Molecular mechanisms of regulation in bone and cartilage metabolism by GSK3β

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591775
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: CHIKUDA Hirotaka The University of Tokyo, 医学部附属病院, 助教 (30345219)
• Co-Investigator(Kenkyū-buntansha): KAWAGUCHI Hiroshi 東京大学, 医学部附属病院, 准教授 (40282660) ; TAKEDA Hideki 東京大学, 医学部附属病院, 助教 (90456111)
• Project Period (FY): 2008 – 2010
• Keywords: GSK3β / Runx2 / 骨代謝 / 関節炎

Research Abstract

GSK3β is known to be involved in insulin/IGF signal and canonical Wnt signal, which play important roles in various kinds of biological processes. This study investigated the molecular mechanisms of regulation in bone and metabolism by GSK-3β. We performed the analyses of skeletal phenotype in GSK3β deficient mice under physiological or pathological conditions and functional analyses using mouse primary osteoblasts, chondrocytes, and various cell-lines. We elucidated the molecular network around GSK3β in osteoblast or chondrocyte differentiation.

Research Products

• [Journal Article] Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions. (2010)
  • Author(s): Fukai A, Kawamura N, Saito T, Oshima Y, Ikeda T, Kugimiya F, Higashikawa H, Yano F, Ogata N, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum 62 Pages: 826-836
  • Peer Reviewed
• [Journal Article] Mechanisms underlying catabolic and anabolic functions of parathyroid hormone on bone by combination of culture systems of mouse cells. (2010)
  • Author(s): Shinoda Y, Kawaguchi H, Higashikawa A, Hirata M, Miura T, Saito T, Nakamura K, Chung UI, Ogata N
  • Journal Title: J Cell Biochem 109 Pages: 755-763
  • Peer Reviewed
• [Journal Article] Runx1 and Runx2 cooperate during sternum morphogenesis. (2010)
  • Author(s): Kimura A, Inose H, Yano F, Fujita K, Ikeda T, Sato S, Iwasaki M, Jinno T, Ae K, Fukumoto S, Takeuchi Y, Itoh H, Imamura T, Kawaguchi H, Chung UI, Martin JF, Iseki S, Shinomiya K, Takeda S
  • Journal Title: Development 137 Pages: 1159-1167
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. (2010)
  • Author(s): Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, Nishida N, Akune T, Yoshimura N, Nakagawa T, Nakamura K, Tokunaga K, Chung UI, Kawaguchi H
  • Journal Title: Nat Med 16 Pages: 678-686
  • Peer Reviewed
• [Journal Article] Title : Identification of oxytetracycline as a chondrogenic compound using a cell-based screening system. (2010)
  • Author(s): Hojo H, Yano F, Ohba S, Igawa K, Nakajima K, Komiyama Y, Kan A, Ikeda T, Yonezawa T, Woo JT, Takato T, Nakamura K, Kawaguchi H, Chung UI
  • Journal Title: J Bone Miner Metab 28 Pages: 627-633
  • Peer Reviewed
• [Journal Article] A local application of recombinant human fibroblast growth factor-2 for tibial shaft fractures: a randomized, placebo-controlled trial. (2010)
  • Author(s): Kawaguchi H, Oka H, Jingushi S, Izumi T, Fukunaga M, Sato K, Matsushita T, Nakamura K
  • Journal Title: J Bone Miner Res 25 Pages: 2459-2467
  • Peer Reviewed
• [Journal Article] Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type x collagen gene. (2009)
  • Author(s): Higashikawa A, Saito T, Ikeda T, Kamekura S, Kawamura N, Kan A, Oshima Y, Ohba S, Ogata N, Takeshita K, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum 60 Pages: 166-178
  • Peer Reviewed
• [Journal Article] C/EBPβ promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57^<Kip2>. (2009)
  • Author(s): Hirata M, Kugimiya F, Fukai A, Ohba S, Kawamura N, Ogasawara T, Kawasaki Y, Saito T, Yano F, Ikeda T, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: PLoS ONE 4 Pages: e4543
  • Peer Reviewed
• [Journal Article] Transcriptional induction of SOX9 by NF-κB family member RelA in chondrogenic cells. (2009)
