Pathological role of mitochondrial oxidative stress in cartilage degeneration

• Project/Area Number: 26462319
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Juntendo University
• Principal Investigator: Nojiri Hidetoshi 順天堂大学, 医学部, 准教授 (10317456)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 酸化ストレス / 軟骨 / 変形性関節症 / 加齢 / 変性 / メカニカルストレス / スーパーオキシド / Sod2

Outline of Final Research Achievements

We herein demonstrate that mechanical loading promoted mitochondrial superoxide generation and selective Sod2 downregulation in chondrocytes in vivo and that mitochondrial superoxide inducer also downregulated Sod2 expression in chondrocytes in vitro. A genetically manipulated model revealed that Sod2 deficiency in chondrocytes also resulted in mitochondrial superoxide overproduction and dysfunction, thus leading to cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Our findings demonstrate that mitochondrial superoxide plays a pivotal role in the development and progression of osteoarthritis, and the mitochondrial superoxide balance may therefore be a promising target for the treatment of cartilage degeneration.

Research Products

• [Journal Article] Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration (2015)
  • Author(s): Koike, M., Nojiri, H., Ozawa, Y., Watanabe, K., Muramatsu, Y., Kaneko, H., Morikawa, D., Kobayashi, K., Saita, Y., Sasho, T., Shirasawa, T., Yokote, K., Kaneko, K., Shimizu, T.
  • Journal Title: Sci. Rep. Volume: 5 Issue: 1 Pages: 11722-11722
  • DOI: 10.1038/srep11722
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. (2015)
  • Author(s): Kobayashi K1, Nojiri H2, Saita Y2, Morikawa D1, Ozawa Y3, Watanabe K3, Koike M1, Asou Y4, Shirasawa T5, Yokote K6, Kaneko K2, Shimizu T3.
  • Journal Title: Scientific Reports Volume: Mar 16;5 Issue: 1 Pages: 9148-9148
  • DOI: 10.1038/srep09148
  • Peer Reviewed / Open Access
• [Journal Article] Brain-specific superoxide dismutase 2 deficiency causes perinatal death with spongiform encephalopathy in mice. (2015)
  • Author(s): Izuo, N., Nojiri, H., Uchiyama, S., Noda, Y., Kawakami, S., Kojima, S., Sasaki, T., Shirasawa, T., Shimizu, T.
  • Journal Title: Oxid. Med. Cell. Longev. Volume: 2015 Pages: 238914-238914
  • DOI: 10.1155/2015/238914
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 加齢に伴う運動器の機能低下と酸化ストレスの関係 (2016)
  • Author(s): 野尻英俊
  • Organizer: 第４４回日本関節病学会
  • Place of Presentation: 別府
  • Year and Date: 2016-11-12
  • Invited
• [Presentation] 加齢に伴う運動器の機能低下と酸化ストレス (2016)
  • Author(s): 野尻英俊
  • Organizer: 第１１回ファンクショナルフード学会
  • Place of Presentation: 東京
  • Year and Date: 2016-08-26
  • Invited
• [Presentation] 末期変形性関節症の軟骨細胞内スーパーオキシドは顕著に増加する. (2016)
  • Author(s): 野尻英俊
  • Organizer: 第１６回日本抗加齢医学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-06-10
• [Presentation] OA発症メカニズム (2014)
  • Author(s): 小池正人、野尻英俊
  • Organizer: 第29回日本整形外科基礎学術集会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] Chondrocyte-specific Deletion of Sod2 Exacerbates Cartilage Degeneration Associated with Low Mitochondrial Membrane Potential in Mice. (2014)
  • Author(s): Koike M, Nojiri H
  • Organizer: American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting
  • Place of Presentation: Houston
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Chondrocyte-specific deletion of Sod2 exacerbates age-related cartilage degeneration in mice. (2014)
  • Author(s): Koike M, Nojiri H
  • Organizer: Australia and New Zealand Bone & Mineral Society (ANZBMS) 24th Annual Scientific Meeting
  • Place of Presentation: Queenstown
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] 関節軟骨におけるSod2欠損は加齢性軟骨変性を助長する (2014)
  • Author(s): 小池正人、野尻英俊
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-24 – 2014-07-26
• [Presentation] Sod2 deficiency in chondrocytes accelerates age-related osteoarthritis in mice. (2014)
  • Author(s): Koike M, Nojiri H
  • Organizer: 2014 Osteoarthritis Research Society International (OARSI) world congress 2014
  • Place of Presentation: Paris
  • Year and Date: 2014-04-24 – 2014-04-27
• [Book] Systems Biology of Free Radicals and Antioxidants (2014)
  • Author(s): Shimizu T, Nojiri H, et al.
  • Publisher: Springer-Verlag Berlin Heidelberg
• [Book] Aging: Oxidative Stress and Dietary Antioxidants (2014)
  • Author(s): Shibuya S, Nojiri H, et al.
  • Publisher: Elsevier Inc.
• [Patent(Industrial Property Rights)] 関節症若しくは関節炎の、治療剤又は予防剤 (2015)
  • Inventor(s): 野尻英俊
  • Industrial Property Rights Holder: 野尻英俊
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-18