An Investigation of molecular mechanisms of initiation and progression of ossification of the spinal ligaments

• Project/Area Number: 15H05681
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: INOSE HIROYUKI 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (30615711)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥23,920,000 (Direct Cost: ¥18,400,000、Indirect Cost: ¥5,520,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 骨代謝 / 軟骨代謝 / 靭帯骨化 / 骨・軟骨代謝 / ゲノム / 靱帯骨化 / 細胞周期 / 発生・分化 / 異所性骨化

Outline of Final Research Achievements

Through comprehensive analysis of gene expression in ligament samples from ossification of the posterior longitudinal ligament (OPLL) patients, we identified that Cyclin dependent kinase 1 (Cdk1) was involved in the initiation and progression of OPLL. The role of Cdks in this process have not been extensively studied. In this study, we demonstrated that Cdk1 regulates skeletal development based on chondrocyte-specific loss-of-function experiments performed in a mouse model. Cdk1 functions as a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Furthermore, using an osteoblast-specific loss-of-function mouse model, we demonstrated that Cdk1 regulates osteoblast proliferation and differentiation.

Academic Significance and Societal Importance of the Research Achievements

靭帯骨化症については、現段階で薬物的治療が困難であり、　巧緻機能障害や歩行障害が出現した場合には手術治療を行うしかない。しかしながら、手術には一定のリスクが存在する。そこで、我々は網羅的な遺伝子発現の解析において靭帯骨化の発生・進展に関与すると推測されるCdk1に注目した。そして、Cdk1による骨・軟骨代謝の調節機構を本研究により明らかにした。また、薬理学的なCdk1の抑制により靭帯細胞の増殖を抑制することが出来ることを見出した。従って、本研究の結果は靭帯骨化症に対する薬理学的な治療の基盤となりうると考えられる。

