Development of combination therapy of tanezumab and intra-articular injection in an osteoarthritic rat model

• Project/Area Number: 18K16642
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Hokkaido University
• Principal Investigator: Iwasaki Koji 北海道大学, 医学研究院, 特任助教 (40771895)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 神経成長因子 / 変形性膝関節症 / 保存治療 / 抗神経成長因子抗体 / 除痛 / アルギン酸 / 疼痛 / 抗NGF抗体 / 鎮痛

Outline of Final Research Achievements

Knee osteoarthritis (OA) was induced in an 8-week-old male Sprague–Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100μg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100μg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.
Keywords:

Academic Significance and Societal Importance of the Research Achievements

変形性膝関節症（OA)は高齢者に多く発症し，その治療は高齢化が進む日本の医療において重要である．膝OAに対する保存治療には，NSAIDS，麻薬などが用いられているが，その効果の程度，副作用から除痛効果が強く安全性の高い薬剤が期待されている．抗NGF抗体の全身投与治療は，優れた除痛効果をもたらすが，膝OAの増悪を引き起こすことが報告されている．本研究の結果，膝OAラットにおいて抗NGF抗体の関節注射治療は，全身投与と比べ少量の抗NGF抗体で除痛効果が得られ，膝OA増悪を惹起しないことが明らかになり，有効な膝OA治療方法としての可能性が示唆された．

Research Products

• [Journal Article] Local Administration of Low-Dose Nerve Growth Factor Antibody Reduced Pain in a Rat Osteoarthritis Model (2021)
  • Author(s): Tian Yuan、Onodera Tomohiro、Terkawi Mohamad Alaa、Iwasaki Koji、Hishimura Ryosuke、Liang Dawei、Miyazaki Takuji、Iwasaki Norimasa
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 5 Pages: 2552-2552
  • DOI: 10.3390/ijms22052552
• [Presentation] 人工膝関節置換術の手術侵襲によるNGF濃度変化の検討 (2021)
  • Author(s): 小野寺 智洋, 松原 新史, 松岡 正剛, 岩崎 浩司, 菱村 亮介, 近藤 英司, 安藤 梓, 山本 美幸, 森岡 靖英, 岩崎 倫政
  • Organizer: 日本整形外科学術総会
• [Presentation] The Effect of Surgical Invasion by Total Knee arthroplasty on intra-articular Nerve Growth Factor (NGF) concentration (2021)
  • Author(s): Tomohiro Onodera, Shinji Matsubara, Masatake Matsuoka, Koji Iwasaki, Eiji Kondo, Yasuhide Morioka, Norimasa Iwasak1
  • Organizer: ORS 2021 Annual meeting
  • Int'l Joint Research
• [Presentation] Local Administration of Low-Dose Nerve Growth Factor Antibody Reduced Pain in a Rat Osteoarthritis Model (2021)
  • Author(s): Y. Tian, T. Onodera, M.A. Terkawi, K. Iwasaki, R. Hishimura, T. Miyazaki, D. Liang, L. Xu, N. Iwasaki
  • Organizer: ORS 2021 Annual meeting
  • Int'l Joint Research
• [Presentation] Local administration of low-dose NGF antibody reduced pain in rat osteoarthritis model (2019)
  • Author(s): Y. Tian, T. Onodera, M.A. Terkawi, K. Iwasaki, R. Hishimura, T. Miyazaki, D. Liang, L. Xu, N. Iwasaki
  • Organizer: 15th World Congress ICRS
  • Int'l Joint Research
• [Presentation] 変形性関節症ラットモデルにおいてNGF抗体の関節内注射は低用量で除痛効果が得られる (2019)
  • Author(s): Yuan Tian, Tomohiro Onodera, Mohamad Alaa Terkawi, Koji Iwasaki, Ryousuke Hishimura, Takuji Miyazaki, Dawei Liang, Norimasa Iwasaki
  • Organizer: 第34回日本整形外科学会基礎学術集会