Identification of cells responsible for osteoclastogenesis in arthritis

• Project/Area Number: 25670636
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAYANAGI Hiroshi 東京大学, 医学(系)研究科(研究院), 教授 (20334229)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 破骨細胞 / RANKL

Outline of Final Research Achievements

In order to functionally demonstrate in vivo which cell types drive pathogenic osteoclast differentiation we used Tnfsf11a floxed mice for the depletion of RANKL in T-cells and synovial fibroblasts during collagen antibody-induced arthritis (CAIA). The accurate assessment of the osteoclast erosions was performed by micro-CT analysis. Significant increases in osteoclast numbers and bone erosions were observed in the Tnfsf11flox/Δ Lck-Cre and Tnfsf11flox/Δ Col2a1-Cre groups during CAIA, however, the Tnfsf11flox/Δ Col6a1-Cre mice showed significant protection against osteoclast formation and bone erosions. Thus, it is suggested that RANKL expression by synovial fibroblasts rather than T-cells govern the osteoclast differentiation that leads to inflammation-associated joint destruction.

Research Products

• [Journal Article] Osteoimmunology in 2014: Two-faced immunology-from osteogenesis to bone resorption. (2015)
  • Author(s): Takayanagi H.
  • Journal Title: Nat Rev Rheumatol., Volume: 11 Issue: 2 Pages: 74-76
  • DOI: 10.1038/nrrheum.2014.219
  • Peer Reviewed
• [Journal Article] Arthritogenic T cells in autoimmune arthritis. (2015)
  • Author(s): Komatsu N, Takayanagi H.
  • Journal Title: Int J Biochem Cell Biol. Volume: 58 Pages: 92-96
  • DOI: 10.1016/j.biocel.2014.11.008
  • Peer Reviewed
• [Journal Article] SnapShot: Osteoimmunology. (2015)
  • Author(s): Takayanagi H.
  • Journal Title: Cell Metab. Volume: 21 Issue: 3 Pages: 502-502
  • DOI: 10.1016/j.cmet.2015.02.001
  • Peer Reviewed
• [Journal Article] The immune system, bone and RANKL. (2014)
  • Author(s): Guerrini MM, Takayanagi H.
  • Journal Title: Arch Biochem Biophys. 561: 1118-123 (2014) Volume: 561 Pages: 1118-1123
  • DOI: 10.1016/j.abb.2014.06.003
  • Peer Reviewed
• [Journal Article] The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. (2014)
  • Author(s): Masahiro Shinohara, Betty Y. Chan, Joseph J. Buggy, Yusuke Nagai, Tatsuhiko Kodama, Hiroshi Asahara, Hiroshi Takayanagi.
  • Journal Title: Bone Volume: 60 Pages: 8-15
  • DOI: 10.1016/j.bone.2013.11.025
  • Peer Reviewed
• [Journal Article] Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. (2014)
  • Author(s): Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, JA. and Takayanagi, H.
  • Journal Title: Nature Medicine Volume: 20 Issue: 1 Pages: 62-68
  • DOI: 10.1038/nm.3432
  • Peer Reviewed / Open Access
• [Journal Article] Immunology and bone. (2013)
  • Author(s): Danks, L., Takayanagi, H.
  • Journal Title: J Biochem. Volume: 154 Issue: 1 Pages: 29-39
  • DOI: 10.1093/jb/mvt049
  • NAID: 40019683285
  • Peer Reviewed
• [Presentation] RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation (2015)
  • Author(s): Lynett Danks、小松 紀子、Matteo M Guerrini、澤新一郎、中島友紀、高柳広
  • Organizer: 第9回炎症・脂質代謝・メタボリサーチフォーラム
  • Place of Presentation: 東京大学
  • Year and Date: 2015-02-28
  • Invited
• [Presentation] RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation (2015)
  • Author(s): Lynett Danks and H. Takayanagi
  • Organizer: The Fourth Bizan Immunology Symposium at University of Tokushima (BISUT4)
  • Place of Presentation: 徳島、徳島大学蔵本キャンパス 藤井メモリアルホール
  • Year and Date: 2015-01-29
  • Invited
• [Presentation] 関節リウマチ骨破壊と骨免疫学 (2014)
  • Author(s): 高柳広
  • Organizer: 日本関節病学会
  • Place of Presentation: 虎ノ門ヒルズ、東京
