Analysis of cartilage formation and differentiation through regulation of chondrocyte signaling and transcription of matrix genes

• Project/Area Number: 18390415
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Osaka University
• Principal Investigator: TSUMAKI Noriyuki Osaka University, 医学系研究科, 独立准教授 (50303938)
• Co-Investigator(Kenkyū-buntansha): YOSIKAWA Hideki 大阪大学, 医学系研究科, 教授 (60191558) ; 岡本 美奈 大阪大学, 医学系研究科, 特任研究員 (50457008)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,020,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥2,220,000); Fiscal Year 2008: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2007: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2006: ¥6,400,000 (Direct Cost: ¥6,400,000)
• Keywords: 内軟骨性骨化 / 軟骨発生 / 骨形成因子 / トランスジェニックマウス / コラーゲン / 動物モデル / 関節

Research Abstract

軟骨細胞分化におけるBMPシグナルの役割を詳細に解析するために、Smad7を軟骨細胞分化の各段階で過剰発現させるconditional transgenic mouseシステムを開発し、解析した。その結果、Smad7は軟骨形成阻害し、その原因として、BMPによって活性化されるMAPK経路のSmad7による抑制が示唆された。また、軟骨コラーゲン遺伝子のエピジェネティックな転写制御のメカニズムについてはXI型コラーゲン遺伝子のプロモーター領域にインシュレーターを発見し、ゲノム上の隣接遺伝子の転写制御に関与していることを明らかにした。

