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Investigation of the molecular mechanisms through which SIRT1 modulates osteoarthritis progression.

Research Project

Project/Area Number 21591934
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionTokyo Medical and Dental University

Principal Investigator

ASO Yoshinori  東京医科歯科大学, 大学院・医歯学総合研究科, 寄附講座教員 (50345279)

Co-Investigator(Kenkyū-buntansha) 四宮 謙一  東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (20111594)
竹田 秀  慶應義塾大学, 医学部, 准教授 (30376727)
立川 哲彦  昭和大学, 歯学部, 教授 (10085772)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsSirt1 / 老化 / 軟骨 / Sirt6
Research Abstract

Members of the sirtuin(SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian Sirt6 leads to growth retardation, shortened life span(die around p24) and an aging-like phenotype in mice. SIRT6-/-mice fail to thrive and exhibit osteopenia, with 30% reduction in bone mineral density and lordokyphosis at 3. 5 weeks of age. However, the roles of Sirt6 in bone and cartilage metabolism are unclear. The aim of this study is to investigate the Sirt6 signal pathway in the maintenance of cartilage. For this purpose, histological evaluation was performed in Sirt6-/-mice and WT littermates. Sirt6 was expressed in articular chondrocyte and growth plate chondrocyte. At birth, the length of tibiae and femur was 10-20% shorter in Sirt6-/-compared to wild-type littermates. In the growth plate(GP), PCNA expression was reduced in Sirt6-/-mice. The number of TUNEL positive cells was comparative between Sirt6-/-and littermate at this stage. At two weeks after birth, growth retardation was apparent in Sirt6-/-., with reduced proliferating zone in GP, delayed formation of secondary ossification center and decreased primary spongiosa. Col2 mRNA expression was reduced in Sirt6-/-primary chondrocyte, indicating chondrocyte differentiation was retarded by Sirt6 deficiency. Sirt6-/-mice is reported to exhibit severe metabolic defects with precipitous drops in serum glucose and IGF-1 levels. Thus, to evaluate the involvement of exogenous glucose and IGF-1 in the prevention of chondrocyte differentiation, Sirt6 was knocked-down by siRNA in primary chondrocyte and chondrocyte-like cell line ATDC5. Real time PCR analysis revealed the expression of chondrocyte marker genes, including Col2, Col10 and aggrecan, were reduced in vitro. Interestingly, autologous IGF-1 expression in chondrocyte was not affected by Sirt6 deficiency. Our data indicate that Sirt6 controls cell growth and differentiation in embryonic and postnatal chondrocytes.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (15 results)

All 2012 2011 2010 2009

All Journal Article (7 results) Presentation (8 results)

  • [Journal Article] Procyanidin B3 prevents articular cartilage degeneration and heterotopic cartilage formation in a mouse surgical osteoarthritis model2012

    • Author(s)
      Hailati Aini, Hiroki Ochi, Munetaka Iwata, Atsushi Okawa, Daisuke Koga, Mutsumi Okazaki, Atsushi Sano, Yoshinori Asou
    • Journal Title

      PLoS ONE

      Volume: (in press)

    • Related Report
      2011 Final Research Report
  • [Journal Article] Runx2 expression correlates with the degree of disc aging : a comparison between Magnetic Resonance Imaging and Runx2 expression2012

    • Author(s)
      Itoh H., Hara Y., Yagawa M., Kato T., Ochi H., Koga D., Okawa A., Shinomiya K., Asou Y.
    • Journal Title

      J Vet Med Sci

      Volume: (in press)

    • Related Report
      2011 Final Research Report
  • [Journal Article] Sirt6 regulates chondrocyte proliferation and differentiation during endochondral ossification2011

    • Author(s)
      Boku K., Ochi H., Tsuji K., Koga D., Okawa A., Morita S., Takeda S., Asou Y.
    • Journal Title

      Journal of Bone and Mineral Research suppl

    • Related Report
      2011 Final Research Report
  • [Journal Article] Osteopontin deficiency impairs wear debris-induced osteolysis via regulation of cytokine secretion from murine macrophages2010

    • Author(s)
      Shimizu S, Okuda N, Kato N, Rittling SR, Okawa A, Shinomiya K, Muneta T, Denhardt DT, Noda M, Tsuji K, Asou Y
    • Journal Title

