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Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice
  1. Tokio Matsuzaki,
  2. Takehiko Matsushita,
  3. Koji Takayama,
  4. Tomoyuki Matsumoto,
  5. Kotaro Nishida,
  6. Ryosuke Kuroda,
  7. Masahiro Kurosaka
  1. Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  1. Correspondence to Dr Takehiko Matsushita, Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan; matsushi{at}med.kobe-u.ac.jp

Abstract

Objectives Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific Sirt1-conditional knockout (CKO) mice were analysed using an experimental OA model.

Methods OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and Sirt1-CKO (Sirt1flox/flox; Col2a1-Cre) mice generated using the Cre-loxP system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in Sirt1-CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control (Sirt1flox/flox) mice.

Results The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. Sirt1-CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old Sirt1-CKO mice than in control mice. Sirt1-CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in Sirt1-CKO mice compared with control mice 2 weeks after surgery.

Conclusions Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA.

  • Chondrocytes
  • Osteoarthritis
  • Knee Osteoarthritis

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