Research Products

• [Journal Article] Smad7 Inhibits Chondrocyte Differentiation at Multiple Steps during Endochondral Bone Formation and Down-regulates p38 MAPK Pathways. (2008)
  • Author(s): Iwai, T., Murai, J., Yoshikawa, H., Tsumaki, N.
  • Journal Title: J Biol Chem 283 Pages: 27154-27164
  • Peer Reviewed
• [Journal Article] Insulation of the Ubiquitous Rxrb Promoter from the Cartilage-specific Adjacent Gene Col11a2. (2008)
  • Author(s): Murai, J., Ikegami, D., Okamoto, M., Yoshikawa, H., Tsumaki, N.
  • Journal Title: J Biol Chem 283 Pages: 27677-27687
  • Peer Reviewed
• [Journal Article] Characteristics of fracture and related factors in patients with rheumatoid arthritis. (2008)
  • Author(s): Nampei, A., Hashimoto, J., Koyanagi, J., Ono, T., Hashimoto, H., Tsumaki, N., Tomita, T., Sugamoto, K., Nishimoto, N., Ochi, T., Yoshikawa, H.
  • Journal Title: Mod Rheumatol 18 Pages: 170-176
  • NAID: 10024150369
  • Peer Reviewed
• [Journal Article] Smad7 Inhibits Chondrocyte Differentiation at Multiple Steps during Endochondral Bone Formation and Down-regulates p38 MAPK Pathways (2008)
  • Author(s): Iwai, T., Murai, J., Yoshikawa, H., and Tsumaki, N.
  • Journal Title: J Biol Chem 283 Pages: 27154-27164
  • Peer Reviewed
• [Journal Article] Insulation of the Ubiquitous Rxrb Promoter from the Cartilage-specific Adjacent Gene (2008)
  • Author(s): Murai, J., Ikegami, D., Okamoto, M., Yoshikawa, H., and Tsumaki, N.
  • Journal Title: Col11a2. J Biol Chem 283 Pages: 27677-27687
  • Peer Reviewed
• [Journal Article] Characteristics of fracture and related factors in patients with rheumatoid arthritis (2008)
  • Author(s): Nampei, A., Hashimoto, J., Koyanagi, J., Ono, T., Hashimoto, H., Tsumaki, N., Tomita, T., Sugamoto, K., Nishimoto, N., Ochi, T., and Yoshikawa, H.
  • Journal Title: Mod Rheumatol 18 Pages: 170-176
  • NAID: 10024150369
  • Peer Reviewed
• [Journal Article] Smad7 Inhibits Chondrocyte Differentiation at Multiple Steps during Endochondral Bone Formation and Down-regula tes p38 MAPK Pathways. (2008)
  • Author(s): Iwai, T., Murai, J., Yoshikawa, H., Tsumaki, N
  • Journal Title: J. Biol. Chem. 283 Pages: 27154-27164
  • Peer Reviewed
• [Journal Article] Insulation of the Ubiquitous Rxrb Promoter from the Cartilage-specific Adjacent Gene. (2008)
  • Author(s): Murai, J., Ikegami, D., Okamoto, M., Yoshikawa, H., Tsumaki, N.
  • Journal Title: J. Biol. Chem. 283 Pages: 27677-27687
  • Peer Reviewed
• [Journal Article] Characteristics of fracture and related factors in patients with rheumatoid arthritis. (2008)
  • Author(s): Nampei, A., Hashimoto, J., Koyanagi, J., Ono, T., Hashimoto, H., Tsumaki, N., Tomita, T., Sugamoto, K., Nishimoto, N., 0chi, T., Yoshikawa, H.
  • Journal Title: Mod. Rheumatol. 18 Pages: 170-176
  • NAID: 10024150369
  • Peer Reviewed
• [Journal Article] Low-intensity pulsed ultrasound increases bone ingrowth into porous hydroxyapatite ceramic. (2007)
  • Author(s): Iwai, T., Harada, Y., Imura, K., Iwabuchi, S., Murai, J., Hiramatsu, K., Myoui, A., Yoshikawa, H., Tsumaki, N.
  • Journal Title: J Bone Miner Metab 25 Pages: 392-399
  • NAID: 10024125465
  • Peer Reviewed
• [Journal Article] Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts. (2007)
  • Author(s): Sugiki, T., Uyama, T., Toyoda, M., Morioka, H., Kume, S., Miyado, K., Matsumoto, K., Saito, H., Tsumaki, N., Takahashi, Y., Toyama, Y., Umezawa, A.
  • Journal Title: J Cell Biochem 100 Pages: 1240-1254
  • Peer Reviewed
• [Journal Article] Low-intensity pulsed ultrasound increases bone ingrowth into porous hydroxyapatite ceramic (2007)
  • Author(s): Iwai, T., Harada, Y., Imura, K., Iwabuchi, S., Murai, J., Hiramatsu, K., Myoui, A., Yoshikawa, H., and Tsumaki, N.
  • Journal Title: J Bone Miner Metab 25 Pages: 392-399
  • NAID: 10024125465
  • Peer Reviewed
• [Journal Article] Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts (2007)
  • Author(s): Sugiki, T., Uyama, T., Toyoda, M., Morioka, H., Kume, S., Miyado, K., Matsumoto, K., Saito, H., Tsumaki, N., Takahashi, Y., Toyama, Y., and Umezawa, A.
  • Journal Title: J Cell Biochem 100 Pages: 1240-1254
  • Peer Reviewed
• [Journal Article] Low-intensity pulsed ultrasound increases bone ingrowth into porous hydroxyapatite ceramic (2007)
  • Author(s): Iwai T, Harada Y, Imura K, Iwabuchi S, Murai J, Hiramatsu K, Myoui A, Yoshikawa H, Tsumaki N
  • Journal Title: J Bone Miner Metab 25 Pages: 392-399
  • NAID: 10024125465
