title: Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice.
abstract: OBJECTIVE
  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 (Sirt1(flox)/(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 (Sirt1(flox)/(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.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Tokio
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism* / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Chondrocytes; Knee Osteoarthritis; Osteoarthritis