  • Author(s): Ushita M, Saito T, Ikeda T, Yano F, Higashikawa A, Ogata N, Chung UI, Nakamura K, Kawaguchi H
  • Journal Title: Osteoarthritis Cartilage 17 Pages: 1065-1075
  • Peer Reviewed
• [Journal Article] Screening of chondrogenic factors by a real-time fluorescence monitoring cell line ATDC5-C2ER : Identification of sorting nexin 19 as a novel factor. (2009)
  • Author(s): Kan A, Ikeda T, Saito T, Yano F, Fukai A, Ogata N, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum 60 Pages: 3314-3323
  • Peer Reviewed
• [Journal Article] Association of microsomal prostaglandin E synthase 1 deficiency with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders. (2008)
  • Author(s): Yamakawa K, Kamekura S, Kawamura N, Saegusa M, Kamei D, Murakami M, Kudo I, Uematsu S, Akira S, Chung UI, Nakamura K, Kawaguchi H
  • Journal Title: Arthritis Rheum 58 Pages: 172-183
  • Peer Reviewed
• [Journal Article] Analysis of the Runx2 promoter in osseous and non-osseous cells and identification of HIF2A as a potent transcriptional activator. (2008)
  • Author(s): Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK, Kawaguchi H, Ohba S, Chung UI, Choi JY
  • Journal Title: Gene 416 Pages: 53-60
  • Peer Reviewed
• [Journal Article] Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. (2008)
  • Author(s): Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T, Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima T, Kuramochi A, Miyashita T, Oda H, Nakamura K, Takato T, Chung UI
  • Journal Title: Dev Cell 14 Pages: 689-699
  • Peer Reviewed
• [Journal Article] Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes. (2008)
  • Author(s): Kawasaki Y, Kugimiya F, Chikuda H, Kamekura S, Ikeda T, Kawamura N, Saito T, Shinoda Y, Higashikawa A, Yano F, Ogasawara T, Ogata N, Hoshi K, Hofmann F, Woodgett JR, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: J Clin Invest 118 Pages: 2506-2515
  • Peer Reviewed
• [Journal Article] The Distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: Findings in murine models and in human disease. (2008)
  • Author(s): Sato S, Kimura A, Ozdemir J, Asou Y, Miyazaki M, Jinno T, Ae K, Liu X, Osaki M, Takeuchi Y, Fukumoto S, Kawaguchi H, Haro H, Shinomiya K, Karsenty G, Takeda S
  • Journal Title: Arthritis Rheum 58 Pages: 2764-2775
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9. (2008)
  • Author(s): Shinoda Y, Ogata N, Higashikawa A, Manabe I, Shindo T, Yamada T, Kugimiya F, Ikeda T, Kawamura N, Kawasaki Y, Tsushima K, Takeda N, Nagai R, Hoshi K, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem 283 Pages: 24682-24689
  • Peer Reviewed
• [Presentation] 変形性関節症up-to-date-その診断、治療、そして分子メカニズム研究の最前線 (2010)
  • Author(s): 川口浩
  • Organizer: 第25回日本整形外科学会基礎学術集会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20101014-20101015
• [Presentation] Endochondral ossification signal : A potential therapeutic target for osteoarthritis. (2010)
  • Author(s): 川口浩
  • Organizer: 2010 World Congress on Osteoarthritis (OARSI).
  • Place of Presentation: Brussels, Belgium.
  • Year and Date: 20100923-20100926
• [Presentation] 骨粗鬆症の治療戦略 up-to-date:骨折予防・骨強度の視点から (2010)
  • Author(s): 川口浩
  • Organizer: 第83回日本整形外科学会学術総会
  • Place of Presentation: 東京国際フォーラム、東京
  • Year and Date: 20100527-20100530
• [Presentation] Molecular backgrounds of cartilage degradation during osteoarthritis development. (2010)
  • Author(s): 川口浩
  • Organizer: 第19回国際リウマチシンポジウム
  • Place of Presentation: 神戸ポートピアホテル、兵庫
  • Year and Date: 20100422-20100425
• [Presentation] cGMP-dependent kinase II (cGKII)はGSK3βをリン酸化・不活化することによって軟骨細胞の肥大分化を制御する (2010)
  • Author(s): 川崎洋介、釘宮典孝、筑田博隆、池田敏之、斎藤琢、矢野文子、中村耕三、鄭雄一、川口浩
  • Organizer: 第23回日本軟骨代謝学会
  • Place of Presentation: 鹿児島県医師会館、鹿児島