Research Products

• [Journal Article] Comparison of Rigid and Soft-Brace Treatments for Acute Osteoporotic Vertebral Compression Fracture: A Prospective, Randomized, Multicenter Study (2019)
  • Author(s): Kato Tsuyoshi, Inose Hiroyuki, Shoichi Ichimura, Yasuaki Tokuhashi, Hiroaki Nakamura, Masatoshi Hoshino, Daisuke Togawa, Toru Hirano, Hirotaka Haro, Tetsuro Ohba, Takashi Tsuji, Kimiaki Sato, Yutaka Sasao, Masahiko Takahata, Koji Otani, Suketaka Momoshima , Ukihide Tateishi, Makoto Tomita, Ryuichi Takemasa, et al.
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 2 Pages: 198-198
  • DOI: 10.3390/jcm8020198
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of cyclin-dependent kinase 1 impairs bone formation, but does not affect the bone-anabolic effects of parathyroid hormone. (2018)
  • Author(s): Takahashi A, Mulati M, Saito M, Numata H, Kobayashi Y, Ochi H, Sato S, Kaldis P, Okawa A, Inose H.
  • Journal Title: J Biol Chem. Volume: 293 Issue: 50 Pages: 19387-19399
  • DOI: 10.1074/jbc.ra118.004834
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The impact of sarcopenia on the results of lumbar spinal surgery (2018)
  • Author(s): Inose H, Yamada T,
  • Journal Title: osteoporosis and sarcopenia Volume: 4 Issue: 1 Pages: 33-36
  • DOI: 10.1016/j.afos.2018.02.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of Decompression, Decompression Plus Fusion, and Decompression Plus Stabilization for Degenerative Spondylolisthesis: A Prospective, Randomized Study. (2018)
  • Author(s): Inose H, Kato T, Yuasa M, Yamada T, Maehara H, Hirai T, Yoshii T, Kawabata S, Okawa A.
  • Journal Title: Clin Spine Surg. Volume: 31 Issue: 7 Pages: 347-352
  • DOI: 10.1097/bsd.0000000000000659
  • NAID: 40022239693
  • Peer Reviewed / Open Access
• [Journal Article] 脊柱靱帯骨化症研究の進歩】基礎研究 靱帯骨化発生・進展に注目した骨・軟骨代謝調節機構の解明 (2018)
  • Author(s): 猪瀬 弘之, 斎藤 正徳, ミラディリ・ムラテ , 高橋 晃, 大川 淳.
  • Journal Title: 整形外科 Volume: 69 Pages: 525-531
• [Journal Article] Bone Turnover Markers as a New Predicting Factor for Nonunion After Spinal Fusion Surgery (2018)
  • Author(s): Inose H, Yamada T, Mulati M, Hirai T, Ushio S, Yoshii T, Kato T, Kawabata S, Okawa A.
  • Journal Title: SPINE Volume: 1 Issue: 1 Pages: 29-34
  • DOI: 10.1097/brs.0000000000001995
  • Peer Reviewed
• [Journal Article] Comparison of decompression, decompression plus fusion, and decompression plus stabilization for degenerative spondylolisthesis (2018)
  • Author(s): Inose H, Kato T, Yuasa M, Yamada T, Maehara H, Hirai T, Yoshii T, Kawabata S, Okawa A
  • Journal Title: Clinical spine surgery Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] A foreign body granuloma after the usage of polyglycolic acid mesh and fibrin glue for dural repair. A case report. (2017)
  • Author(s): Kawabata A, Inose H (corresponding author), Ukegawa D, Kawabata S, Yamada T, Okawa A.
  • Journal Title: J Orthop Sci Volume: 2 Issue: 2 Pages: 371-374
  • DOI: 10.1016/j.jos.2015.08.003
  • Peer Reviewed
• [Journal Article] Bone Turnover Markers as a New Predicting Factor for Non-union AfterSpinal Fusion Surgery. (2016)
  • Author(s): Inose H (corresponding author), Yamada T, Mulati M, Hirai T, Ushio S, Yoshii T, Kato T, Kawabata S, Okawa A.
  • Journal Title: Spine (Phila Pa 1976) Volume: 印刷中
  • Peer Reviewed
• [Journal Article] The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development. (2016)
  • Author(s): Saito M, Mulati M, Talib SZ, Kaldis P, Takeda S, Okawa A, Inose H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 20622-20622
  • DOI: 10.1038/srep20622
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 骨芽細胞増殖は骨形成に必須であるが、PTHによる骨同化作用には必須でない. (2018)
  • Author(s): 高橋 晃, 猪瀬 弘之, 大川 淳
  • Organizer: 第33回 日本整形外科学会基礎学術集会
• [Presentation] 骨芽細胞増殖に注目した骨代謝調節機構の解明. (2018)
  • Author(s): 猪瀬 弘之, 高橋 晃, 大川 淳.
  • Organizer: 第91回 日本整形外科学会学術総会
• [Presentation] 長鎖ノンコーディングRNAによる骨芽細胞分化の調整機構. (2018)
  • Author(s): Mulati Mieradili, 髙橋 晃, 猪瀬 弘之, 大川 淳
  • Organizer: 第38回 日本骨形態計測学
• [Presentation] 骨芽細胞増殖はPTH投与による骨同化作用において必須ではない. (2018)
  • Author(s): 髙橋 晃, Mulati Mieradili, 猪瀬 弘之, 大川 淳.
  • Organizer: 第38回 日本骨形態計測学会
• [Presentation] 骨芽細胞増殖は骨形成には必須であるが、PTH投与による骨同化作用においては必須でない. (2018)
  • Author(s): 高橋 晃, 猪瀬 弘之, 大川 淳.
  • Organizer: 第36回 日本骨代謝学会学術集会
• [Presentation] Bone turnover markers as a predicting factor for nonunion after spinal surgery (2017)
  • Author(s): Inose H, Okawa A
  • Organizer: The 90th annual meeting of the Japanese Orthopaedic Association.
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-05-18
  • Int'l Joint Research
• [Presentation] The impact of Sarcopenia on the results of spinal surgery. (2017)
  • Author(s): Inose H, Okawa A
  • Organizer: World congress on osteporosis, osteoarthritis and musculosketelar diseases
  • Place of Presentation: Florence（Itaｌｙ)
  • Year and Date: 2017-03-23
  • Int'l Joint Research
• [Presentation] Cdk1 is essential for bone formation and fracture repair (2017)
  • Author(s): Takahashi A, Inose H
  • Organizer: American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] CDK1は骨芽細胞の増殖、骨量維持及び骨折治癒に必須である (2017)
  • Author(s): 高橋晃、猪瀬弘之、大川淳
  • Organizer: 第37回日本骨形態計測学会
• [Presentation] 細胞周期制御因子Cdk1は骨量維持及び骨癒合に必須である (2017)
  • Author(s): 高橋晃、猪瀬弘之、大川淳
  • Organizer: 第35回日本骨代謝学会
• [Presentation] 細胞周期制御因子Cdk1は骨量維持及び骨癒合に必須である (2017)
  • Author(s): 高橋晃、猪瀬弘之、大川淳
  • Organizer: 第32回日本整形外科基礎学術集会
• [Presentation] Investigation of predicting factors for nonunion after spinal fusion (2016)
  • Author(s): Inose H, Okawa A
  • Organizer: The 89th annual meeting of the Japanese Orthopaedic Association.
  • Place of Presentation: 横浜パシフィコ（神奈川県横浜市）
  • Year and Date: 2016-05-12
  • Int'l Joint Research
• [Presentation] 細胞周期制御因子による軟骨細胞増殖・分化の調節機構 (2016)
  • Author(s): 猪瀬 弘之
  • Organizer: 第89回日本整形外科学会学術総会
  • Place of Presentation: 横浜パシフィコ（神奈川県横浜市
  • Year and Date: 2016-05-12
• [Presentation] The cell cycle regulation of chondrocyte development (2015)
  • Author(s): H Inose, M Saito, P kaldis, A Okawa
  • Organizer: ASBMR 2015 Annual Meeting
  • Place of Presentation: 米国ワシントン州シアトル
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] 細胞周期制御因子による軟骨代謝の調節 (2015)
  • Author(s): 猪瀬弘之、齊藤正徳、大川淳
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-05-21