title: Aging Promotes Sirtuin 3-Dependent Cartilage Superoxide Dismutase 2 Acetylation and Osteoarthritis.
abstract: To quantify functional age-related changes in the cartilage antioxidant network in order to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology.
  
  
  
  We evaluated histopathologic changes of knee OA in 10-, 20-, and 30-month-old male F344BN rats and analyzed cartilage oxidation according to the ratio of reduced to oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by quantitative reverse transcription-polymerase chain reaction and selected reaction-monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age-related changes in the mitochondrial deacetylase sirtuin 3 (SIRT-3) in rats and mice.
  
  
  
  Cartilage oxidation and OA severity in F344BN rats increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2-specific activity decreased with age due to elevated posttranslational lysine acetylation. Consistent with these findings, SIRT-3 levels decreased substantially with age, and treatment with SIRT-3 increased SOD2 activity in an age-dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT-3 treatment. Moreover, in C57BL/6J mice, cartilage SIRT-3 expression decreased with age, and whole-body deletion of SIRT-3 accelerated the development of knee OA.
  
  
  
  Our results show that SIRT-3 mediates age-related changes in cartilage redox regulation and protects against early-stage OA. These findings suggest that mitochondrial acetylation promotes OA and that restoration of SIRT-3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation-dependent inhibition of SOD2 activity.
authors: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Yao
authors: Y
authors: Fu
authors: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Michael
authors: M
authors: Kinter
authors: Oklahoma Medical Research Foundation, Oklahoma City.
authors: Joanna
authors: J
authors: Hudson
authors: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Kenneth M
authors: KM
authors: Humphries
authors: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Rachel S
authors: RS
authors: Lane
authors: University of Oklahoma College of Medicine and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Jeremy R
authors: JR
authors: White
authors: Oklahoma Medical Research Foundation, University of Oklahoma College of Medicine, and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Michael
authors: M
authors: Hakim
authors: Gladstone Institutes and University of California, San Francisco.
authors: Yong
authors: Y
authors: Pan
authors: Gladstone Institutes and University of California, San Francisco.
authors: Eric
authors: E
authors: Verdin
authors: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors: Timothy M
authors: TM
authors: Griffin
mesh_terms: D000107:Acetylation; D000375:Aging / Q000502:physiology*; D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000201:enzymology*; D018384:Oxidative Stress; D051381:Rats; D056566:Sirtuin 3 / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2