Research of HIF function in pathophysiology and therapeutics of osteoarthritis

• Project/Area Number: 23689065
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: SAITO Taku 東京大学, 医学部附属病院, 特任准教授 (30456107)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000); Fiscal Year 2013: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2012: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000); Fiscal Year 2011: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: 変形性関節症 / 軟骨代謝学 / 軟骨細胞 / 再生医療

Research Abstract

In Hif2a+/- mice, osteoarthritis was markedly inhibited. In Col2a1-CreERT2;Hif2a-f/f mice, similar results were obtained. In contrast, articular cartilage degradation was accelerated in Col2a1-CreERT2;Hif1a-f/f mice, indicating opposite functions of HIF1A and HIF2A in articular cartilage. Further analyses revealed that HIF1A suppressed expression of catabolic factors.

Research Products

• [Journal Article] Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling (2014)
  • Author(s): Mori Y, Saito T, Chang SH, Kobayashi H, Ladel CH, Guehring H, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 289 Pages: 10192-200
• [Journal Article] Positive feedback between NF-κB and TNF-αpromotes leukemia-initiating cell capacity (2014)
  • Author(s): Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M
  • Journal Title: J Clin Invest Volume: 124 Pages: 528-42
• [Journal Article] Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. (2014)
  • Author(s): Mori Y, Saito T, Chang SH, Kobayashi H, Ladel CH, Guehring H, Chung UI, Kawaguchi H.
  • Journal Title: J Biol Chem Volume: 289 Issue: 14 Pages: 10192-200
  • DOI: 10.1074/jbc.m113.524090
  • Peer Reviewed / Open Access
• [Journal Article] Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. (2014)
  • Author(s): Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 2 Pages: 528-542
  • DOI: 10.1172/jci68101
  • Peer Reviewed
• [Journal Article] Generation of Col2a1-EGFP-iPS cells for monitoring chondrogenic differentiation (2013)
  • Author(s): Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, Eto K, Nakauchi H, Tanaka S, Chung UI, Kawaguchi H
  • Journal Title: PLoS ONE Volume: 8
• [Journal Article] Transcriptional induction of ADAMTS5 by an NF-κB family member RelA/p65 in chondrocytes during osteoarthritis development (2013)
  • Author(s): Kobayashi H, Hirata M, Saito T, Itoh S, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 288 Pages: 28620-9
• [Journal Article] Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration (2013)
  • Author(s): Yano F, Hojo H, Ohba S, Saito T, Honnami M, Mochizuki M, Takato T, Kawaguchi H, Chung UI
  • Journal Title: Biomaterials Volume: 34 Pages: 5581-7
• [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 Pages: 9924-32
• [Journal Article] Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development (2013)
  • Author(s): Hosaka Y, Saito T (equally contr ibuted), Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung UI, Kawaguchi H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 1875-80
• [Journal Article] β-catenin Regulates PTH/PTHrP Receptor Signals and Chondrocyte Hypertrophy through Binding to Its Intracellular C-terminal Region (2013)
  • Author(s): Yano F, Saito T (equally contr ibuted), Ogata N, Yamazawa T, Iino M, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum Volume: 65 Pages: 429-35
• [Journal Article] A novel disease-modifying osteoarthritis drug targeting Runx1 (2013)
  • Author(s): Yano F, Hojo H, Ohba S, Fukai A, Hosaka Y, Ikeda T, Saito T, Hirata M, Chikuda H, Takato T, Kawaguchi H, Chung UI
  • Journal Title: Ann Rheum Dis Volume: 72 Pages: 748-53
• [Journal Article] Generation of Col2a1-EGFP iPS cells for monitoring chondrogenic differentiation (2013)
  • Author(s): Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, Eto K, Nakauchi H, Tanaka S, Chung UI, Kawaguchi H
