Development of a therapy for immobilization induced muscle atrophy by targeting Smads

• Project/Area Number: 17K10941
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: KANAJI Arihiko 慶應義塾大学, 医学部(信濃町), 講師 (20286511)
• Co-Investigator(Kenkyū-buntansha): 宮本 健史 慶應義塾大学, 医学部(信濃町), 特任教授 (70383768)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 整形外科 / 筋代謝 / 医歯薬学 / 外科系臨床医学 / 整形外科学 / 筋・神経病学

Outline of Final Research Achievements

Muscle atrophy is a risk for fall leading to fragility fractures in elderly. Thus, inhibiting muscle atrophy in elderly is mandatory. We have previously demonstrated that Smad2 and Smad3 proteins accumulated in atrophic muscles in an immobilization induced muscle atrophy model in mice. Muscle specific targeting Smad2 and Smad3 resulted in significant inhibition of the immobilization induced muscle atrophy in mice. To determine if Smad2 and Smad3 could be inhibited globally in adults, we tried to establish Smad3 flox mice. We successfully established the Smad3 flox mice. Smad2 flox mice were already gifted by a collaborator. Now we successfully generated inducible Smad2 and Smad3 doubly deficient mice in adults. We found that Smad2 and Smad3 could be targeted in adult mice. We also screened Smad3 inhibitors by a drug repositioning screen, and identified some agents as Smad3 inhibiting chemical compounds.

Academic Significance and Societal Importance of the Research Achievements

現在、様々な分子が筋萎縮に対する治療標的と考えられているが筋萎縮に対する治療薬は存在しない。我々はSmad2/Smad3が不動性筋萎縮の治療標的であることを見出していたが、Smad2/Smad3のノックアウトマウスは胎生致死であるため、アダルトにおける筋萎縮の治療標的としては有用であるかが不明であった。今回のスタディでは、Smad2/Smad3はアダルトにおいて治療標的となり得ることを明らかにした点で学術的意義がある。また人為的にSmad2/Smad3を抑制するための薬剤も同定できており、今後の筋萎縮の治療法の開発にもつなげ得る成果を得た点において、社会的意義があると考えている。