  • Peer Reviewed
• [Journal Article] Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. (2006)
  • Author(s): Okamoto, M., Murai, J., Yoshikawa, H., Tsumaki, N.
  • Journal Title: J Bone Miner Res 21(7) Pages: 1022-1033
  • Peer Reviewed
• [Journal Article] Oxygen tension regulates chondrocyte differentiation and function during endochondral ossification. (2006)
  • Author(s): Hirao, M., Tamai, N., Tsumaki, N., Yoshikawa, H., Myoui, A.
  • Journal Title: J Biol Chem 281(41) Pages: 31079-31092
  • Peer Reviewed
• [Journal Article] Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development (2006)
  • Author(s): Okamoto, M., Murai, J., Yoshikawa, H., and Tsumaki, N.
  • Journal Title: J Bone Miner Res 21(7) Pages: 1022-1033
  • Peer Reviewed
• [Journal Article] Oxygen tension regulates chondrocyte differentiation and function during endochondral ossification (2006)
  • Author(s): Hirao, M., Tamai, N., Tsumaki, N., Yoshikawa, H., and Myoui, A.
  • Journal Title: J Biol Chem 281(41) Pages: 31079-31092
  • Peer Reviewed
• [Journal Article] Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development (2006)
  • Author(s): Okamoto, M., Murai, J., Yoshikawa, H., Tsumaki, N
  • Journal Title: J Bone Miner Res 21, 7 Pages: 1022-1033
• [Journal Article] Oxygen tension regulates chondrocyte differentiation and function during endochondral ossification. (2006)
  • Author(s): Hirao M., Tamai, N., Tsumaki N., Yoshikawa, H., Myoui, A
  • Journal Title: J Biol Chem, 281(41) : 31079-92, 2006. 281, 41 Pages: 31079-31092
• [Journal Article] 遺伝子改変マウスを用いたBMPシグナルによる骨・軟骨形成機構の解析. (2006)
  • Author(s): 妻木範行, 吉川秀樹
  • Journal Title: Arthritis 4, 1 Pages: 4-9
• [Journal Article] 最新原著レビュー 低出カ超音波パルス照射は片側仮骨延長法を用いた高位脛骨骨切り術における延長仮骨治癒を促進する. (2006)
  • Author(s): 妻木範行
  • Journal Title: 整形外科 57 Pages: 1531-1535
• [Journal Article] 軟骨・骨形成における骨形成因子(BMP)シグナルの役割. (2006)
  • Author(s): 妻木範行
  • Journal Title: Clinical Calcium 16, 4 Pages: 138-142
• [Journal Article] Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts.
  • Author(s): Sugiki, T., Uyama, T., Toyoda, M., Morioka, H., Kume, S., Miyado, K., Matsumoto, K., Saito, H., Tsumaki, N., Takahashi, Y., Toyama, Y., Umezawa, A
  • Journal Title: J Cell Biochem (in press)
• [Presentation] Smad7 inhibits chondrocyte differentiation at multiple steps during endochondral bone formation. (2008)
  • Author(s): T. Iwai, J. Murai, K. Hiramatsu, D. Ikegami, M. Okamoto, H. Yoshikawa, N. Tsumaki
  • Organizer: 7^<th> Ihternational Conference on Bone Morphogenetic Proteins
  • Place of Presentation: Lake Tahoe, CA, USA
• [Presentation] Expression of dominant negative TGFβ receptors resulted information of hypoplastic cartilage in conditional transgenic mice (2008)
  • Author(s): K. Hiramatsu, T. Iwai, D, Ikegami, H. Yoshikawa, N. Tsumaki
  • Organizer: 7^<th> International Conference on Bone Morphogenetic Proteins
  • Place of Presentation: Lake Tahoe, CA. USA
• [Presentation] Col11a2/Rxrbローカスにおける軟骨特異的転写の制御 (2007)
  • Author(s): 村井純子、岡本美奈、吉川秀樹、妻木範行
  • Organizer: 第1回骨・軟骨フロンティア
  • Place of Presentation: 東京
  • Year and Date: 2007-12-01
• [Presentation] 内軟骨性骨化におけるBMPシグナルの作用 (2007)
  • Author(s): 妻木範行
  • Organizer: 第14回BMP研究会
  • Place of Presentation: 大阪
  • Year and Date: 2007-07-22
• [Presentation] Role of Smad7 during endochondral bone formation. (2007)
  • Author(s): T. Iwai, J. Murai, H. Yoshikawa, N. Tsumaki
  • Organizer: Gordon Research Conference
  • Place of Presentation: Cartilage Biology & Pathology, Ventura, CA USA
• [Presentation] Role of Smad7 during endochondral bone formation (2007)
  • Author(s): T. Iwai, J. Murai, H. Yoshikawa, N. Tsumaki
  • Organizer: Gordon Research Conference, Cartilage Biology &amp; Pathology, Ventura
  • Place of Presentation: CA USA
• [Presentation] Function of the CTCF-bindig site between the Rxrb and the Col11a2 Genes (2007)
  • Author(s): J. Murai, M, Okamoto, H. Yoshikawa, N. Tsumaki
  • Organizer: 29th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Honolulu, Hawaii, USA
• [Presentation] In vivoでのRxrb/Col11a2 locusにおけるCTCF結合領域の機能解析 (2007)
  • Author(s): 村井純子、岡本美奈、吉川秀樹、妻木範行
  • Organizer: 第25回日本骨代謝学会
  • Place of Presentation: 大阪
• [Book] 最新整形外科学体系1運動器の生物学と生体力学(越智隆弘総編中村利孝、吉川秀樹編)骨形成 (2008)
  • Author(s): 越智隆弘, 中村利孝、吉川秀樹
  • Publisher: 中山書店
• [Book] 最新整形外科学体系 1 運動器の生物学と生体力学(越智隆弘, 中村利孝, 吉川秀樹, 骨形成) (2008)
  • Publisher: 中山書店
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/dbcb/homepage/index.html