Investigation of stress response mechanism of chondrocytes by reproduction of physiological hypoxic environment

• Project/Area Number: 26462312
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Arai Yuji 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (50347449)
• Co-Investigator(Kenkyū-buntansha): 久保 俊一 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20178031) ; 中川 周士 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30643382) ; 土田 真嗣 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10719834)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HIF-1α / hyaluronic acid / CD44 / articular cartilage / extracellular matrix / hypoxia / 軟骨 / 低酸素 / ヒアルロン酸 / 変形性関節症 / 低酸素環境 / 細胞外マトリックス / 高分子ヒアルロン酸 / HSP70

Outline of Final Research Achievements

High molecular weight hyaluronic acid (HA) is widely used clinically as an intra-articular injection for osteoarthritis, but the pharmacological effect under hypoxic condition is not clear. The purpose of this study is to clarify the effect of HA on articular cartilage under hypoxia. It was revealed that the cartilage assimilatory pharmacological action of the exogenous macromolecule HA on articular cartilage is promoted in hypoxic condition. As a mechanism, it was shown that the expression of CD44 was enhanced by the HIF-1α pathway and the binding affinity to the exogenous polymer HA was improved. Maintaining the hypoxic environment around chondrocytes is important for exerting the anabolic effect of exogenous high molecular weight HA.

Research Products

• [Journal Article] Hypoxia Potentiates Anabolic Effects of Exogenous Hyaluronic Acid in Rat Articular Cartilage (2016)
  • Author(s): Ichimaru S. et al.
  • Journal Title: Int J Mol Sci. Volume: 17 Issue: 7 Pages: 1013-1013
  • DOI: 10.3390/ijms17071013
  • Peer Reviewed / Open Access
• [Journal Article] HIF-1α-induced HSP70 regulates anabolic responses in articular chondrocytes under hypoxic conditions (2014)
  • Author(s): Tsuchida S, Arai Y, Takahashi KA, Kishida T, Terauchi R, Honjo K, Nakagawa S, Inoue H, Ikoma K, Ueshima K, Matsuki T, Mazda O, Kubo T
  • Journal Title: J Orthop Res Volume: (Epub ahead of print) Issue: 8 Pages: 975-980
  • DOI: 10.1002/jor.22623
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/24677016
  • Peer Reviewed / Open Access
• [Presentation] The effect of treadmill running on knee articular cartilage in rats (2017)
  • Author(s): Seiji Shimomura, Hiroaki Inoue, Yuji Arai, Shuji Nakagawa, Shinji Tsuchida, Shohei Ichimaru, Osam Mazda, Toshikazu Kubo
  • Organizer: 20th World Congress of the Osteoarthritis Research Society International (OARSI)
  • Int'l Joint Research
• [Presentation] Regulation of inflammatory cytokine expression and osteoclastgenesis by gap junctional protein in vitro and in vivo. (2017)
  • Author(s): Seiji Shimomura, Shinji Tsuchida, Yuji Arai, Shuji Nakagawa, Hiroaki Inoue, Shohei Ichimaru, Yuta Fujii, Osam Mazda, Toshikazu Kubo
  • Organizer: The 5th annual meeting of the international cytokine and interferon society
  • Int'l Joint Research
• [Presentation] トレッドミル走行がラット膝関節軟骨に与える影響 (2016)
  • Author(s): 下村征史，井上裕章，新井祐志，中川周士，土田真嗣，市丸昌平，松田 修，久保俊一
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2016-10-13
• [Presentation] 低酸素環境下における外因性ヒアルロン酸の薬理効果の変化 (2016)
  • Author(s): 市丸昌平，中川周士，新井祐志，土田真嗣，井上裕章，下村征史，松田 修，久保俊一
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2016-10-13
• [Presentation] Pharmacological effects of exogenous hyaluronan in articular cartilage under hypoxia (2016)
  • Author(s): Ichimaru S, Nakagawa S, Arai Y, Tsuchida S, Inoue H, Shimomura S, Mazda O, Kubo T
  • Organizer: 19th World Congress of the Osteoarthritis Research Society International (OARSI)
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] Pharmacological effects of exogenous hyaluronic acid in articular cartilage under hypoxia (2016)
  • Author(s): Ichimaru S, Nakagawa S, Arai Y, Tsuchida S, Inoue H, Shimomura S, Mazda O, Kubo T
  • Organizer: 第29回日本軟骨代謝学会
  • Place of Presentation: 広島
  • Year and Date: 2016-02-19
• [Presentation] 低酸素環境下にある軟骨細胞に対する外因性ヒアルロン酸の薬理効果 (2015)
  • Author(s): 市丸昌平，中川周士，新井祐志，土田真嗣，井上裕章，本城邦晃，白井寿治，寺内 竜，松田 修，久保俊一
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山
  • Year and Date: 2015-10-22
• [Presentation] HSP70 induced by HIF-1α regulates anabolic responses in chondrocytes under hypoxic conditions (2015)
  • Author(s): Kuniaki Honjo, Shinji Tsuchida, Shuji Nakagawa, Hiroaki Inoue, Masazumi Saito, Shohei Ichimaru, Seiji Shimomura, Atsuo Inoue, Ryu Terauchi, Osam Mazda, Yoshikazu Kubo
  • Organizer: World Congress of the Osteoarthritis Research Society International (OARSI) annual meeting 2015
  • Place of Presentation: Seattle, USA
  • Year and Date: 2015-04-30
  • Int'l Joint Research
• [Presentation] The anabolic effects of HIF-1α-induced HSP70 in rabbit articular chondrocyte under hypoxic conditions (2015)
  • Author(s): Shohei Ichimaru, Shinji Tsuchida, Yuji Arai, Shuji Nakagawa, Hiroaki Inoue, Tomohiro Matsuki, Kuniaki Honjo, Keiichiro Ueshima, Osam Mazda, Toshikazu Kubo
  • Organizer: Orthopaedic Research Society 2015 annual meeting
  • Place of Presentation: Las Vegas
  • Year and Date: 2015-03-28 – 2015-03-31