2011 Fiscal Year Final Research Report
Investigation of the molecular mechanisms through which SIRT1 modulates osteoarthritis progression.
| Project/Area Number |
21591934
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Tokyo Medical and Dental University |
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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)
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| Project Period (FY) |
2009 – 2011
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| Keywords | Sirt1 / 老化 / 軟骨 |
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| 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.
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Research Products
(13 results)
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[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
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Journal Title
Arthritis Rheum
Volume: 62(5)
Pages: 1329-37
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