  • Journal Title: PLoS One Volume: 16;8(9) Issue: 9 Pages: e74137-e74137
  • DOI: 10.1371/journal.pone.0074137
  • Peer Reviewed
• [Journal Article] Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development. (2013)
  • Author(s): Kobayashi H, Hirata M, Saito T, Itoh S, Chung UI, Kawaguchi H.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 40 Pages: 28620-9
  • DOI: 10.1074/jbc.m113.452169
  • Peer Reviewed
• [Journal Article] Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration. (2013)
  • Author(s): Yano F, Hojo H, Ohba S, Saito T, Honnami M, Mochizuki M, Takato T, Kawaguchi H, Chung UI.
  • Journal Title: Biomaterials Volume: 34 Pages: 5581-7
  • 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, Saito T, et al.
  • Journal Title: J Biol Chem. Volume: E-pub
  • Peer Reviewed
• [Journal Article] Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. (2013)
  • Author(s): Hosaka Y, Saito T (equally contributed), et al.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Pages: 1875-1880
  • Peer Reviewed
• [Journal Article] β-catenin Regulates PTH/PTHrP Receptor Signals and Chondrocyte Hypertrophy through Binding to Its Intracellular C-terminal Region. (2013)
  • Author(s): Yano F, Saito T (equally contributed), et al.
  • Journal Title: Arthritis Rheum Volume: 65 Pages: 429-435
  • Peer Reviewed
• [Journal Article] A novel disease-modifying osteoarthritis drug targeting Runx1. (2013)
  • Author(s): Yano F, Saito T, et al.
  • Journal Title: Ann Rheum Dis. Volume: 72 Pages: 748-753
  • Peer Reviewed
• [Journal Article] Gli1 Protein Participates in Hedgehog-mediated Specification of 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 Pages: 17860-9
• [Journal Article] GSK-3αand GSK-3βproteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation (2012)
  • Author(s): Itoh S, Saito T, Hirata M, Ushita M, Ikeda T, Woodgett JR, Algül H, Schmid RM, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 287 Pages: 29227-36
• [Journal Article] C/EBPβand RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2αas the inducer in chondrocytes (2012)
  • Author(s): Hirata M, Kugimiya F, Fukai A, Saito T, Yano F, Ikeda T, Mabuchi A, Sapkota BR, Akune T, Nishida N, Yoshimura N, Nakagawa T, Tokunaga K, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Hum Mol Genet Volume: 21 Pages: 1111-23
• [Journal Article] Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice (2012)
  • Author(s): Fukai A, Kamekura S, Chikazu D, Nakagawa T, Hirata M, Saito T, Hosaka Y, Ikeda T, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum Volume: 64 Pages: 198-203
• [Journal Article] Gli1 Protein Participates in Hedgehog-mediated Specification of Osteoblast Lineage during Endochondral Ossification. (2012)
  • Author(s): Hojo H, Saito T, et al.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 17890-17869
  • Peer Reviewed
• [Journal Article] GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation. (2012)
  • Author(s): Itoh S, Saito T, et al.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 29227-29236
  • Peer Reviewed
• [Journal Article] C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. (2012)
  • Author(s): Hirata M, Saito T, et al.
  • Journal Title: Hum Mol Genet. Volume: 21 Pages: 11111-11123
  • Peer Reviewed
• [Journal Article] Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice. (2012)
  • Author(s): Fukai A, Saito T, et al.
  • Journal Title: Arthritis Rheum. Volume: 64 Pages: 198-2003
  • Peer Reviewed
• [Journal Article] C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes (2012)
  • Author(s): Hirata M, Saito T, et al.
  • Journal Title: Hum Mol Genet. Volume: 21 Pages: 1111-23
  • Peer Reviewed
• [Journal Article] Reduction of peritendinous adhesions by hydrogel containing biocompatible phospholipid polymer MPC for tendon repair (2011)
