Differentiation mechanism of foreign body giant cells

• Project/Area Number: 18K09017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Matsubara Takehiro 東京大学, 医学部附属病院, 講師 (40361498)
• Co-Investigator(Kenkyū-buntansha): 岡田 慶太 東京大学, 医学部附属病院, 助教 (50759173) ; 宮本 健史 慶應義塾大学, 医学部(信濃町), 特任教授 (70383768) ; 松本 卓巳 東京大学, 医学部附属病院, 講師 (70436468)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 異物巨細胞 / 異物反応 / カルシウム振動 / 破骨細胞 / マウス腹腔内異物投与モデル / 異物排除と寛容 / マクロファージ分化

Outline of Final Research Achievements

We analyzed differentiation of foreign body giant cells (FBGCs) and their function. The origin of FBGCs is monocyte, and is same as osteoclasts. We invented in vitro efficient culture system of FBGCs. With this culture system, we clarified differentiation of FBGCs were inhibited in Osteoclast's differentiation factor KO mice.
Next, we focused on calcium oscillations (Ca oscillations), which is necessary for osteoclast differentiation. We made a review paper of Ca oscillations in osteoclast differentiation. In FBGCs differentiation, Ca oscillations were also important, because Ca oscillations were interfered directly with FBGCs' differentiation factors. We clarified an important mechanism of FBGCs differentiation. In addition, we got hints to improve bio-compatibility of implants through this study.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、異物巨細胞の分化メカニズムが明らかになった。異物反応への理解が一層深まり、かつ生体親和性の高いインプラントのヒントが多く得られた。
異物反応の適切な理解に基づき、異物反応調整因子を搭載したインプラント開発に進めていく予定にしている。また基礎研究としても、特に免疫感染症領域において、異物が寛容されるメカニズムが生体内免疫拒絶反応を考える上で貴重なモデルとなりうる。学際的発展の可能性が高まったと自負している。

