Molecular mechanisms of locomotor degenerative changes due to crosstalk of aging control factors

• Project/Area Number: 18H02920
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ASOU YOSHINORI 東京医科歯科大学, 大学院医歯学総合研究科, ジョイントリサーチ講座教授 (50345279)
• Co-Investigator(Kenkyū-buntansha): 辻 邦和 東京医科歯科大学, 大学院医歯学総合研究科, ジョイントリサーチ講座教授 (20323694)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: SIRT6 / PAI-1 / osteoporosis / ageing / FGF23 / SOST / Sirt6 / 骨細胞 / 加齢 / 骨代謝 / ＰＡＩ－１ / Ｓｉｒｔ６ / 老化 / 骨 / 筋肉

Outline of Final Research Achievements

This year, we crossed Dmp1cre::Sirt6f/f mice (Sirt6cKO) with PAI-1KO mice to generate Dmp1cre::Sirt6f/f;;PAI-1-/- mice (dKO mice) to verify the signal cross-talk between Sirt6 and PAI-1. dKO mice showed reduced FGF 23, and SOST expression was reduced to levels comparable to controls. Aged PAI-1KO mice had more bone mass and higher blood phosphorus levels than wild-type mice of the same week of age. These results indicate that FGF 23 and SOST expression is regulated by SIRT6 and that the mechanism is at least partly mediated by PAI-1 regulation.

Academic Significance and Societal Importance of the Research Achievements

我々の成果は、サーチュインアゴニストのニコチンアミドモノヌクレオチドや、経口PAI-1阻害剤などの、加齢に伴う骨代謝の障害に対する治療への応用の可能性を示唆する。

Research Products

• [Int'l Joint Research] Harvard School of Dental Medicine(米国)
• [Journal Article] A novel PAI-1 inhibitor prevents ageing-related muscle fiber atrophy. (2021)
  • Author(s): Aihemaiti A, Yamamoto N, Piao J, Oyaizu T, Ochi H, Sato S, Okawa A, Miyata T, Tsuji K, Ezura Y, Asou Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 534 Pages: 849-856
  • DOI: 10.1016/j.bbrc.2020.10.089
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of long-term plate fixation with different fixation modes on the radial cortical bone in dogs. (2021)
  • Author(s): Muroi N, Ochi H, Shimada M, Asou Y, Hara Y.
  • Journal Title: PLoS One. Volume: Feb 19;16(2) Issue: 2 Pages: e0247410-e0247410
  • DOI: 10.1371/journal.pone.0247410
  • Peer Reviewed / Open Access
• [Journal Article] Proanthocyanidin-rich grape seed extract improves bone loss, bone healing, and implant osseointegration in ovariectomized animals (2020)
  • Author(s): Tenkumo T, Aobulikasimu A, Asou Y, Shirato M, Shishido S, Kanno T, Niwano Y, Sasaki K, Nakamura K.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 8812-8812
  • DOI: 10.1038/s41598-020-65403-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PAI-1活性制御によるサルコペニア予防の可能性 (2020)
  • Author(s): 麻生 義則・アディハム アハマット
  • Journal Title: 月刊「細胞」 Volume: 52 Pages: 709-712
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of type II collagen and aggrecan genes is regulated through distinct epigenetic modifications of their multiple enhancer elements (2019)
  • Author(s): Nham Giang Thi Hien、Zhang Xiang、Asou Yoshinori、Shinomura Tamayuki
  • Journal Title: Gene Volume: 704 Pages: 134-141
  • DOI: 10.1016/j.gene.2019.04.034
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Osteocyte Sirt6 has crucial roles in bone and phosphate metabolism through senescence- dependent and -independent manner (2019)
  • Author(s): Alkebaier Aobulikasimu*1 , Hiroki Ochi1 , Jinying Piao1 , Shingo Sato1 , Kunikazu Tsuji2 , Atsushi Okawa1 , Yoshinori Asou1
  • Organizer: 米国骨代謝学会（国際学会）
  • Int'l Joint Research
• [Presentation] 骨細胞Sirt6による骨代謝、リン代謝制御機構 (2019)
  • Author(s): Alkebaier Aobulikasimu、越智広樹、朴金瑛、佐藤信吾、辻邦和、大川淳、麻生義則
  • Organizer: 日本整形外科基礎学会
• [Presentation] PAI-1 accelerates sarcopenia and ageing-related osteoporosis. (2019)
  • Author(s): Aidehamu Aihemaiti,Naoki Yamamoto,Alkebaier Aobulikasimu,Hiroki Ochi, Shingo Sato,Kunikazu Tsuji,Toshio Miyata,Atsushi Okawa,Yoshinori Asou
  • Organizer: 米国骨代謝学会（国際学会）
  • Int'l Joint Research
• [Presentation] PAI-1はロコモティブシンドローム、サルコペニアを加速する。 (2019)
  • Author(s): アディハム アハマット1) アクバル アブルカスム 越智 広樹 山本 尚輝 小柳津 卓哉 宮田 敏男 佐藤 信吾 畑 裕 辻 邦和 大川 淳 麻生 義則
  • Organizer: 日本整形外科基礎学会
• [Presentation] PAI-1阻害は筋骨格系組織の退行性変化を予防する。 (2019)
  • Author(s): アディハム アハマット1) アクバル アブルカスム 越智 広樹 山本 尚輝 小柳津 卓哉 宮田 敏男 佐藤 信吾 畑 裕 辻 邦和 大川 淳 麻生 義則
  • Organizer: 骨関節フォーラム
• [Presentation] 骨細胞のSirt6はSOST発現を介して骨代謝を制御する (2018)
  • Author(s): Alkebaier Aobulikasimu*1, Zulipiya Aibibula1, Jinying Piao1, Shingo Sato2, Hiroki Ochi2, Kunikazu Tsuji3, Atsushi Okawa1, Yoshinori Asou1
  • Organizer: 日本整形外科基礎学会
• [Presentation] Osteocyte Sirt6 has crucial roles in bone and phosphate metabolism (2018)
  • Author(s): Alkebaier Aobulikasimu*1, Zulipiya Aibibula1, Jinying Piao1, Shingo Sato2, Hiroki Ochi2, Kunikazu Tsuji3, Atsushi Okawa1, Yoshinori Asou1
  • Organizer: annual meeting for american society of bone and mineral research
  • Int'l Joint Research
• [Presentation] 骨細胞Sirt6による骨代謝制御機構 (2018)
  • Author(s): Alkebaier Aobulikasimu、Zulipiya Aibibula、朴金瑛、金光文、越智広樹、佐藤信吾、大川淳、麻生義則
  • Organizer: 骨関節フォーラム