Development of treatment strategies for intervertebral disc degeneration by modulating mTOR signaling

• Project/Area Number: 16K20051
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Kobe University
• Principal Investigator: YURUBE Takashi 神戸大学, 医学部附属病院, 特定助教 (10514648)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 椎間板変性 / mTOR / オートファジー / 脊椎 / 整形外科

Outline of Final Research Achievements

This study aimed to clarify effectiveness of biological therapies for intervertebral disc degeneration by modulating mTOR signaling. In our study, RNA interference technique revealed that suppression of the mTOR complex 1 (mTORC1) had protective effects against disc cellular apoptosis, senescence, and extracellular matrix degradation. Furthermore, administration of mTORC1 inhibitors to find potential clinical applications showed similar beneficial effects on disc cells through Akt induction. Then, specific autophagy inhibition by RNA interference clearly presented anti-apoptotic and anti-senescent effects of autophagy. Based on these findings, biological modulation of mTOR signaling and autophagy is a potential therapeutic strategy for degenerative disc disease.

Research Products

• [Journal Article] Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction. (2017)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Miyazaki S, Kuroda R, Nishida K.
  • Journal Title: Osteoarthritis Cartilage Volume: 25 Issue: 12 Pages: 2134-2146
  • DOI: 10.1016/j.joca.2017.08.019
  • Peer Reviewed / Open Access
• [Journal Article] 脊椎椎間板髄核におけるオートファジーの重要性とその誘導による椎間板変性予防の可能性 (2017)
  • Author(s): 由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良祐、西田康太郎
  • Journal Title: 中部日本整形外科災害外科学会雑誌 Volume: 60(3) Pages: 547-548
  • NAID: 130006108244
• [Journal Article] 椎間板では他の筋骨格系組織よりもオートファジーの関与が大きく、その活性は変性とともに減少する (2017)
  • Author(s): 由留部崇、平田裕亮、伊藤雅明、垣内裕司、寺嶋良樹、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、黒田良佑、西田康太郎
  • Journal Title: Journal of Spine Research Volume: 8 Pages: 106-111
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 椎間板の微小環境－細胞代謝、オートファジーの観点から (2017)
  • Author(s): 由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良佑、西田康太郎
  • Journal Title: 整形・災害外科 Volume: 60 Pages: 279-285
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Involvement of autophagy in intervertebral disc degeneration and its contribution to cell homeostasis with the maintenance of notochordal phenotype (2018)
  • Author(s): Yurube T, Ito M, Kakiuchi Y, Takeoka Y, Kakutani K, Takada T, Kanda Y, Miyazaki S, Kuroda R, Nishida K
  • Organizer: The 64th Annual Meeting, Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor to protect human disc cells through AKT rather than autophagy induction (2018)
  • Author(s): Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kanda Y, Kakutani K, Takada T, Kuroda R, Nishida K
  • Organizer: The 64th Annual Meeting, Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Involvement and roles of autophagy in maintaining notochordal cell homeostasis of the intervertebral disc nucleus pulposus (2017)
  • Author(s): Yurube T, Ito M, Kakiuchi Y, Terashima Y, Takeoka Y, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
  • Organizer: The 63rd Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] Selective mTORC1 inhibition through RNA interference for Raptor is protective against human disc cellular apoptosis, senescence, and extracellular matrix degradation with Akt and autophagy induction (2017)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
  • Organizer: The 63rd Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] Autophagy contributes to cell survival, anti-apoptosis, anti-senescence and extracellular matrix homeostasis in human disc nucleus pulposus cells (2017)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
  • Organizer: The 63rd Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor in human intervertebral disc nucleus pulposus cells (2017)
  • Author(s): Kakiuchi Y, Yurube T, Ito M, Takeoka Y, Terashima Y, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
  • Organizer: The 63rd Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] Inhibition of autophagy through ATG5 knock down induces apoptosis and senescence in human intervertebral disc cells (2017)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
  • Organizer: The 8th Annual Meeting of the Cervical Spine Research Society Asia Pacific Section
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2017-03-09
  • Int'l Joint Research
• [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor for protecting human intervertebral disc nucleus pulposus cells (2017)
  • Author(s): Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kakutani K, Maeno K, Takada T, Terashima Y, Kuroda R, Nishida K
  • Organizer: The 8th Annual Meeting of the Cervical Spine Research Society Asia Pacific Section
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2017-03-09
  • Int'l Joint Research
• [Presentation] mTORシグナル経路におけるRAPTORへの選択的な干渉はヒト椎間板細胞における細胞死，細胞老化と細胞外基質分解を抑制する (2017)
  • Author(s): 由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、黒田良佑、西田康太郎
  • Organizer: 第30回日本軟骨代謝学会
  • Place of Presentation: 京都市勧業館みやこめっせ（京都府京都市）
  • Year and Date: 2017-03-03
• [Presentation] 椎間板髄核におけるオートファジーの重要性とその脊索表現型保持への関与の可能性 (2017)
