title: Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model.
abstract: OBJECTIVE
  We and others previously demonstrated that sirtuin 1 (SIRT-1) regulates apoptosis and cartilage-specific gene expression in human chondrocytes and mouse models. This study was undertaken to determine if SIRT-1 enzymatic activity plays a protective role in cartilage homeostasis in vivo, by investigating mice with SIRT-1 mutations to characterize their cartilage.
  
  
  METHODS
  Articular cartilage was harvested from the paws and knees of 5- and 6-month-old wild-type (WT) mice and mice homozygous for SIRT-1tm2.1Mcby (SIRT-1y/y), an allele carrying a point mutation that encodes a SIRT-1 protein with no enzymatic activity (y/y mice). Mice ages 2 days old and 6-7 days old were also examined. Mouse joint cartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures.
  
  
  RESULTS
  We found that articular cartilage tissue sections from y/y mice of up to 6 months of age contained reduced levels of type II collagen, aggrecan, and glycosaminoglycan compared to sections from WT mice. In contrast, protein levels of matrix metalloproteinase 8 (MMP-8), MMP-9, and MMP-13 were elevated in the cartilage of y/y mice. In addition, chondrocyte apoptosis was elevated in SIRT-1 mutant mice as compared to their WT littermates. Consistent with these observations, protein tyrosine phosphatase 1b was elevated in the y/y mice.
  
  
  CONCLUSIONS
  Our in vivo findings in this animal model demonstrate that mice with defective SIRT-1 also have defective cartilage, with elevated rates of cartilage degradation with age. Hence, normal cartilage homeostasis requires enzymatically active SIRT-1 protein.
authors.affiliation: Cartilage Biology and Orthopedic Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA. gabayo@mail.nih.gov
authors.forename: Odile
authors.initials: O
authors.lastname: Gabay
authors.forename: Christelle
authors.initials: C
authors.lastname: Sanchez
authors.forename: Mona
authors.initials: M
authors.lastname: Dvir-Ginzberg
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gagarina
authors.forename: Kristien J
authors.initials: KJ
authors.lastname: Zaal
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Song
authors.forename: Xiao Hong
authors.initials: XH
authors.lastname: He
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
mesh_terms: D053674:Aggrecans; D000818:Animals; D002356:Cartilage / Q000201:enzymology*; D018929:Cell Culture Techniques; D019902:Chondrocytes / Q000201:enzymology*; D024043:Collagen Type II; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D010003:Osteoarthritis / Q000503:physiopathology*; D017354:Point Mutation; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D056564:Sirtuin 1