Runx1 contributes to articular cartilage maintenance through enhancement of cartilage matrix production and suppression of hypertrophic differentiation

• Project/Area Number: 25713052
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: Yano Fumiko 東京大学, 医学部附属病院, 助教 (80529040)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥24,570,000 (Direct Cost: ¥18,900,000、Indirect Cost: ¥5,670,000); Fiscal Year 2015: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2014: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2013: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: Runx1 / ルブリシン / Prg4 / 変形性膝関節症 / 関節軟骨

Outline of Final Research Achievements

We analysed OA development of Col2a1-Cre;Runx1fl/fl and Runx1fl/fl mice by surgical induction of joint instability, and expression of marker proteins in the articular cartilage by immunostainings. The cartilage degradation and the osteophyte formation of Col2a1-Cre;Runx1fl/fl the joints after 8 weeks was accelerated compared with the Runx1fl/fl littermate joints. To know the regulation of chondrocyte differentiation by Runx1, we analysed a function of downstream molecules and interaction with co-factors. Knockdown of Runx1 in articular chondrocytes increased hypertrophic markers, and decreased Bapx1 and chondrogenic markers. The similar results were observed in the Col2a1-Cre;Runx1fl/fl knee joint cartilage. Notably, suppression of hypertrophic markers by Runx1 was diminished by silencing of Bapx1 by siRNA. The present data suggest that Runx1 contributes to articular cartilage maintenance through suppression of hypertrophic differentiation via Bapx1 induction.

