Transcription factor Hes1 modulates osteoarthritis development

• Project/Area Number: 15K10461
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: TAKETOMI Syuji 東京大学, 医学部附属病院, 講師 (70570018)
• Co-Investigator(Kenkyū-buntansha): 乾 洋 東京大学, 医学部附属病院, 助教 (60583119) ; 矢野 文子 東京大学, 医学部附属病院, 特任講師 (80529040)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 変形性膝関節症 / Notch シグナル / Hes1 / Notchシグナル / 変形性関節症

Outline of Final Research Achievements

Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors.
OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. ChIP-seq identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding. We further identified calcium/ calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors.

Research Products

• [Journal Article] Bone regeneration by human dental pulp stem cells using a helioxanthin derivative and cell-sheet technology (2018)
  • Author(s): Fujii Y, Kawase-Koga Y, Hojo H, Yano F, Sato M, Chung UI, Ohba S, Chikazu D
  • Journal Title: Stem Cell Res Ther Volume: 9 Pages: 24
  • DOI: 10.1186/s13287-018-0783-7
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• [Journal Article] The Relationship between Soft-Tissue Balance and Intraoperative Kinematics of Guided Motion Total Knee Arthroplasty (2018)
  • Author(s): Inui H, Taketomi S, Yamagami R, Shirakawa N, Kawaguchi K, Tanaka S
  • Journal Title: J Knee Surg Volume: Epub Pages: ー
  • DOI: 10.1055/s-0038-1636545
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• [Journal Article] Surgical timing of anterior cruciate ligament reconstruction to prevent associated meniscal and cartilage lesions (2018)
  • Author(s): Taketomi S, Inui H, Yamagami R, Kawaguchi K, Nakazato K, Kono K, Kawata M, Nakagawa T, Tanaka S
  • Journal Title: J Orthop Sci Volume: Epub Pages: ー
  • DOI: 10.1016/j.jos.2018.02.006
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• [Journal Article] The effects of presence of a backside screw hole on biotribological behavior of phospholipid polymer-grafted crosslinked polyethylene (2018)
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  • Journal Title: J Biomed Mater Res B Appl Biomater Volume: 106 Pages: 610-618
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• [Journal Article] A Mouse Intervertebral Disc Degeneration Model by Surgically-Induced Instability (2017)
  • Author(s): Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F, Tanaka S, Saito T
  • Journal Title: Spine Volume: ー Pages: ー
  • DOI: 10.1097/BRS.0000000000002427
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• [Journal Article] Sandwich-type PLLA-nanosheets loaded with BMP-2 induce bone regeneration in critical-sized mouse calvarial defects (2017)
  • Author(s): Huang KC, Yano F, Murahashi Y, Takano S, Kitaura Y, Chang SH, Soma K, Ueng SWN, Tanaka S, Ishihara K, Okamura Y, Moro T, Saito T
  • Journal Title: Acta Biomater Volume: 59 Pages: 12-20
  • DOI: 10.1016/j.actbio.2017.06.041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bone-Patellar Tendon-Bone Autograft versus Hamstring Tendon Autograft for Anatomical Anterior Cruciate Ligament Reconstruction with Three-Dimensional Validation of Femoral and Tibial Tunnel Positions (2017)
  • Author(s): Taketomi S, Inui H, Yamagami R, Shirakawa N, Kawaguchi K, Nakagawa T, Tanaka S.