      Arthritis Rheum

      Volume: 62(5) Pages: 1329-37

    • NAID

      40019208000

    • Related Report
      2011 Final Research Report
  • [Journal Article] The roles of TNFR1 in lipopolysaccharide-induced bone loss : dual effects of TNFR1 on bone metabolism via osteoclastogenesis and osteoblast survival2010

    • Author(s)
      Ochi, H ; Hara, Y ; Tagawa, M ; Shinomiya, K ; Asou, Y
    • Journal Title

      J Orthop Res

      Volume: 28(5) Pages: 657-63

    • Related Report
      2011 Final Research Report
  • [Journal Article] TNF-alpha-induced NF-kappaB signaling reverses age-related declines in VEGF induction and angiogenic activity in intervertebral disc tissues2009

    • Author(s)
      Ohba T, Haro H, Ando T, Wako M, Suenaga F, Asou Y, Koyama K, Hamada Y, Nakao A
    • Journal Title

      J Orthop Res

      Volume: 27(2) Pages: 229-35

    • Related Report
      2011 Final Research Report
  • [Journal Article] Effects of compressive loading on biomechanical properties of disc and peripheral tissue in a rat tail model2009

    • Author(s)
      Nakamura T, Iribe T, Asou Y, Miyairi H, Ikegami K, Takakuda K
    • Journal Title

      Eur Spine J

    • Related Report
      2011 Final Research Report
  • [Presentation] Sirt6 Regulates Chondrocyte Proliferation and Differentiation during Endochondral Ossification2011

    • Author(s)
      麻生義則, ほか
    • Organizer
      American Society for Bone and Mineral Research (ASBMR) 2011 Annual Meeting
    • Place of Presentation
      米国サンディエゴ
    • Year and Date
      2011-09-19
    • Related Report
      2011 Annual Research Report
  • [Presentation] サーチュイン遺伝子Sirt6による軟骨代謝制御2011

    • Author(s)
      麻生義則, ほか
    • Organizer
      東京骨関節フォーラム
    • Place of Presentation
      東京
    • Year and Date
      2011-08-06
    • Related Report
      2011 Annual Research Report
  • [Presentation] Sirt6 regulates chondrocyte proliferation and differentiation during endochondral ossification2011

    • Author(s)
      Boku K., Ochi H., Tsuji K., Koga D., Okawa A., Morita S., Takeda S., Asou Y.
    • Organizer
      Annual meeting for American society for bone and mineral research
    • Related Report
      2011 Final Research Report
  • [Presentation] Short term high-fat diet induces osteophyte formation apoptosis and degeneration of articular chondrocyte in murine knee joint2011

    • Author(s)
      Iwata M, Ochi H, Hara Y, Koga D, Tagawa M, Okawa A, Asou Y
    • Organizer
      OARSI world congress on osteoarthritis
    • Related Report
      2011 Final Research Report
  • [Presentation] TNFR1 deficiency facilitates articular cartilage ossification and osteophyte formation2011

    • Author(s)
      Hailati A., Yamauchi Y., Ochi H., Koga D., Okawa A., Ogishima S., Okazaki M., Asou Y
    • Organizer
      OARSI world congress on osteoarthritis
    • Related Report
      2011 Final Research Report
  • [Presentation] サーチュイン遺伝子Sirt6による軟骨代謝制御2011

    • Author(s)
      朴金瑛,辻邦和,古賀大介,森田定雄,大川淳,竹田秀,麻生義則
    • Organizer
      東京骨関節フォーラム
    • Related Report
      2011 Final Research Report
  • [Presentation] 短期高脂肪食負荷によるマウス変形性膝関節症モデルの樹立2011

    • Author(s)
      岩田宗峻,越智広樹,原康,多川政弘,古賀大介,大川淳,麻生義則
    • Organizer
      東京骨関節フォーラム
    • Related Report
      2011 Final Research Report
  • [Presentation] Chondroprotective effects of procyanidin in murine articular chondrocytes2010

    • Author(s)
      Aini Hailati,麻生義則,越智弘樹,古賀大介,加藤剛,大川淳,佐野淳,岡崎睦
    • Organizer
      日本分子生物学会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-10
    • Related Report
      2011 Final Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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