Elucidation of the role of Sirt6 in the chondrocyte metabolism

• Project/Area Number: 24592257
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ASOU Yoshinori 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (50345279)
• Co-Investigator(Kenkyū-buntansha): 辻 邦和 東京医科歯科大学, 大学院医歯(薬)学総合研究科, 准教授 (20323694) ; 荻島 創一 東北大学, 学内共同利用施設等, 准教授 (40447496)
• Co-Investigator(Renkei-kenkyūsha): 荻島 創一 東北大学, 東北メディカルメガバンク機構, 講師 (40447496)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: サーチュイン / 軟骨代謝 / 老化 / 加齢 / 骨代謝 / Sirt6

Outline of Final Research Achievements

The aim of this study was to investigate the Sirt6 signal pathway in cartilage metabolism.Sirt6 was expressed in primary chondrocytes and the chondrocyte-like cell line ATDC5. At birth, the length of the tibia and femur was shorter in Sirt6-/-. In the growth plate (GP), PCNA expression was reduced in Sirt6-/- mice. The number of TUNEL positive cells was comparable between Sirt6-/- and littermates. Two weeks after birth, growth retardation was apparent in Sirt6-/-, with reduced proliferating zone and hypertrophic zone in the growth plate, delayed ossification of secondary ossification center and decreased primary spongiosa. mRNA and protein expression of Col2a1, Col10a1 and Ihh in the growth plate was reduced in Sirt6-/- primary chondrocytes. Functional analysis revealed Sirt6 positively regulates chondrocyte differentiation via the Atf4 -Ihh axis.

