors of Nanog in the promoted osteogenic differentiation of mesenchymal cells. (2013)
  • Author(s): Ogasawara T, Saito T, Ohba S, Abe T, Yonehara Y, Takato T
  • Organizer: 35th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Baltimore, MD, USA
• [Presentation] Postoperative evaluation of custom-made artificial bones fabricated by inkjet printers using computed tomography (2013)
  • Author(s): Kanno Y, Saijo H, Mori Y, Chung UI, Takato T
  • Organizer: Frontiers 2013 EPFL Symposium
  • Place of Presentation: Lausanne, Switzerland
• [Presentation] ラット歯周炎モデルの確立と骨形成性低分子化合物による歯槽骨再生療法の検討 (2013)
  • Author(s): 波田野典子, 大庭伸介, 鄭雄一, 高戸毅
  • Organizer: 第67回日本口腔科学会総会
  • Place of Presentation: 宇都宮（栃木県総合文化センター ）
• [Presentation] in situ Tissue Engineering型カスタムメイド人工骨の骨癒合状態のCTによる評価 (2013)
  • Author(s): 菅野勇樹, 西條英人, 鄭雄一, 森良之, 高戸毅
  • Organizer: 第58回日本口腔外科学会総会・学術大会
  • Place of Presentation: 福岡（福岡国際会議場）
• [Presentation] 今後の臨床展開が期待される骨軟骨再生医療（会長講演） (2013)
  • Author(s): 高戸毅
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
• [Presentation] Application of Bone and Cartilage Regenerative Medicine in Oral and Maxillofacial Areas (2012)
  • Author(s): Takato T
  • Organizer: ACOMS 2012
  • Place of Presentation: Kuta, Bali-Indonesia
• [Presentation] Gli1 Participates in the Indian Hedgehog-mediated Osteogenesis during Endochondral Ossification (2012)
  • Author(s): Hojo H, Ohba S, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata H, Suzuki K, Takato T, Kawaguchi H, Chung UI
  • Organizer: 34th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Minneapolis, MN, USA (Travel Award)
• [Presentation] Development of a Novel Tetrapod-shaped Drug-eluting Artificial Bone (2012)
  • Author(s): Maeda Y, Ohba S, Hojo H, Shimohata N, Yano F, Yamamoto K, Hatano N, Takato T, Chung UI
  • Organizer: 34th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Minneapolis, MN, USA
• [Presentation] Osteo-chondrogenic Function of BMP is Directed Toward Osteogenesis by Hh-Gli1 in the Perichondrium (2012)
  • Author(s): Hojo H, Ohba S, Taniguchi K, Shirai M, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Mishina Y, Yamada M, Konno T, Takato T, Kawaguchi H, Kambara H, Chung UI
  • Organizer: 34th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Minneapolis, MN, USA
• [Presentation] The Present and Future of Bone and Cartilage Regenerative Medicine in the Oral and Maxillofacial Area (2012)
  • Author(s): Takato T
  • Organizer: XXI Congress of the European Association for Cranio-Maxillo- Facial Surgery
  • Place of Presentation: Dubrovnik, Croatia
• [Presentation] Application of bone and cartilage regenerative medicine in oral and maxillofacial areas. (2012)
  • Author(s): Tsuyoshi Takato
  • Organizer: The 4th Congress of the World Union of Wound Healing Societies 2012
  • Place of Presentation: 横浜
  • Invited
• [Presentation] The Present and Future of Bone and Cartilage Regenerative Medicine in the Oral and Maxillofacial Area. (2012)
  • Author(s): Tsuyoshi Takato
  • Organizer: XXI Congress of the European Association for Cranio-Maxillo- Facial Surgery
  • Place of Presentation: Dubrovnik, Croatia
  • Invited
• [Presentation] Application of Bone and Cartilage Regenerative Medicine in Oral and Maxillofacial Areas. (2012)
  • Author(s): Tsuyoshi Takato
  • Organizer: The American College of Oral and Maxillofacial Surgeons 2012
  • Place of Presentation: Kuta, Bali-Indonesia
  • Invited
• [Presentation] Development of a Novel Tetrapod-shaped Drug-eluting Artificial Bone. (2012)
  • Author(s): Yujiro Maeda
  • Organizer: 34th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Minneapolis, MN, USA
• [Presentation] Orthognathic surgery of hemifacial microsomia (2011)
  • Author(s): Tsuyoshi Takato
  • Organizer: Second Seoul symposium on hemifacial microsomia KSPRS Precongress Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-11-10
• [Presentation] 骨軟骨再生医療の現状と展望 (2011)
  • Author(s): 高戸毅
  • Organizer: 第70回日本矯正歯科学会大会&第4回国際会議 日本学術会議歯学委員会シンポジウム
  • Place of Presentation: 名古屋
• [Presentation] 遺伝学的手法と組み合わせたクロマチン免疫沈降-シーケンス法の骨軟骨生物学への応用 (2011)
  • Author(s): 大庭伸介, 鄭雄一, Andrew P. McMahon
  • Organizer: 第24回日本動物細胞工学会
  • Place of Presentation: 東京
• [Book] 軟骨細胞を使った顎・顔面の軟骨再生, 再生医療叢書(日本再生医療学会監修)-6 骨格系(脇谷滋之, 鄭雄一編) (2012)
  • Author(s): 星和人, 高戸毅
  • Publisher: 朝倉書店, 東京
• [Book] 多能性幹細胞を使った骨再生, 再生医療叢書(日本再生医療学会監修)-6 骨格系(脇谷滋之, 鄭雄一編) (2012)
  • Author(s): 大庭伸介, 鄭雄一
  • Publisher: 朝倉書店, 東京
• [Book] 「１５章消化器疾患 ５口腔疾患」内科学（門脇孝･永井良三編） (2012)
  • Author(s): 森良之
  • Total Pages: 1929
  • Publisher: 西村書店
• [Remarks] 東京大学医学部附属病院顎口腔外科・歯科矯正歯科ホームページ
  • URL: http://plaza.umin.ac.jp/~oralsurg/
• [Remarks] 東京大学医学部附属病院 顎口腔外科・歯科矯正歯科
  • URL: http://plaza.umin.ac.jp/~oralsurg/
• [Remarks] 東京大学医学部附属病院 ティッシュ・エンジニアリング部
  • URL: http://square.umin.ac.jp/t-e/
• [Remarks]
  • URL: http://plaza.umin.ac.jp/~oralsurg/