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] Bone cell communication and osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: The 3rd Cold Spring Harbor Asia conference - Frontiers of Immunology in Health and Diseases
  • Place of Presentation: 上海、中国
  • Year and Date: 2014-11-05
  • Invited
• [Presentation] Immune complex and osteoclast (2014)
  • Author(s): H. Takayanagi
  • Organizer: New York osteoimmunology conference
  • Place of Presentation: NY、アメリカ
  • Year and Date: 2014-10-30
  • Invited
• [Presentation] 骨免疫の最前線 (2014)
  • Author(s): 高柳広
  • Organizer: 第57回秋季日本歯周病学会学術大会
  • Place of Presentation: 神戸、神戸国際展示場
  • Year and Date: 2014-10-19
  • Invited
• [Presentation] TH17 mediated control of bone (2014)
  • Author(s): H. Takayanagi
  • Organizer: 2nd IMMUNOBONE International Symposium
  • Place of Presentation: Potsdam, German
  • Year and Date: 2014-10-13
  • Invited
• [Presentation] 骨免疫学と関節炎治療の進歩 (2014)
  • Author(s): 高柳広
  • Organizer: 日本脊椎関節炎学会 第24回学術集会
  • Place of Presentation: ナレッジキャピタルコングレコンベンションセンター、大阪
  • Year and Date: 2014-10-04
  • Invited
• [Presentation] What Changes Has Osteoimmunology Brought About? (2014)
  • Author(s): H. Takayanagi
  • Organizer: ASBMR 2014 Annual Meeting
  • Place of Presentation: George R. Brown Convention Center, Houston, USA
  • Year and Date: 2014-09-12
  • Invited
• [Presentation] 骨免疫学の進歩 (2014)
  • Author(s): 高柳広
  • Organizer: BD 学術セミナー 2014
  • Place of Presentation: 東京、マンダリンホテル
  • Year and Date: 2014-08-29
  • Invited
• [Presentation] Perspective on osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: Semaphorin osteonetwork meeting
  • Place of Presentation: Montreal, Canad
  • Year and Date: 2014-08-10
  • Invited
• [Presentation] 骨リモデリングの制御機構と新規治療法への展望 (2014)
  • Author(s): 高柳広
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪、グランキューブ大阪（大阪国際会議場）
  • Year and Date: 2014-07-26
  • Invited
• [Presentation] 関節炎における病原T細胞と骨免疫学 (2014)
  • Author(s): 高柳広
  • Organizer: 阪大免疫塾
  • Place of Presentation: 大阪大学医学部学友会館、大阪
  • Year and Date: 2014-07-15
  • Invited
• [Presentation] Overview: Osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄、万国津梁館
  • Year and Date: 2014-07-03
  • Invited
• [Presentation] Autoimmune arthritis and osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: RIKEN IMS-JSI International Symposium on Immunology 2014
  • Place of Presentation: 横浜ベイホテル東急、神奈川
  • Year and Date: 2014-06-26
  • Invited
• [Presentation] Cell communication in osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: 5th International Conference on Osteoimmunology:
  • Place of Presentation: Kos, Greece
  • Year and Date: 2014-06-17
  • Invited
• [Presentation] Overview of Osteoimmunology (2014)
  • Author(s): H. Takayanagi
  • Organizer: The 2nd Bio Theumatology International Congress(BRIC2014)
  • Place of Presentation: AZIMUT Moscow Olympic Hotel, Russia
  • Year and Date: 2014-06-06
  • Invited
• [Presentation] 骨免疫学から見た関節リウマチ・骨粗鬆症治療の進歩 (2014)
  • Author(s): 高柳広
  • Organizer: 千葉リウマチ医の会
  • Place of Presentation: 京成ホテルミラマーレ、千葉
  • Year and Date: 2014-05-31
  • Invited
• [Presentation] 自己免疫性関節炎と骨免疫学 (2014)
  • Author(s): 高柳広
  • Organizer: 大阪大学微生物病研究所アドバンストセミナー
  • Place of Presentation: 大阪大学微生物病研究所
  • Year and Date: 2014-05-12
  • Invited
• [Presentation] 骨免疫学
  • Author(s): 高柳広
  • Organizer: 第50回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Invited
• [Presentation] Osteo immunology in RA
  • Author(s): 高柳広
  • Organizer: 第57回 日本リウマチ学会総会･学術集会/第22回 国際リウマチシンポジウム
  • Place of Presentation: 国立京都国際会館
  • Invited
• [Presentation] 骨免疫学から見た関節リウマチ治療の進歩
  • Author(s): 高柳広
  • Organizer: 第17回奈良膠原病研究会