Research Products

• [Journal Article] Enhancement of Runx2 expression is potentially linked to β-catenin accumulation in canine intervertebral disc degeneration. (2015)
  • Author(s): Iwata M, Aikawa T, Hakozaki T, Arai K, Ochi H, Haro H, Tagawa M, Asou Y, Hara Y.
  • Journal Title: J Cell Physiol. Volume: Jan;230(1) Issue: 1 Pages: 180-190
  • DOI: 10.1002/jcp.24697
  • Peer Reviewed
• [Journal Article] Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. (2015)
  • Author(s): Kobayashi K1, Nojiri H2, Saita Y2, Morikawa D1, Ozawa Y3, Watanabe K3, Koike M1, Asou Y4, Shirasawa T5, Yokote K6, Kaneko K2, Shimizu T3.
  • Journal Title: Scientific Reports Volume: Mar 16;5 Issue: 1 Pages: 9148-9148
  • DOI: 10.1038/srep09148
  • Peer Reviewed / Open Access
• [Journal Article] Tumor necrosis factor-α enhances RANKL expression in gingival epithelial cells via protein kinase A signaling. (2014)
  • Author(s): Fujihara R, Usui M, Yamamoto G, Nishii K, Tsukamoto Y, Okamatsu Y, Sato T, Asou Y, Nakashima K, Yamamoto M.
  • Journal Title: J Periodontal Res. Volume: Aug;49(4) Issue: 4 Pages: 503-507
  • DOI: 10.1111/jre.12131
  • Peer Reviewed
• [Journal Article] Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. (2013)
  • Author(s): Piao J, Tsuji K, Ochi H, Iwata M, Koga D, Okawa A, Morita S, Takeda S, Asou Y.
  • Journal Title: Ｓｃｉｅｎｔｉｆｉｃ Ｒｅｐｏｒｔ Volume: october 23 Issue: 1 Pages: 3022-3022
  • DOI: 10.1038/srep03022
  • Peer Reviewed
• [Journal Article] Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. (2013)
  • Author(s): Morikawa D, Nojiri H, Saita Y, Kobayashi K, Watanabe K, Ozawa Y, Koike M, Asou Y, Takaku T, Kaneko K, Shimizu T.
  • Journal Title: J Bone Miner Res Volume: november 28(11) Issue: 11 Pages: 2368-80
  • DOI: 10.1002/jbmr.1981
  • Peer Reviewed
• [Journal Article] Variations in gene and protein expression in canine chondrodystrophic nucleus pulposus cells following long-term three-dimensional culture. (2013)
  • Author(s): Iwata M, Ochi H, Asou Y, Haro H, Aikawa T, Harada Y, Nezu Y, Yogo T, Tagawa M, Hara Y.
  • Journal Title: PLoS One Volume: May 2;8(5)
  • Peer Reviewed
• [Journal Article] Sema3A regulates bone-mass accrual through sensory innervations (2013)
  • Author(s): Fukuda T, Takeda S, Xu R, Ochi H, Sunamura S, Sato T, Shibata S, Yoshida Y, Gu Z, Kimura A, Ma C, Xu C, Bando W, Fujita K, Shinomiya K, Hirai T, Asou Y, Enomoto M, Okano H, Okawa A, Itoh H
  • Journal Title: Nature. Volume: 497 Issue: 7450 Pages: 490-493
  • DOI: 10.1038/nature12115
  • Peer Reviewed
• [Journal Article] Evaluation of the association between runt-related transcription factor 2 expression and intervertebral disk aging in dogs. (2012)
  • Author(s): Itoh H, Hara Y, Tagawa M, Kato T, Ochi H, Koga D, Okawa A, Asou Y.
  • Journal Title: Am J Vet Res Volume: Oct;73(10):1553-9. Pages: 1553-9
  • Peer Reviewed
• [Journal Article] Runx2 haploinsufficiency ameliorates the development of ossification of the posterior longitudinal ligament. (2012)
  • Author(s): Iwasaki M, Piao J, Kimura A, Sato S, Inose H, Ochi H, Asou Y, Shinomiya K, Okawa A, Takeda S.
  • Journal Title: PLoS One Volume: 7 Issue: 8 Pages: e43372-e43372
  • DOI: 10.1371/journal.pone.0043372
  • Peer Reviewed
• [Journal Article] Procyanidin B3 prevents articular cartilage degeneration and heterotopic cartilage formation in a mouse surgical osteoarthritis model. (2012)
  • Author(s): Aini H, Ochi H, Iwata M, Okawa A, Koga D, Okazaki M, Sano A, Asou Y.
  • Journal Title: PLoS One Volume: 7(5) Issue: 5 Pages: e37728-e37728
  • DOI: 10.1371/journal.pone.0037728
  • Peer Reviewed
• [Presentation] サーチュイン遺伝子Sirt6による軟骨代謝制御機構の解析 (2014)
  • Author(s): 朴金瑛１ 辻邦和2 越智広樹3 古賀大介1 大川淳1 竹田秀3 麻生義則1
  • Organizer: 日本整形外科学会基礎学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] 高脂肪食負荷による膝蓋下脂肪体肥大化は力学的負荷とは独立して変形性膝関節症を惹起する。 (2014)
  • Author(s): 岩田宗峻1 越智広樹2 原康1 多川政弘1 古賀大介3 大川淳3 麻生義則3
  • Organizer: 日本整形外科学会基礎学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] サーチュイン遺伝子Sirt6による軟骨代謝制御 (2012)
  • Author(s): 朴金瑛 辻邦和 越智広樹 森田定雄 古賀大介 大川淳 竹田秀 麻生義則
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 名古屋
• [Presentation] 短期高脂肪食負荷に対するマウス膝関節の初期組織学的反応 (2012)
  • Author(s): Munetaka Iwata, Hiroki Ochi, Yasushi Hara, Daisuke Koga, Masahiro Tagawa, Atsushi Okawa, Yoshinori Asou
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 名古屋
• [Presentation] サーチュイン遺伝子Sirt6による軟骨代謝制御 (2012)
  • Author(s): 麻生 義則
  • Organizer: 東京医科歯科大学第４回硬組織疾患ゲノムセンターセミナー
  • Place of Presentation: 東京
  • Invited
• [Presentation] Sirt6 regulate proliferation and differentiation of the postnatal growth plate chondrocyte via Ihh signaling.
  • Author(s): Jinying Piao1, Kunikazu Tsuji2, Hiroki Ochi3, Sadao Morita1, Daisuke Koga4, Atsushi Okawa4, Shu Takeda5, Yoshinori Asou4
  • Organizer: Annual meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Baltimore USA
• [Presentation] The distinct role of the infrapatellar fat pad in a murine high-fat diet-induced osteoarthritis model.
  • Author(s): Munetaka Iwata1, Hiroki Ochi2, Yasushi Hara1, Masahiro Tagawa1, Daisuke Koga3, Atsushi Okawa3, Yoshinori Asou3
  • Organizer: Annual meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Baltimore USA