  • Journal Title: J Knee Surg Volume: Epub Pages: ー
  • DOI: 10.1055/s-0037-1615813
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• [Journal Article] Annual trends in knee arthroplasty and tibial osteotomy: Analysis of a national database in Japan (2017)
  • Author(s): Kawata M, Sasabuchi Y, Inui H, Taketomi S, Matsui H, Fushimi K, Chikuda H, Yasunaga H, Tanaka S
  • Journal Title: Knee Volume: 24 Pages: 1198-1205
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  • Peer Reviewed
• [Journal Article] Effects of initial graft tension on femoral tunnel widening after anatomic anterior cruciate ligament reconstruction using a bone-patellar tendon-bone graft (2017)
  • Author(s): Taketomi S, Inui H, Tahara K, Shirakawa N, Tanaka S, Nakagawa T
  • Journal Title: Arch Orthop Trauma Surg Volume: 137 Pages: 1285-1291
  • DOI: 10.1007/s00402-017-2728-5
  • Peer Reviewed
• [Journal Article] A modified technique to reduce tibial keel cutting errors during an Oxford unicompartmental knee arthroplasty. (2017)
  • Author(s): Inui H, Taketomi S, Tahara K, Yamagami R, Sanada T, Tanaka S
  • Journal Title: Knee Surg Sports Traumatol Arthrosc Volume: 25 Pages: 710-716
  • DOI: 10.1007/s00167-016-4151-9
  • Peer Reviewed
• [Journal Article] The role of medial meniscus posterior root tear and proximal tibial morphology in the development of spontaneous osteonecrosis and osteoarthritis of the knee. (2017)
  • Author(s): Yamagami R, Taketomi S, Inui H, Tahara K, Tanaka S
  • Journal Title: Knee Volume: 24 Pages: 390-395
  • DOI: 0.1016/j.knee.2016.12.004.
  • Peer Reviewed
• [Journal Article] Regulation of Chondrocyte Survival in Mouse Articular Cartilage by p63. (2017)
  • Author(s): Taniguchi Y, Kawata M, Ho Chang S, Mori D, Okada K, Kobayashi H, Sugita S, Hosaka Y, Inui H, Taketomi S, Yano F, Ikeda T, Akiyama H, Mills AA, Chung UI, Tanaka S, Kawaguchi H, Saito T
  • Journal Title: Arthritis Rheumatol Volume: 69 Pages: 598-609
  • DOI: 10.1002/art.39976
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Different regulation of limb development by p63 transcript variants (2017)
  • Author(s): Kawata M, Taniguchi Y, Mori D, Yano F, Ohba S, Chung UI, Shimogori T, Mills AA, Tanaka S, Saito T
  • Journal Title: PLoS One Volume: 12 Pages: e0174122
  • DOI: 10.1371/journal.pone.0174122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impingement of the Mobile Bearing on the Lateral Wall of the Tibial Tray in Unicompartmental Knee Arthroplasty. (2016)
  • Author(s): Inui H, Taketomi S, Yamagami R, Sanada T, Shirakawa N, Tanaka S
  • Journal Title: J Arthroplasty Volume: 31 Pages: 1459-1464
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• [Journal Article] Myositis ossificans after navigated knee surgery: A report of two cases and literature review. (2016)
  • Author(s): Yamagami R, Taketomi S, Inui H, Sanada T, Nakagawa T, Tanaka S.
  • Journal Title: Knee Volume: 23 Pages: 561-564
  • DOI: 10.1016/j.knee.2015.11.023
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• [Journal Article] Snapping Pes Syndrome after Unicompartmental Knee Arthroplasty (2016)
  • Author(s): Inui H, Taketomi S, Yamagami R, Tahara K, Tanaka S
  • Journal Title: Knee Surg Relat Res Volume: 28 Pages: 172-175
  • DOI: 10.5792/ksrr.2016.28.2.172
  • Peer Reviewed
• [Journal Article] Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability. (2016)
  • Author(s): Chang SH, Yasui T, Taketomi S, Matsumoto T, Kim-Kaneyama JR, Omiya T, Hosaka Y, Inui H, Omata Y, Yamagami R, Mori D, Yano F, Chung U, Tanaka S, Saito T.
  • Journal Title: Osteoarthritis Cartilage Volume: 24 Pages: 688-697
  • DOI: 10.1016/j.joca.2015.11.00
  • Peer Reviewed
• [Journal Article] Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes (2016)
  • Author(s): Kobayashi H, Chang SH, Mori D, Itoh S, Hirata M, Hosaka Y, Taniguchi Y, Okada K, Mori Y, Yano F, Chung UI, Akiyama H, Kawaguchi H, Tanaka S, Saito T
  • Journal Title: Nat Commun Volume: 10 Pages: 13336
  • DOI: 10.1038/ncomms13336
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability (2016)
  • Author(s): Chang SH, Yasui T, Taketomi S, Matsumoto T, Kim-Kaneyama JR, Omiya T, Hosaka Y, Inui H, Omata Y, Yamagami R, Mori D, Yano F, Chung U, Tanaka S, Saito T.