Research Products

• [Int'l Joint Research] ハーバード大学/ボストン子供病院/整形外科研究室(アメリカ)
• [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 Issue: 3 Pages: e0174122-e0174122
  • DOI: 10.1371/journal.pone.0174122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of Chondrocyte Survival in Mouse Articular Cartilage by p63. (2017)
  • Author(s): Taniguchi Y, Kawata M, Chang SH, 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, and Saito T*
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 3 Pages: 598-609
  • DOI: 10.1002/art.39976
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes. (2016)
  • Author(s): Kobayashi H, Chang S, Mori D, Itoh S, Hirata M, Hosaka Y, Taniguchi Y, Okada K, Mori Y, Yano F, Chung U, Akiyama H, Kawaguchi H, Tanaka S, Saito T.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 13336-13336
  • DOI: 10.1038/ncomms13336
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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 Issue: 4 Pages: 688-697
  • DOI: 10.1016/j.joca.2015.11.008
  • Peer Reviewed
• [Journal Article] <b>Regulation of mouse chondrocyte differentiation by CCAAT/enhancer-binding pr</b><b>oteins </b> (2015)
  • Author(s): Okuma T, Hirata M, Yano F, Mori D, Kawaguchi H, Chung UI, Tanaka S, Saito T
  • Journal Title: Biomedical Research Volume: 36 Issue: 1 Pages: 21-29
  • DOI: 10.2220/biomedres.36.21
  • NAID: 130004903876
  • ISSN: 0388-6107, 1880-313X
  • 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 Issue: 3 Pages: 227-234
  • DOI: 10.1089/cell.2014.0059
  • Peer Reviewed / Open Access
• [Journal Article] <b>Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem </b><b>cells </b> (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: Biomedical Research Volume: 36 Issue: 3 Pages: 179-186
  • DOI: 10.2220/biomedres.36.179
  • NAID: 130005083858
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2. (2015)
  • Author(s): Sugita S, Taketomi S, Saito T, et al.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 10 Pages: 3080-5
  • DOI: 10.1073/pnas.1419699112
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disease-modifying effects of TD-198946 on progressed osteoarthritis in a mouse model. (2014)
  • Author(s): Yano F, Saito T, et al.
  • Journal Title: Ann Rheum Dis. Volume: 73 Issue: 11 Pages: 2062-4
  • DOI: 10.1136/annrheumdis-2014-205672
  • Peer Reviewed
• [Journal Article] Identification of SCAN domain zinc-finger gene ZNF449 as a novel factor of chondrogenesis. (2014)
  • Author(s): Okada K, Saito T, et al.
  • Journal Title: PLoS One. Volume: 9 Issue: 12 Pages: e115169-e115169
  • DOI: 10.1371/journal.pone.0115169
  • Peer Reviewed / Open Access
• [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] Cell-sheet technology combined with a thienoindazole derivative small comnound TD-198946 for cartilage regeneration (2013)
  • Author(s): Yano F, Hojo H, et al.
  • Journal Title: Biomaterials Volume: 34 Issue: 22 Pages: 5581-5587
  • DOI: 10.1016/j.biomaterials.2013.04.008
  • Peer Reviewed
• [Journal Article] Tenomodulin expression in the periodontal ligament enhances cellular adhesion (2013)
  • Author(s): Y. Komiyama, S. Ohba, N. Shimohata, K. Nakajima, H. Hojo, F. Yano, T. Takato, D. Docheva, C. Shukunami, Y. Hiraki, and UI. Chung.
  • Journal Title: PLoS One Volume: 8 Issue: 4 Pages: e60203-e60203
  • DOI: 10.1371/journal.pone.0060203
  • 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] A novel disease-modifying osteoarthritis drug candidate targeting Runx1. (2013)
  • Author(s): Yano, F. et al.
  • Journal Title: Ann Rheum Dis. Volume: 72 Issue: 5 Pages: 748-753
  • DOI: 10.1136/annrheumdis-2012-201745
  • Peer Reviewed
• [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
  • 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
  • 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
• [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: ovotel Brugge Centrum Brugge
  • Year and Date: 2016-02-28
  • Int'l Joint Research
• [Presentation] 変形性関節症の新規治療候補薬の作用解析 (2016)
  • Author(s): 矢野文子、斎藤琢、宮本健史
  • Organizer: 東大病院先端医療開発フォーラム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール
  • Year and Date: 2016-02-02
• [Presentation] 軟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
  • Year and Date: 2015-11-30
  • Invited
• [Presentation] A novel disease-modifying osteoarthritis drug candidate targeting Runx1 (2015)
  • Author(s): Fumiko Yano
  • Organizer: LMU-Utokyo Symposium
  • Place of Presentation: Innnovation Center for Biotechnology, Munich
  • Year and Date: 2015-10-27
• [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
  • Year and Date: 2015-09-11
• [Presentation] 変形性関節症の新規治療候補薬の作用解析 (2015)
  • Author(s): 矢野文子, 斎藤琢
  • Organizer: 東大病院先端医療開発フォーラム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール（東京）
  • Year and Date: 2015-01-22
• [Presentation] 変形性関節症治療を目指した軟骨再生医療研究 (2014)
  • Author(s): 矢野文子、齋藤琢
  • Organizer: 第42回日本関節病学会 共催シンポジウム
  • Place of Presentation: 虎ノ門ヒルズ（東京・港区）
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] 新規OA治療候補化合物はRunx1をターゲットとしている (2014)
  • Author(s): 矢野文子、北條宏徳、大庭伸介、深井厚、保坂陽子、池田敏之、斎藤琢、平田真、筑田博隆、高戸毅、川口浩、鄭 雄一
  • Organizer: 第33回日本運動器移植・再生医学研究会
  • Place of Presentation: 第一ホテル両国（東京・墨田区）
  • Year and Date: 2014-09-27
• [Presentation] novel disease-modifying osteoarthritis drug candidate targeting Runx1 (2014)
  • Author(s): Fumiko Yano, Yoko Hosaka, Atsushi Fukai, Taku Saito, Hironori Hojo, Shinsuke Ohba, Hiroshi Kawaguchi, Tsuyoshi Takato, Ung-il Chung
  • Organizer: 第14回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール（東京・文京区）
  • Year and Date: 2014-04-26
• [Presentation] 新規ＯＡ治療候補化合物はRunx1をターゲットとしている. (2014)
  • Author(s): 矢野文子, 北條宏徳, 大庭伸介, 深井厚，保坂陽子，池田敏之, 斎藤琢, 平田真， 筑田博隆，高戸毅, 川口浩, 鄭雄一
  • Organizer: 第27回日本軟骨代謝学会
  • Place of Presentation: 京都府医師会館
  • Invited
• [Presentation] A novel disease-modifying osteoarthritis drug candidate targeting Runx1. (2013)
  • Author(s): Fumiko Yano, Yoko Hosaka, Atsushi Fukai, Taku Saito, Hironori Hojo, Shinsuke Ohba, Hiroshi Kawaguchi, Tsuyoshi Takato, Ung-il Chung
  • Organizer: Frontiers 2013 EPFL Symposium.
  • Place of Presentation: Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland
• [Presentation] 新規ＯＡ治療候補化合物はRunx1をターゲットとしている.
  • Author(s): 矢野文子, 保坂陽子，斎藤琢, 北條宏徳, 大庭伸介, 高戸毅, 鄭雄一
  • Organizer: FIRST合同国際シンポジウム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール
• [Presentation] A novel disease-modifying osteoarthritis drug candidate targeting Runx1
  • Author(s): Fumiko Yano, Yoko Hosaka, Atsushi Fukai, Taku Saito, Hironori Hojo, Shinsuke Ohba, Hiroshi Kawaguchi, Tsuyoshi Takato, Ung-il Chung
  • Organizer: 第13回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール
• [Presentation] 変形性関節症の新規治療候補薬の発見
  • Author(s): 矢野文子, 大庭伸介, 鄭雄一
  • Organizer: 東大病院先端医療開発フォーラム
  • Place of Presentation: 東京大学 伊藤国際学術研究センター 伊藤謝恩ホール
• [Remarks] 東京大学 工学系研究科/医学系研究科 鄭雄一研究室
  • URL: http://www.tetrapod.t.u-tokyo.ac.jp/ohba-tei/
• [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 整形外科・脊椎外科
  • URL: http://www.u-tokyo-ortho.jp/about/achievements/achievements.html
• [Remarks] 東京大学 鄭雄一研究室 大庭・矢野・鄭グループ
  • URL: http://www.tetrapod.t.u-tokyo.ac.jp/med/index.html