  • Place of Presentation: 日航奈良ホテル
  • Invited
• [Presentation] Novel antiresorptives - uncoupling or not?
  • Author(s): 高柳広
  • Organizer: The European Calcified Tissue Society, Annual Congress 2013
  • Place of Presentation: ポルトガル、リスボン
  • Invited
• [Presentation] 骨免疫学から見た関節リウマチの病態
  • Author(s): 高柳広
  • Organizer: 第31回日本骨代謝学会学術集会・サテライトシンポジウム
  • Place of Presentation: 神戸国際会議場、ポートピアホテル
  • Invited
• [Presentation] Osteocytes and bone resorption
  • Author(s): 高柳広
  • Organizer: 2013年国際骨代謝学会・日本骨代謝学会 第2回合同国際会議
  • Place of Presentation: 神戸国際会議場、ポートピアホテル
  • Invited
• [Presentation] Osteocytes and Osteoclasts: Crosstalk in Osteoimmunolgy
  • Author(s): 高柳広
  • Organizer: Annual European Congress of Rheumatology(EULAR)2013
  • Place of Presentation: スペイン、マドリッド
  • Invited
• [Presentation] 関節リウマチ骨破壊と骨免疫学
  • Author(s): 高柳広
  • Organizer: 第28回日本乾癬学会
  • Place of Presentation: ベルサール八重洲
  • Invited
• [Presentation] Th17と関節炎治療の進歩
  • Author(s): 高柳広
  • Organizer: 第28回日本乾癬学会
  • Place of Presentation: 東京ドームホテル
  • Invited
• [Presentation] 骨免疫学の最前線
  • Author(s): 高柳広
  • Organizer: 第86回日本生化学大会
  • Place of Presentation: パシフィコ横浜
  • Invited
• [Presentation] Osteoimmunology
  • Author(s): 高柳広
  • Organizer: The 11th World Congress on Inflammation
  • Place of Presentation: ナタール、ブラジル
  • Invited
• [Presentation] Osteoimmunology: The interaction of bone and immune systems
  • Author(s): 高柳広
  • Organizer: Semmelweis Symposium 2013
  • Place of Presentation: ブダペスト、ハンガリー
  • Invited
• [Presentation] Bone cell communication factors
  • Author(s): 高柳広
  • Organizer: Frontiers in Skeltal Biology
  • Place of Presentation: Garvan Institute of Medical Research シドニー、オーストラリア
  • Invited
• [Presentation] 骨粗鬆症の標的としてのRANK-RANKL系
  • Author(s): 高柳広
  • Organizer: 第28回日本臨床リウマチ学会 シンポジウム１
  • Place of Presentation: 幕張メッセ（千葉市）
  • Invited
• [Presentation] Osteoimmunology
  • Author(s): 高柳広
  • Organizer: 第36回日本分子生物学会年会 シンポジウム
  • Place of Presentation: 神戸国際会議場
  • Invited
• [Presentation] Osteoimmunology
  • Author(s): 高柳広
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ（千葉市）
  • Invited
• [Presentation] Bone modeling or remodeling as a target for therapy
  • Author(s): 高柳広
  • Organizer: IOF Regionals 4th Asia-Pacific Osteoporosis Meeting
  • Place of Presentation: 香港、中国Hong Kong Convention and Exhibition
  • Invited
• [Presentation] Bone Cell Communication Factors
  • Author(s): 高柳広
  • Organizer: Gordon Research Conferences 2014 - Bones & Teeth
  • Place of Presentation: Hotel Galvez
  • Invited
• [Presentation] 骨免疫をつなぐRANKLとSemaphorin
  • Author(s): 高柳広
  • Organizer: RANMARK Symposium
  • Place of Presentation: ホテルグランビア京都
  • Invited
• [Presentation] Forefront of osteoimmunology
  • Author(s): 高柳広
  • Organizer: 国際シンポジウム
  • Place of Presentation: 東京医科歯科大学
  • Invited
• [Presentation] 骨免疫学の最前線
  • Author(s): 高柳広
  • Organizer: 岡山免疫懇話会
  • Place of Presentation: 岡山大学大学院
  • Invited
• [Presentation] RANKLシグナルと骨免疫学
  • Author(s): 高柳広
  • Organizer: 骨粗鬆症フロンティア
  • Place of Presentation: 国立国際医療研究センター
  • Invited
• [Book] 日本臨床 (2014)
  • Author(s): 小松紀子、高柳広
  • Total Pages: 5
  • Publisher: 日本臨床社
• [Book] 医学のあゆみ (2014)
  • Author(s): 高場啓之、高柳広
  • Total Pages: 11
  • Publisher: 医歯薬出版社
• [Book] 炎症と免疫 (2014)
  • Author(s): 小松紀子、高柳広
  • Total Pages: 6
  • Publisher: 先端医学社
• [Book] 別冊医学のあゆみ (2014)
  • Author(s): 寺島明日香、高柳広
  • Total Pages: 7
  • Publisher: 医歯薬出版社
• [Book] 月刊カレントテラピー (2014)
  • Author(s): 小野 岳人、高柳広
  • Total Pages: 7
  • Publisher: ライフメディコム
• [Book] 別冊「医学のあゆみ」 骨免疫学 研究最前線 (2013)
  • Author(s): 高柳広
  • Publisher: 医歯薬出版社
• [Book] THE BONE (2013)
  • Author(s): 高柳広
  • Publisher: メディカルレビュー社