  • Journal Title: Osteoarthritis Cartilage Volume: 24 Pages: 688-697
  • DOI: 10.1016/j.joca.2015.11.008
  • Peer Reviewed
• [Journal Article] Myositis ossificans after navigated knee surgery: A report of two cases and literature review (2016)
  • Author(s): Yamagami R, Taketomi S, Inui H, Sanada T, Nakagawa T, Tanaka S
  • Journal Title: Knee Volume: 15 Pages: 291-294
  • DOI: 10.1016/j.knee.2015.11.023
  • Peer Reviewed
• [Journal Article] Secure fixation of femoral bone plug with a suspensory button in anatomical anterior cruciate ligament reconstruction with bone-patellar tendon-bone graft (2016)
  • Author(s): Taketomi S, Inui H, Nakamura K, Yamagami R, Tahara K, Sanada T, Masuda H, Tanaka S, Nakagawa T
  • Journal Title: Joints Volume: 3 Pages: 102-108
  • DOI: 10.11138/jts/2015.3.3.102
  • Peer Reviewed / Open Access
• [Journal Article] Twice cutting method reduces tibial cutting error in unicompartmental knee arthroplasty (2016)
  • Author(s): Inui H, Taketomi S, Yamagami R, Sanada T, Tanaka S
  • Journal Title: Knee Volume: 23 Pages: 173-176
  • DOI: 10.1016/j.knee.2014.11.015
  • Peer Reviewed
• [Journal Article] Missed Medial Malleolar Fracture Associated With Achilles Tendon Rupture: A Case Report and Literature Review (2016)
  • Author(s): Nakajima K, Taketomi S, Inui H, Nakamura K, Sanada T, Tanaka S
  • Journal Title: J Foot Ankle Surg Volume: 55 Pages: 169-172
  • DOI: 10.1053/j.jfas.2014.09.027
  • Peer Reviewed
• [Journal Article] Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells (2015)
  • Author(s): Saito T, Yano F, Mori D, Kawata M, Hoshi K, Takato T, Masaki H, Otsu M, Eto K, Nakauchi H, Chung UI, Tanaka S
  • Journal Title: Biomed Res Volume: 36 Pages: 179-186
  • DOI: 10.2220/biomedres.36.179
  • Peer Reviewed / Open Access
• [Journal Article] Runx1 and Runx3 Are Downstream Effectors of Nanog in Promoting Osteogenic Differentiation of the Mouse Mesenchymal Cell Line C3H10T1/2 (2015)
  • Author(s): Saito T, Ohba S, Yano F, Seto I, Yonehara Y, Takato T, Ogasawara T
  • Journal Title: Cell Reprogram Volume: 17 Pages: 227-234
  • DOI: 10.1089/cell.2014.0059
  • Peer Reviewed
• [Journal Article] Regulation of mouse chondrocyte differentiation by CCAAT/enhancer-binding proteins. (2015)
  • Author(s): Okuma T, Hirata M, Yano F, Mori D, Kawaguchi H, Chung UI, Tanaka S, Saito T
  • Journal Title: Biomed Res Volume: 36 Pages: 21-29
  • DOI: 10.2220/biomedres.36.21
  • Peer Reviewed
• [Journal Article] Effects of Surface Modification and Bulk Geometry on the Biotribological Behavior of Cross-Linked Polyethylene: Wear Testing and Finite Element Analysis (2015)
