Regulation of Articular Chondrocyte Differentiation

• Project/Area Number: 17H04310
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• 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, 准教授 (30456107)
• Co-Investigator(Kenkyū-buntansha): 小林 寛 東京大学, 医学部附属病院, 助教 (20407951) ; 張 成虎 東京大学, 医学部附属病院, 特任臨床医 (80780551)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 整形外科学 / 変形性関節症 / 関節最表層 / 骨軟骨代謝学 / 骨・軟骨代謝学

Outline of Final Research Achievements

Recent studies have suggested that different signaling pathways regulate chondrocytes in different layers of articular cartilage. We examined characters of these chondrocytes and identified that WNT and Notch signaling differently regulate differentiation of superficial zone chondrocytes and deep chondrocytes. We have further revealed the molecular mechanisms of mechanosensing in superficial zone.

Academic Significance and Societal Importance of the Research Achievements

変形性関節症は、関節軟骨の変性に始まり、周辺の骨の硬化性変化、滑膜の炎症性変化を伴って進行し、関節痛を引き起こして運動機能を著しく低下させる疾患である。その治療法には近年目立った進歩はなく、末期患者には人工関節置換術などの手術療法が選択されるものの、病態を制御しうるような本質的な治療法はいまだ存在しない。本研究の成果は関節軟骨がどのように制御されているか、その本質に迫るものであり、今後の治療薬開発の基盤となるものと考える。