  • Author(s): Ishiyama N, Moro T, Ohe T, Miura T, Ishihara K, Konno T, Ohyama T, Yoshikawa M, Kyomoto M, Saito T, Nakamura K, Kawaguchi H
  • Journal Title: J Bone J oint Surg Am Volume: 93 Pages: 142-9
• [Journal Article] Transcriptional regulation of osteoarthritis (2011)
  • Author(s): Saito T, et al.
  • Journal Title: Clin Calcium Volume: 21 Pages: 853-9
• [Presentation] 軟骨におけるNotchシグナルの役割 (2014)
  • Author(s): 齋藤琢
  • Organizer: 第27回日本軟骨代謝学会
  • Place of Presentation: 京都
  • Year and Date: 2014-02-28
• [Presentation] HIFによる関節軟骨の変性メカニズム (2013)
  • Author(s): 齋藤琢
  • Organizer: 第28回日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2013-10-18
• [Presentation] 軟骨分化モニタリングのためのCol2a1-EGFP-iPS細胞の樹立 (2013)
  • Author(s): 齋藤琢他
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-23
• [Presentation] 変形性関節症の分子メカニズムの解明 (2013)
  • Author(s): 齋藤琢
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-22
• [Presentation] マウスモデルをベースにした変形性関節症の分子メカニズムの解明 (2012)
  • Author(s): 齋藤琢
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 2012-07-20
• [Presentation] 軟骨再生医療への新たな取り組み (2012)
  • Author(s): 齋藤琢
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 2012-07-19
• [Presentation] NF-κBファミリーRelAは、ADAMTS5の転写誘導因子として変形性関節症の進行に作用する (2012)
  • Author(s): 小林寛、齋藤琢, 他
  • Organizer: 日本軟骨代謝学会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-03-09
• [Presentation] C/EBPb and RUNX2 Cooperatively Control Cartilage Degradation with MMP-13 as the Target and HIF-2a as the Inducer in Chondrocytes (2011)
  • Author(s): Hirata M, Saito T, et al.
  • Organizer: The American Society for Bone and Mineral Research (ASBMR)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-09-17
• [Presentation] Notch/Rbpj/Hes1 Signal in Chondrocytes Modulates the Terminal Stage of Endochondral Ossification during Skeletal Growth and Osteoarthritis Development (2011)
  • Author(s): Hosaka Y, Saito T, et al.
  • Organizer: The American Society for Bone and Mineral Research (ASBMR)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-09-17
• [Presentation] Functional Redundancy of GSK-3α and GSK-3β to Control Chondrocyte Differentiation through Phosphorylation of RelA/NF-κB p65 (2011)
  • Author(s): Itoh S, Saito T, et al.
  • Organizer: Osteoarthritis Research Society International (OARSI)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-09-16
• [Presentation] Transcriptional induction of ADAMTS5 by NF-κB family member RelA/p65 in chondrocytes during osteoarthritis development (2011)
  • Author(s): Kobayashi H, Saito T, et al.
  • Organizer: International Osteoporosis Federation/Australian and New Zealand Bone & Mineral Society (IOF/ANZBMS)
  • Place of Presentation: Gold coast (AUS)
  • Year and Date: 2011-09-07
• [Presentation] NF-κBファミリーRelAは、ADAMTS5の転写誘導因子として変形性関節症の進行に作用する (2011)
  • Author(s): 小林寛、齋藤琢, 他
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-30
• [Presentation] 軟骨細胞のNotch/Rbpj/Hes1シグナルは骨格形成および変形性関節症における軟骨内骨化の後期過程を制御する (2011)
  • Author(s): 保坂陽子、齋藤琢, 他
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-30
• [Presentation] GSK-3αとGSK-3βは協調的にRelA/NF-κB p65のリン酸化を介して軟骨細胞初期分化を制御する (2011)
  • Author(s): 伊藤祥三、齋藤琢, 他
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-29
• [Presentation] Research on pathophysiology and therapeutic target of osteoarthritis
  • Author(s): Saito T
  • Organizer: 16th Asia Pacific League of Associations for Rheumatology Congress (APLAR)
  • Place of Presentation: Cebu City, Philippines
  • Invited
• [Presentation] 軟骨におけるNotchシグナルの役割
  • Author(s): 齋藤 琢
  • Organizer: 第27回日本軟骨代謝学会
  • Place of Presentation: 京都（京都府医師会館）
  • Invited
• [Presentation] HIFによる関節軟骨の変性メカニズム
  • Author(s): 齋藤 琢
  • Organizer: 第28回日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉（幕張メッセ）
  • Invited
• [Remarks]
  • URL: http://www.u-tokyo-ortho.jp/
• [Remarks] 東京大学 整形外科・脊椎外科
  • URL: http://www.u-tokyo.ac.jp/ortho/
• [Remarks]
  • URL: http://www.h.u-tokyo.ac.jp/ortho/