  • Author(s): Watanabe K, Kyomoto M, Saiga K, Taketomi S, Inui H, Kadono Y, Takatori Y, Tanaka S, Ishihara K, Moro T
  • Journal Title: Biomed Res Int Volume: 2015 Pages: 435432
  • DOI: 10.1155/2015/435432
  • Peer Reviewed / Open Access
• [Presentation] β-cateninシグナルは関節軟骨最表層の維持に必須である (2018)
  • Author(s): 玄 峰俊、矢野 文子、斎藤 琢
  • Organizer: 第31回日本軟骨代謝学会
• [Presentation] β-cateninシグナルは関節軟骨最表層の維持に必須である (2017)
  • Author(s): 玄 峰俊、矢野 文子、斎藤 琢
  • Organizer: 第35回日本骨代謝学会、第32回日本整形外科学会基礎
• [Presentation] 関節軟骨最表層に発現する転写因子 HIF-2α は,関節軟骨の維持に不可欠である (2017)
  • Author(s): 牧井 勇磨、矢野 文子、斎藤 琢
  • Organizer: 第35回日本骨代謝学会、第32回日本整形外科学会基礎
• [Presentation] Runx1 contributes to articular cartilage maintenance through enhancement of cartilage matrix production and suppression of hypertrophic differentiation (2016)
  • Author(s): Fumiko Yano, Taku Saito, Shinsuke Ohba, Sakae Tanaka, Ung-il Chung
  • Organizer: Cold Spring Harbor Asia conference on Bone & Cartilage: From Development to Human Diseases
  • Place of Presentation: The Suzhou Dushu Lake Conference Center
  • Year and Date: 2016-10-24 – 2016-10-28
  • Int'l Joint Research
• [Presentation] Runx1による軟骨分化制御機構 (2016)
  • Author(s): 矢野文子
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-10-13 – 2016-10-14
  • Invited
• [Presentation] Runx1による軟骨分化制御機構 (2016)
  • Author(s): 矢野文子
  • Organizer: 第34回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2016-07-20 – 2016-07-23
  • Invited
• [Presentation] Runx1による軟骨分化制御機構 (2016)
  • Author(s): 矢野文子、斎藤琢、大庭伸介、田中栄、鄭雄一
  • Organizer: 第２回 骨免疫学会
  • Place of Presentation: ホテルモントレ沖縄スパ＆リゾート
  • Year and Date: 2016-07-06 – 2016-07-08
• [Presentation] 骨付き膝蓋腱を用いた解剖学的前十字靱帯再建術における初期張力は術後大腿骨孔拡大に影響する (2016)
  • Author(s): 武冨修治、乾洋、田原圭太郎、白川展之、中村春彦、中川匠、田中栄
  • Organizer: 第89回日本整形外科学会学術総会
  • Place of Presentation: 横浜パシフィコ
  • Year and Date: 2016-05-12 – 2016-05-15
• [Presentation] 関節リウマチ患者由来の滑膜線維芽細胞における刺激応答機構の解析 (2016)
  • Author(s): 土屋遥香、住友秀次、石垣和慶、高地雄太、土田優美、太田峰人、伊沢直広、小俣康徳、松本卓巳、乾洋、武冨修治、門野夕峰、田中栄、藤尾圭志、山本一彦
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜パシフィコ
  • Year and Date: 2016-04-21 – 2016-04-23
• [Presentation] Runx1 contributes to articular cartilage maintenance through enhancement of cartilage matrix production and suppression of hypertrophic differentiation (2016)
  • Author(s): Fumiko Yano, Taku Saito, Shinsuke Ohba, Ung-il Chung
  • Organizer: The second Herbert Fleisch Workshop
  • Place of Presentation: Novotel Brugge Centrum （Brugge, Belgium)
  • Year and Date: 2016-02-28 – 2016-03-01
  • Int'l Joint Research
• [Presentation] 骨再生を誘導する変形関節症治療候補薬のin vivoモデルにおける効果～そのメカにニズムの解析とターゲット分子の探索～ (2015)
  • Author(s): 矢野文子
  • Organizer: 第18回骨代謝研究会