Research Products

• [Journal Article] Primary culture of mouse adipose and fibrous synovial fibroblasts under normoxic and hypoxic conditions (2020)
  • Author(s): SUGIMOTO Hikaru、MURAHASHI Yasutaka、CHIJIMATSU Ryota、MIWA Satoshi、YANO Fumiko、TANAKA Sakae、SAITO Taku
  • Journal Title: Biomedical Research Volume: 41 Issue: 1 Pages: 43-51
  • DOI: 10.2220/biomedres.41.43
  • NAID: 130007801491
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2020-02-01
  • Peer Reviewed / Open Access
• [Journal Article] Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss (2020)
  • Author(s): Omata Yasunori、Frech Michael、Lucas S?bastien、Primbs Tatjana、Knipfer Lisa、Wirtz Stefan、Kadono Yuho、Saito Taku、Tanaka Sakae、Sarter Kerstin、Schett Georg、Zaiss Mario M.
  • Journal Title: Bone Volume: 136 Pages: 115335-115335
  • DOI: 10.1016/j.bone.2020.115335
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion (2019)
  • Author(s): Murahashi Yasutaka、Yano Fumiko、Chijimatsu Ryota、Nakamoto Hideki、Maenohara Yuji、Amakawa Masahiro、Miyake Yoshihide、Yamanaka Hiroyuki、Iba Kousuke、Yamashita Toshihiko、Tanaka Sakae、Saito Taku
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 20329-20329
  • DOI: 10.1038/s41598-019-56861-6
  • Peer Reviewed / Open Access
• [Journal Article] Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone (2019)
  • Author(s): Xuan Fengjun、Yano Fumiko、Mori Daisuke、Chijimatsu Ryota、Maenohara Yuji、Nakamoto Hideki、Mori Yoshifumi、Makii Yuma、Oichi Takeshi、Taketo Makoto Mark、Hojo Hironori、Ohba Shinsuke、Chung Ung-il、Tanaka Sakae、Saito Taku
  • Journal Title: Arthritis Research & Therapy Volume: 21 Issue: 1 Pages: 247-247
  • DOI: 10.1186/s13075-019-2041-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simple and Robust Differentiation of Human Pluripotent Stem Cells toward Chondrocytes by Two Small-Molecule Compounds (2019)
  • Author(s): Kawata Manabu、Mori Daisuke、Kanke Kosuke、Hojo Hironori、Ohba Shinsuke、Chung Ung-il、Yano Fumiko、Masaki Hideki、Otsu Makoto、Nakauchi Hiromitsu、Tanaka Sakae、Saito Taku
  • Journal Title: Stem Cell Reports Volume: 13 Issue: 3 Pages: 530-544
  • DOI: 10.1016/j.stemcr.2019.07.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Excessive mechanical loading promotes osteoarthritis through the gremlin-1?NF-κB pathway (2019)
  • Author(s): Chang Song Ho、Mori Daisuke、Kobayashi Hiroshi、Mori Yoshifumi、Nakamoto Hideki、Okada Keita、Taniguchi Yuki、Sugita Shurei、Yano Fumiko、Chung Ung-il、Kim-Kaneyama Joo-ri、Yanagita Motoko、Economides Aris、Canalis Ernesto、Chen Di、Tanaka Sakae、Saito Taku
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1442-1442
  • DOI: 10.1038/s41467-019-09491-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis (2019)
  • Author(s): Izawa Naohiro、Kurotaki Daisuke、Nomura Seitaro、Fujita Takanori、Omata Yasunori、Yasui Tetsuro、Hirose Jun、Matsumoto Takumi、Saito Taku、Kadono Yuho、Okada Hiroyuki、Miyamoto Takeshi、Tamura Tomohiko、Aburatani Hiroyuki、Tanaka Sakae
  • Journal Title: Journal of Bone and Mineral Research Volume: 34 Issue: 6 Pages: 1143
  • DOI: 10.1002/jbmr.3689
  • Peer Reviewed / Open Access
• [Journal Article] Multi-layered PLLA-nanosheets loaded with FGF-2 induce robust bone regeneration with controlled release in critical-sized mouse femoral defects (2019)
  • Author(s): Murahashi Yasutaka、Yano Fumiko、Nakamoto Hideki、Maenohara Yuji、Iba Kousuke、Yamashita Toshihiko、Tanaka Sakae、Ishihara Kazuhiko、Okamura Yosuke、Moro Toru、Saito Taku
  • Journal Title: Acta Biomaterialia Volume: 85 Pages: 172-179
  • DOI: 10.1016/j.actbio.2018.12.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of the small compound TD ‐198946 on glycosaminoglycan synthesis and transforming growth factor β3‐associated chondrogenesis of human synovium‐derived stem cells in vitro (2019)
  • Author(s): Chijimatsu Ryota、Yano Fumiko、Saito Taku、Kobayashi Masato、Hamamoto Shuichi、Kaito Takashi、Kushioka Junichi、Hart David A.、Chung Ung‐il、Tanaka Sakae、Yoshikawa Hideki、Nakamura Norimasa
  • Journal Title: Journal of Tissue Engineering and Regenerative Medicine Volume: 13 Issue: 3 Pages: 446-458
  • DOI: 10.1002/term.2795
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intra-articular administration of IκBα kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-κB/HIF-2α axis (2018)
  • Author(s): Murahashi Yasutaka、Yano Fumiko、Kobayashi Hiroshi、Makii Yuma、Iba Kousuke、Yamashita Toshihiko、Tanaka Sakae、Saito Taku
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 16475-16475
  • DOI: 10.1038/s41598-018-34830-9
  • Peer Reviewed / Open Access
• [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] Targeting gene expression to specific cells of kidney tubules in vivo, using adenoviral promoter fragments (2017)
  • Author(s): Sumiyo Watanabe , Toru Ogasawara, Yoshifuru Tamura, Taku Saito, Toshiyuki Ikeda, Nobuchika Suzuki, Tatsuo Shimosawa, Shigeru Shibata, Ung-il Chung, Masaomi Nangaku, Shunya Uchida
  • Journal Title: PLoS One Volume: 12 Issue: 3 Pages: 1-14
  • DOI: 10.1371/journal.pone.0168638
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB (2017)
  • Author(s): Saito Taku、Tanaka Sakae
  • Journal Title: Arthritis Research & Therapy Volume: 19 Issue: 1 Pages: 94-94
  • DOI: 10.1186/s13075-017-1296-y
  • Peer Reviewed
• [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
• [Presentation] 過剰な力学的負荷による軟骨変性の分子機構 (2019)
  • Author(s): 齋藤琢
  • Organizer: 第20回運動器科学研究会
  • Invited
• [Presentation] 変形性関節症の分子病態と治療法の開発 (2019)
  • Author(s): 齋藤琢
  • Organizer: 第68回東日本整形災害外科学会
  • Invited
• [Presentation] 変形性関節症の分子病態と治療法開発 (2019)
  • Author(s): 齋藤琢
  • Organizer: 第92回日本整形外科学会学術総会
  • Invited
• [Presentation] 変形性関節症の分子病態と治療法の研究 (2019)
  • Author(s): 齋藤琢
  • Organizer: 第26回埼玉骨・関節疾患研究会
  • Invited
• [Presentation] Runx3は関節軟骨に保護的に作用する (2018)
  • Author(s): 永田向生、齋藤琢、他
  • Organizer: 第33回日本整形外科学会基礎学術集会
• [Presentation] Runx3は関節軟骨に保護的に作用する (2018)
  • Author(s): 永田向生、齋藤琢、他
  • Organizer: 第36回日本骨代謝学会
• [Presentation] 変形性関節症の分子病態と治療法の研究 (2018)
  • Author(s): 齋藤琢
  • Organizer: 第33回日本整形外科学会基礎学術集会
  • Invited
• [Presentation] 変形性関節症の分子病態と治療法の研究 (2018)
  • Author(s): 齋藤琢
  • Organizer: 第6回軟骨・椎間板研究会
  • Invited
• [Presentation] 転写因子HIF-2aは関節軟骨最表層に発現し、関節軟骨に保護的に作用する (2017)
  • Author(s): 牧井勇磨、齋藤琢、他
  • Organizer: 日本骨代謝学会、日本整形外科学会基礎学術集会、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、齋藤琢、他
  • Organizer: 日本骨代謝学会、日本整形外科学会基礎学術集会、日本軟骨代謝学会
• [Remarks] 東京大学医学部整形外科
  • URL: http://www.u-tokyo-ortho.jp/