Aging Promotes Sirtuin 3-Dependent Cartilage Superoxide Dismutase 2 Acetylation and Osteoarthritis

Arthritis Rheumatol. 2016 Aug;68(8):1887-98. doi: 10.1002/art.39618.


Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Aging / physiology*
  • Animals
  • Cartilage, Articular / enzymology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteoarthritis, Knee / enzymology*
  • Oxidative Stress
  • Rats
  • Sirtuin 3 / physiology*
  • Superoxide Dismutase / metabolism*


  • Superoxide Dismutase
  • superoxide dismutase 2
  • Sirtuin 3