  • Place of Presentation: 慶応義塾大学医学部総合医科学研究棟(東京)
  • Year and Date: 2015-11-30
  • Invited
• [Presentation] Runx1による軟骨分化制御機構 (2015)
  • Author(s): 矢野文子
  • Organizer: 第16回運動器科学研究会
  • Place of Presentation: みなみホール（鹿児島）
  • Year and Date: 2015-09-11 – 2015-09-12
• [Presentation] Guided-motion TKAにおける軟部バランスと術中動態の関係 (2015)
  • Author(s): 乾洋、武冨修治、山神良太、田原圭太郎、田中栄
  • Organizer: 第7回日本関節鏡・膝・スポーツ整形外科学会（JOSKAS）
  • Place of Presentation: 札幌コンベンションセンター(札幌）
  • Year and Date: 2015-06-18 – 2015-06-20
• [Presentation] UKAにおけるkeel作成方法によるkeel cutting errorの違い (2015)
  • Author(s): 乾洋、武冨修治、山神良太、田原圭太郎、田中栄
  • Organizer: 第7回日本関節鏡・膝・スポーツ整形外科学会（JOSKAS）
  • Place of Presentation: 札幌コンベンションセンター(札幌）
  • Year and Date: 2015-06-18 – 2015-06-20
• [Presentation] 解剖学的前十字靱帯再建術後2年でのMRI評価―膝屈筋腱と骨付き膝蓋腱との比較― (2015)
  • Author(s): 武冨修治、乾洋、山神良太、田原圭太郎、中川匠、田中栄
  • Organizer: 第7回日本関節鏡・膝・スポーツ整形外科学会（JOSKAS）
  • Place of Presentation: 札幌コンベンションセンター(札幌）
  • Year and Date: 2015-06-18 – 2015-06-20
• [Presentation] 骨付き膝蓋腱を用いた前十字靱帯再建術における膝蓋腱の再生とkneelingについての検討 (2015)
  • Author(s): 田原圭太郎、武冨修治、乾洋、山神良太、中川匠、田中栄
  • Organizer: 第7回日本関節鏡・膝・スポーツ整形外科学会（JOSKAS）
  • Place of Presentation: 札幌コンベンションセンター(札幌）
  • Year and Date: 2015-06-18 – 2015-06-20
• [Presentation] Evaluation of Bone Healing After Anatomical Rectangular Tunnel ACL Reconstruction Using a Bone-Patellar Tendon-Bone Graft With Suspensory Fixation (2015)
  • Author(s): Masuda H, Inui H, Taketomi S, Matsushita T, Nakagawa T
  • Organizer: ISAKOS 2015
  • Place of Presentation: Lyon Convention Centre at the Cité Internationale（Lyon, France）
  • Year and Date: 2015-06-07 – 2015-06-11
  • Int'l Joint Research
• [Presentation] Evaluation of Femoral Socket Aperture Position in Remnant-Preserving Anterior Cruciate Ligament Reconstruction Using Three-Dimensional Fluoroscopy Navigation (2015)
  • Author(s): Taketomi S, Inui H, Yamagami R, Sanada T, Tahara K, Shirakawa N, Tanaka S, Nakagawa T
  • Organizer: ISAKOS 2015
  • Place of Presentation: Lyon Convention Centre at the Cité Internationale（Lyon, France）
  • Year and Date: 2015-06-07 – 2015-06-11
  • Int'l Joint Research
• [Presentation] 患者立脚型評価を用いた解剖学的前十字靱帯再建術後の疼痛の要因の解析－移植腱として骨付き膝蓋腱を用いると痛いのか－ (2015)
  • Author(s): 武冨修治、乾洋、山神良太、田原圭太郎、中川匠、田中栄
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2015-05-21 – 2015-05-24
• [Presentation] 固定にEndobuttonを用いた解剖学的長方形骨孔BTB ACL再建術術後の骨孔描着のトモシンセシスによる評価 (2015)
  • Author(s): 増田裕也、乾洋、武冨修治、松下隆、中川匠
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2015-05-21 – 2015-05-24
• [Remarks] 東京大学医学部附属病院 整形外科・脊椎外科
  • URL: http://www.u-tokyo-ortho.jp/
• [Remarks] 東京大学医学部附属病院 整形外科・脊椎外科
  • URL: http://www.u-tokyo-ortho.jp/examination/academic.html