  • Author(s): 由留部崇、伊藤雅明、垣内裕司、寺嶋良樹、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、黒田良祐、西田康太郎
  • Organizer: 第46回日本脊椎脊髄病学会
• [Presentation] ATG5のノックダウンによるオートファジーの抑制はヒト椎間板細胞のアポトーシスとセネッセンスを誘導し、細胞数を減少させる (2017)
  • Author(s): 伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、黒田良祐、西田康太郎
  • Organizer: 第46回日本脊椎脊髄病学会
• [Presentation] ヒト椎間板髄核臍傍におけるmTOR阻害薬の細胞死、細胞老化、細胞外基質分解抑止効果の比較 (2017)
  • Author(s): 垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、黒田良祐、西田康太郎
  • Organizer: 第46回日本脊椎脊髄病学会
• [Presentation] Involvement of autophagy in intervertebral disc degeneration and its possible contribution to the maintenance of notochordal cell homeostasis (2017)
  • Author(s): Yurube T, Hirata H, Ito M, Terashima Y, Kakiuchi Y, Takeoka Y, Miyazaki S, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
  • Organizer: The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
  • Int'l Joint Research
• [Presentation] Inhibition of autophagy through ATG5 knock down induces apoptosis and senescence in human intervertebral disc cells (2017)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
  • Organizer: The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
  • Int'l Joint Research
• [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor for protecting human intervertebral disc nucleus pulposus cells (2017)
  • Author(s): Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kakutani K, Maeno K, Takada T, Terashima Y, Kuroda R, Nishida K
  • Organizer: The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
  • Int'l Joint Research
• [Presentation] mTORC1阻害薬テムシロリムスはヒト椎間板髄核細胞において細胞死、細胞老化、細胞外基質分解を抑制する (2017)
  • Author(s): 垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、黒田良祐、西田康太郎
  • Organizer: 第36回運動器移植再生医学研究会
• [Presentation] 脊椎椎間板変性へのオートファジーの関与とその脊索由来細胞における恒常性維持機構の可能性 (2017)
  • Author(s): 由留部崇、伊藤雅明、寺嶋良樹、垣内裕司、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、土井田稔、黒田良祐、西田康太郎
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] オートファジーの抑制はヒト椎間板細胞においてアポトーシス、セネッセンスを誘導し、細胞数を減少させる (2017)
  • Author(s): 伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、土井田稔、黒田良祐、西田康太郎
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] ｍTORC1阻害薬テムシロリスムはヒト椎間板髄核細胞において細胞死、細胞老化、細胞外基質分解を抑制する (2017)
  • Author(s): 垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、土井田稔、黒田良祐、西田康太郎
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] Involvement of autophagy in intervertebral disc degeneration and its contribution to cell survival with the maintenance of notochordal phenotype (2017)
  • Author(s): Yurube T, Hirata H, Ito M, Terashima Y, Kakiuchi Y, Takeoka Y, Kakutani K, Takada T, Miyazaki S, Kuroda R, Nishida K
  • Organizer: The 45th Annual Meeting, Cervical Spine Research Society
  • Int'l Joint Research
• [Presentation] 脊椎椎間板髄核では他の筋骨格・神経組織よりもオートファジーの関与が大きく、変性が進行するとその活性は減少する (2016)
  • Author(s): 由留部崇、平田裕亮、伊藤雅明、垣内裕司、寺嶋良樹、角谷賢一朗、前野耕一郎、高田徹、黒坂昌弘、西田康太郎
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
• [Presentation] 椎間板変性モデルについて (2016)
  • Author(s): 西田康太郎、由留部崇、高田徹、角谷賢一朗、前野耕一郎、伊藤雅明、寺嶋良樹、垣内裕司、武岡由樹
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] mTORシグナル経路への選択的な干渉はオートファジーとAktの活性化を誘導し、ヒト椎間板細胞における細胞死、細胞老化と細胞外基質分解を抑制する：椎間板遺伝子治療の可能性 (2016)
  • Author(s): 伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、宮崎真吾、寺嶋良樹、垣内裕司、黒坂昌弘、西田康太郎
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
• [Presentation] 脊椎椎間板髄核におけるオートファジーの重要性とその誘導による椎間板変性予防の可能性 (2016)
  • Author(s): 由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良佑、西田康太郎
  • Organizer: 第127回中部日本整形外科災害外科学会学術集会
  • Place of Presentation: まつもと市民芸術館・ホテルブエナビスタ（長野県松本市）
  • Year and Date: 2016-09-30
• [Presentation] Intervertebral disc nucleus pulposus has intensive involvement of autophagy compared to other musculoskeletal tissues and its degeneration is linked with decreased autophagy (2016)
  • Author(s): Yurube T, Hirata H, Ito M, Kakiuchi Y, Kakutani K, Maeno K, Takada T, Miyazaki S, Terashima Y, Kurosaka M, Nishida K
  • Organizer: The 43rd Annual Meeting of the International Society for the Study of the Lumbar Spine (Spineweek 2016)
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2016-05-16
  • Int'l Joint Research
• [Presentation] Selective interference of mTOR signaling is protective against human disc cellular apoptosis, senescence, and extracellular matrix degradation with autophagy induction (2016)
  • Author(s): Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Miyazaki S, Terashima Y, Kakiuchi Y, Kurosaka M, Nishida K
  • Organizer: The 43rd Annual Meeting of the International Society for the Study of the Lumbar Spine (Spineweek 2016)
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2016-05-16
  • Int'l Joint Research
• [Presentation] 椎間板では他の筋骨格系組織よりもオートファジーの関与が大きく、その活性は変性とともに減少する：オートファジー制御による椎間板変性予防の可能性 (2016)
  • Author(s): 由留部崇、平田裕亮、伊藤雅明、垣内裕司、角谷賢一朗、前野耕一郎、宮崎真吾、寺嶋良樹、黒坂昌弘、西田康太郎
  • Organizer: 第45回日本脊椎脊髄病学会
  • Place of Presentation: 幕張メッセ（千葉県千葉市）
  • Year and Date: 2016-04-14
• [Presentation] mTORシグナル経路への選択的な干渉はオートファジーとAktの活性化を誘導し、ヒト椎間板細胞における細胞死、老化と細胞外基質分解を抑制する (2016)
  • Author(s): 伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、宮崎真吾、寺嶋良樹、垣内裕司、黒坂昌弘、西田康太郎
  • Organizer: 第45回日本脊椎脊髄病学会
  • Place of Presentation: 幕張メッセ（千葉県千葉市）
  • Year and Date: 2016-04-14