Research Products

• [Journal Article] Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice (2021)
  • Author(s): Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 542 Pages: 48-53
  • DOI: 10.1016/j.bbrc.2021.01.026
  • Peer Reviewed
• [Journal Article] Surgical Treatment of Pathological Tibial Shaft Fracture in Adult Patient With Gnathodiaphyseal Dysplasia (2021)
  • Author(s): Takeda Ryutaro、Yasui Tetsuro、Kasai Taro、Matsumoto Takumi、Matsubara Takehiro、Tanaka Sakae
  • Journal Title: JBJS Case Connector Volume: 11 Issue: 2
  • DOI: 10.2106/jbjs.cc.21.00005
  • Peer Reviewed
• [Journal Article] Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption (2020)
  • Author(s): Okada Hiroyuki、Okabe Koji、Tanaka Sakae
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 1 Pages: 180-180
  • DOI: 10.3390/ijms22010180
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-inducible factor-1 alpha maintains mouse articular cartilage through suppression of NF-κB signaling (2020)
  • Author(s): Okada Keita、Mori Daisuke、Makii Yuma、Nakamoto Hideki、Murahashi Yasutaka、Yano Fumiko、Chang Song Ho、Taniguchi Yuki、Kobayashi Hiroshi、Semba Hiroaki、Takeda Norihiko、Piao Wen、Hanaoka Kenjiro、Nagano Tetsuo、Tanaka Sakae、Saito Taku
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5425-5425
  • DOI: 10.1038/s41598-020-62463-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw (2020)
  • Author(s): Soma T, Iwasaki R, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Ito E, Okada H, Watanabe H, Miyamoto K, Matsumoto M, Nakamura M, Asoda S, Kawana H, Nakagawa T, Miyamoto T
  • Journal Title: J Bone Miner Metab Volume: - Issue: 3 Pages: 372-384
  • DOI: 10.1007/s00774-020-01174-2
  • Peer Reviewed
• [Journal Article] Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells (2020)
  • Author(s): Maenohara Yuji、Chijimatsu Ryota、Tachibana Naohiro、Uehara Kosuke、Xuan Fengjun、Mori Daisuke、Murahashi Yasutaka、Nakamoto Hideki、Oichi Takeshi、Chang Song Ho、Matsumoto Takumi、Omata Yasunori、Yano Fumiko、Tanaka Sakae、Saito Taku
  • Journal Title: Journal of Bone and Mineral Research Volume: 36 Issue: 4 Pages: 792-802
  • DOI: 10.1002/jbmr.4226
  • Peer Reviewed / Open Access
• [Journal Article] CTLA4-Ig directly inhibits osteoclastogenesis by interfering with intracellular calcium oscillations in bone marrow macrophages. (2019)
  • Author(s): Okada H, Kajiya H, Omata Y, Matsumoto T, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Nakamura S, Koyama T, Sudo S, Shin M, Okamoto F, Watanabe H, Tachibana N, Hirose J, Saito T, Takai T, Matsumoto M, Nakamura M, Okabe K, Miyamoto T, Tanaka S.
  • Journal Title: J Bone Miner Res Volume: 34 Issue: 9 Pages: 1744-1752
  • DOI: 10.1002/jbmr.3754
  • Peer Reviewed
• [Presentation] Dectin-2はFcRγと会合し、カルシウム振動に干渉し異物反応を制御する (2020)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、岡部幸司、宮本健史、田中栄
  • Organizer: 第38回日本骨代謝学会
• [Presentation] 破骨細胞分化初期の共刺激-カルシウムオシレーション-NFATc1 軸 ~特に共刺激周囲の補因子について (2020)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、岡部幸司、宮本健史、田中栄
  • Organizer: 第93回日本生化学会大会 シンポジウム「Calcineurin/NFATシグナルのダイバーシティ」
  • Invited
• [Presentation] Dectin-2, a Fc receptor gamma-harboring receptor, regulates foreign body reaction by interfering with intracellular calcium oscillation. (2020)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、岡部幸司、宮本健史、田中栄
  • Organizer: ASBMR 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] CTLA4-Ig (Abatacept) Directly Inhibited Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations via Fc receptor gamma (2020)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、松本卓巳、首藤俊一、進正史、岡本富士雄、廣瀬旬、岡部幸司、宮本健史、田中栄
  • Organizer: 第97回日本生理学会
• [Presentation] 単球由来巨細胞の分化誘導スイッチ : カルシウムオシレーション (2019)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、斎藤琢、岡部幸司、宮本健史、田中栄
  • Organizer: 第5回日本骨免疫学会
• [Presentation] Calcium oscillations in early osteoclast differentiation (2019)
  • Author(s): 岡田寛之、鍛治屋浩浩、小俣康徳、斎藤琢、岡部幸司、宮本健史、田中栄
  • Organizer: 第20回運動器科学研究会
• [Presentation] CTLA4-Ig directly inhibited osteoclastogenesis by interfering with intracellular calcium oscillations in bone marrow macrophages (2019)
  • Author(s): Hiroyuki Okada, Hiroshi Kajiya, Yasunori Omata, Takumi Matsumoto, Shunichi Sudo, Masashi Shin, Fujio Okamoto, Jun Hirose, Koji Okabe, Takeshi Miyamoto, Sakae Tanaka
  • Organizer: ASBMR 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] ITAM受容体は破骨細胞分化初期のCalcium oscillationを巧みに調節する (2019)
  • Author(s): 岡田寛之、鍛治屋浩、小俣康徳、進正史、岡本富士雄、斎藤琢、岡部幸司、宮本健史、田中栄
  • Organizer: 第37回日本骨代謝学会
• [Presentation] CTLA4-Igによる破骨細胞形成直接抑制メカニズム (2018)
  • Author(s): 岡田寛之、鍛冶屋浩、松本卓巳、廣瀬旬、岡部幸司、宮本健史、田中栄
  • Organizer: 20th Asia Pacific League of Associations for Rheumatology Congress、第4回日本骨免疫学会
  • Int'l Joint Research
• [Presentation] Fine tuning of calcium oscillations by ITAM receptors regulates RANKL-induced osteoclast differentiation. (2018)
  • Author(s): 岡田寛之、鍛冶屋浩、松本卓巳、廣瀬旬、岡部幸司、宮本健史、田中栄
  • Organizer: ASBMR 2018 Annual Meeting
  • Int'l Joint Research
• [Remarks] 東京大学医学部附属病院 整形外科
  • URL: http://www.u-tokyo-ortho.jp/