Research Products

• [Journal Article] Insulin-like growth factor-I is required to maintain muscle volume in adult mice. (2019)
  • Author(s): Nakamura S, Sato Y, Kobayashi T, Oike T, Kaneko Y, Miyamoto K, Funayama A, Oya A, Nishiwaki T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab. Volume: 印刷中 Issue: 4 Pages: 627-635
  • DOI: 10.1007/s00774-018-0964-6
  • Peer Reviewed
• [Journal Article] ２．Laser Resonance Frequency Analysis: A Novel Measurement Approach to Evaluate Acetabular Cup Stability During Surgery. (2019)
  • Author(s): Kikuchi S, Mikami K, Nakashima D, Kitamura T, Hasegawa N, Nishikino M, Kanaji A, Nakamura M, Nagura T.
  • Journal Title: Sensors (Basel) Volume: 19 Issue: 22 Pages: 4876-4876
  • DOI: 10.3390/s19224876
  • Peer Reviewed
• [Journal Article] Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Is Up-Regulated and Involved in Hyaluronan Degradation in Human Osteoarthritic Cartilage. (2018)
  • Author(s): Shimizu H, Shimoda M, Mochizuki S, Miyamae Y, Abe H, Chijiiwa M, Yoshida H, Shiozawa J, Ishijima M, Kaneko K, Kanaji A, Nakamura M, Toyama Y, Okada Y.
  • Journal Title: Am J Pathol. Volume: 188 Issue: 9 Pages: 2109-2119
  • DOI: 10.1016/j.ajpath.2018.05.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pronounced femur malunion after pathological bone fracture due to a simple bone cyst in the shaft of the femur, treated using Ilizarov fixation: a case report. (2018)
  • Author(s): Nishiwaki T, Uchikawa S, Kusakabe H, Seki A, Eguchi Y, Takayama S, Oya A, Nakamura M, Matsumoto M, Kanaji A.
  • Journal Title: J Med Case Rep. Volume: 12 Issue: 1 Pages: 173-173
  • DOI: 10.1186/s13256-018-1710-3
  • Peer Reviewed
• [Journal Article] Curved periacetabular osteotomy via a novel intermuscular approach between the sartorius and iliac muscles. (2018)
  • Author(s): Nishiwaki T, Oya A, Fukuda S, Nakamura S, Nakamura M, Matsumoto M, Kanaji A.
  • Journal Title: Hip Int. Volume: 28 Issue: 6 Pages: 642-648
  • DOI: 10.1177/1120700018772047
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions (2018)
  • Author(s): Oya A, Katsuyama E, Morita M, Sato Y, Kobayashi T, Miyamoto K, Nishiwaki T, Funayama A, Fujita Y, Kobayashi T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab Volume: - Issue: 6 Pages: 679-690
  • DOI: 10.1007/s00774-017-0890-z
  • Peer Reviewed
• [Journal Article] Pelvic Tilt Displacement Before and After Artificial Hip Joint Replacement Surgery (2018)
  • Author(s): Nishiwaki T, Hata R, Oya A, Nakamura M, Matsumoto M, Kanaji A.
  • Journal Title: J Arthroplasty Volume: 33 Issue: 3 Pages: 925-930
  • DOI: 10.1016/j.arth.2017.10.014
  • Peer Reviewed
• [Journal Article] Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases. (2018)
  • Author(s): Nishiwaki T, Uchikawa S, Kusakabe H, Seki A, Eguchi Y, Takayama S, Toyama Y, Nakamura M, Matsumoto M, Kanaji A.
  • Journal Title: J Orthop Sci. Volume: 23 Issue: 5 Pages: 853-856
  • DOI: 10.1016/j.jos.2016.09.004
  • Peer Reviewed
• [Presentation] 簡易ナビゲ-ションシステムと関節包靭帯温存手技を併用した人工股関節全置換術の有用性 (2019)
  • Author(s): 金治有彦，大矢昭仁，大野由紀雄，二木康夫，中村雅也，松本守雄
  • Organizer: 日本最小侵襲整形外科学会
• [Presentation] 仰臥位前外側進入による臼蓋側人工股関節再置換術の短期成績 (2019)
  • Author(s): 金治有彦，大矢昭仁，古郡宏行，大野由紀雄，中村賢，菊池駿介，木村篤史，二木康夫，中村雅也，松本守雄
  • Organizer: 日本股関節学会
• [Presentation] 関節包靭帯弛緩性が仰臥位前外側進入関節包靭帯温存THAの術後成績に与える影響 (2019)
  • Author(s): 金治有彦，大矢昭仁，古郡宏行，大野由紀雄，中村賢，菊池駿介，木村篤史，二木康夫，中村雅也，松本守雄
  • Organizer: 日本股関節学会
• [Presentation] 関節包靭帯を温存した股関節鏡視下関節唇縫合術の適応と限界 (2019)
  • Author(s): 金治有彦，大矢昭仁，大野由紀雄，二木康夫，中村雅也，松本守雄
  • Organizer: 日本股関節学会
• [Presentation] Accuracy of Implant Positioning and Leg Length Equality in Total Hip Arthroplasty in Supine Position for Dysplastic Hip (2019)
  • Author(s): Kanaji A，Nishiwaki T，Oya A，Ogawa R，Niki Y，Nakamura M，Matsumoto M
  • Organizer: American Academy of Orthopaedic Surgeons (AAOS)
  • Int'l Joint Research
• [Presentation] 仰臥位THAにおける関節靭帯温存の有用性ー術前脚長差1cm以下の症例での検討ー (2019)
  • Author(s): 金治有彦，大矢昭仁，小川亮，中村賢，木村篤史，菊池駿介，二木康夫，中村雅也，松本守雄
  • Organizer: 日本整形外科学会学術総会
• [Presentation] 変形性股関節症・股関節唇損傷に対する疼痛対策 (2019)
  • Author(s): 金治有彦
  • Organizer: 日本人工関節学会
• [Presentation] 牽引手術台使用仰臥位関節包靱帯温存人工股関節全置換術の術後成績 -術直前牽引時の関節裂隙開大の程度が術後成績に与える影響- (2019)
  • Author(s): 金治有彦，大矢昭仁，古郡宏行，中村賢，菊池駿介，木村篤史，二木康夫，中村雅也，松本守雄
  • Organizer: 日本人工関節学会