The approach of molecular treatments for the intervertebral disc degeneration.

• Project/Area Number: 15K10406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kobe University
• Principal Investigator: Maeno Koichiro 神戸大学, 医学研究科, 医学研究員 (70403269)
• Co-Investigator(Kenkyū-buntansha): 西田 康太郎 神戸大学, 医学研究科, 准教授 (00379372) ; 由留部 崇 神戸大学, 医学部附属病院, その他 (10514648) ; 角谷 賢一朗 神戸大学, 医学研究科, 助教 (10533739)
• Research Collaborator: Miyazaki Shingo 神戸大学, 大学院医学研究科, 大学院生 ; Terashima Yoshiki 神戸大学, 大学院医学研究科, 大学院生 ; Ito Masaaki 神戸大学, 大学院医学研究科, 大学院生 ; Takeoka Yoshiki 神戸大学, 大学院医学研究科, 大学院生 ; Kakiuti Yuji 神戸大学, 大学院医学研究科, 大学院生
• Project Period (FY): 2015-04-01 – 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 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 椎間板 / mTOR / Raptor / siRNA / アポトーシス / オートファジー / セネッセンス / mTORC1阻害薬 / Rictor / 椎間板変性

Outline of Final Research Achievements

mTORC1 suppression through RNAi for Raptor showed protective effects against human NP cell apoptosis, senescence, and matrix degradation. This study suggests that selective inhibition for mTORC1 but not mTORC2 is beneficial to human NP cells, which depends on Akt as well as autophagy induction. Thus, Raptor is a potent target for new molecular treatments for human degenerative disc disease. And also, in our results, the first generation mTOR inhibitors suppressed mTOR signaling, induced autophagy and Akt, and showed protective effects against human disc NP cell apoptosis and senescence. In clinical use, adverse immunosuppression of mTOR inhibitors would recommend its local intra-discal injection rather than its systemic administration. To accomplish successful local delivery of agents, water solubility is a key factor. Therefore, intra-discal injection of temsirolimus that has improved water solubility is a potential therapeutic application to human 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
• [Presentation] Inhibition of autophagy through ATG5 knock down induces apoptosis and senescence, resulting in reduced cellularity, 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: 63th Annual Meeting of 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 intervertebral 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: 63th Annual Meeting of 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: 63th Annual Meeting of 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: 8th Annual Meeting of Cervical Spine Research Society -Asia Pacific Section-
  • Place of Presentation: Kobe (JAPAN)
  • Year and Date: 2017-03-09
  • 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: 8th Annual Meeting of Cervical Spine Research Society -Asia Pacific Section-
  • Place of Presentation: Kobe (JAPAN)
  • Year and Date: 2017-03-09
  • Int'l Joint Research
• [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] 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] 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] 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] 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, 寺嶋 良樹, 垣内 裕司, 武岡 由樹, 黒田 良祐, 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（福岡県博多市）
  • Year and Date: 2016-10-13
• [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: 43th Annual Meeting of the International Society for the Study of the Lumbar Spine
  • 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, Maeno K, et.al.,
  • Organizer: The 43rd annual meeting of International Society for the Study of the Lumbar Spine
  • Place of Presentation: Singapore
  • Year and Date: 2016-05-16
• [Presentation] mTORシグナル経路への選択的な干渉はAktの活性化およびオートファジーを誘導し、ヒト椎間板における細胞死、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
• [Presentation] mTORシグナル経路への選択的な干渉はAktの活性化およびオートファジーを誘導し、ヒト椎間板における細胞死・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、前野 耕一郎ほか
  • Organizer: 第45回日本脊椎脊髄病学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2016-04-14