  • Year and Date: 20100402-20100403
• [Presentation] Molecular backgrounds of cartilage degradation during osteoarthritis progression. (2010)
  • Author(s): 川口浩
  • Organizer: 2010 Anti-aging and Well-being International Symposium.
  • Place of Presentation: Daegu, Korea.
  • Year and Date: 2010-02-19
• [Presentation] Therapeutic target molecules for cartilage degradation in osteoarthritis progression. (2010)
  • Author(s): 川口浩
  • Organizer: System Biology and Drug Discovery.
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2010-02-09
• [Presentation] 変形性関節症の治療標的分子へのアプローチ (2009)
  • Author(s): 川口浩
  • Organizer: 第82回日本生化学(シンポジウム「運動器形成・再生のための分子基盤」)
  • Place of Presentation: 神戸国際会議場、兵庫
  • Year and Date: 20091021-20091024
• [Presentation] Cyclic GMP-dependent protein kinase II promotes chondrocyte hypertrophy and skeletal growth. (2009)
  • Author(s): Kawaguchi H, Chikuda H, Kawasaki Y, Hofmann F
  • Organizer: 4th International Conference on cGMP.
  • Place of Presentation: Rosensburg, Germany.
  • Year and Date: 20090619-20090621
• [Presentation] cGKIIはGSK3βをリン酸化することによって軟骨細胞の肥大分化を制御する (2009)
  • Author(s): 川崎洋介、釘宮典孝、筑田博隆、中村耕三、鄭雄一、川口浩
  • Organizer: 第82回日本整形外科学会学術総会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 20090514-20090517
• [Presentation] 変形性関節症の診断と治療:最近の進歩(カトレア教育研修講演:Arthritis診断と治療 最新のトピックス) (2009)
  • Author(s): 川口浩
  • Organizer: 第81回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪、東京
  • Year and Date: 20090423-20090426
• [Presentation] Cartilage degeneration during osteoarthritis progression. (2009)
  • Author(s): 川口浩
  • Organizer: 第18回国際リウマチシンポジウム
  • Place of Presentation: グランドプリンスホテル新高輪、東京
  • Year and Date: 20090423-20090426
• [Presentation] Molecular backgrounds of cartilage degeneration during osteoarthritis progression (Special Lecture: OARSI-KORS Co-sponsored Symposium). (2009)
  • Author(s): 川口浩
  • Organizer: The 35th Annual Meeting of the Korean Orthopaedic Research Society.
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2009-10-14
• [Presentation] Transcriptional regulation of cartilage degeneration during osteoarthritis progression. (2009)
  • Author(s): 川口浩
  • Organizer: The 2nd International Cartilage and Osteoarthritis Symposium.
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2009-10-10
• [Presentation] Transcriptional regulation of osteoarthritis progression (Symposium: Update on Osteoarthritis : from Bench to Bedside -APLAR-OARSI Co-Sponsored Symposium). (2008)
  • Author(s): 川口浩
  • Organizer: The 13th Congress of the Asia Pacific League of Associations for Rheumatology (APLAR 2008).
  • Place of Presentation: Yokohama, Japan.
  • Year and Date: 20080923-20080927
• [Presentation] 変形性関節症の疫学研究の現状と問題点:ROAD (Research on Osteoarthritis against Disabilit)プロジェクト(シンポジウム:変形性膝関節症のマネージメント-最新の臨床エビデンスとエキスパートオピニオン-) (2008)
  • Author(s): 川口浩、岡敬之、村木重之、阿久根徹、馬淵昭彦、吉村典子、中村耕三
  • Organizer: 第81回日本整形外科学会学術総会
  • Place of Presentation: 北海道厚生年金会館、北海道
  • Year and Date: 20080522-20080525
• [Book] 関節・軟骨疾患の分子医学:変形性関節症の治療標的分子の探索(BIO CLINICA)((特集:骨・軟骨疾患の分子医学) 25(1)) (2010)
  • Author(s): 川口浩
  • Total Pages: 41-45
• [Book] 変形性関節症における軟骨破壊のメカニズム(Osteovisual)(Arthritis 16(3)) (2009)
  • Author(s): 川口浩
  • Total Pages: 149-153
• [Book] 遺伝子変異マウスによる変形性関節症の病態解明へのアプローチ(The Bone)((特集:変形性関節症の基礎と臨床) 23(1)) (2009)
  • Author(s): 川口浩
  • Total Pages: 35-40
• [Book] 変形性関節症:研究・診療の現状と問題点(日本老年病学会雑誌)((骨粗鬆症と変形性関節症:研究と診療の最前線) 46(2)) (2009)
  • Author(s): 川口浩
  • Total Pages: 121-127
• [Book] 変形性関節症の治療標的分子の解明(骨のremodelingにおけるDickkopf-1の役割)(リウマチ科(特集:変形性関節症の病態と治療 -最近の進歩) 39(6)) (2008)
  • Author(s): 川口浩
  • Total Pages: 498-505
• [Book] インスリン・IGFと骨(CLINICAL CALCIUM)(特集:ホルモンと骨粗鬆症 UPDATE)19 (7): 1015-1025, 2009.
  • Author(s): 川口浩