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

Abstract

Objective To quantify functional age-related changes in the cartilage antioxidant network to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology. Methods We evaluated knee OA histopathology in 10, 20, and 30-month old male F344BN rats and analyzed cartilage oxidation by the ratio of reduced:oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by qRT-PCR 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 (SIRT3), in rats and mice. Results Cartilage oxidation and OA severity 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 post-translational lysine acetylation. Consistent with these findings, SIRT3 decreased substantially with age, and treatment with SIRT3 increased SOD2 activity in an age-dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT3 treatment. Moreover, in C57BL6 mice, cartilage SIRT3 expression decreased with age and whole-body deletion of SIRT3 accelerated the development of knee OA. Conclusion Our results show that SIRT3 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 SIRT3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation-dependent inhibition of SOD2 activity.

Review: Metabolic Regulation of Inflammation in Osteoarthritis

“…Cartilage SIRT-3 expression was also recently shown to decrease with age, and SIRT-3 deficiency increases acetylation of the antioxidant enzyme SOD2, resulting in impaired SOD2 activity in chondrocytes (75). In addition, whole-body deletion of SIRT-3 accelerates the development of knee OA (75). Expression of SIRT-6 is significantly decreased in human OA chondrocytes as well (76).…”

Building and maintaining joints by exquisite local control of cell fate

“…Genome‐wide DNA methylation changes have been shown in hip and knee cartilage in human osteoarthritis patients and have been linked to differential expression of 70 genes, including the osteoarthritis‐associated genes VIT , ROR2 , and WLS . Altered activity of the Sirtuin family of histone deacetylases, in particular SIRT1, SIRT3, and SIRT6, has also been implicated in arthritis . In particular, increased histone acetylation within articular cartilage has been linked to ectopic hypertrophy in the mouse knee, including increased expression of matrix metalloproteases (e.g., MMP‐13) that degrade joint cartilage …”

Protective effects of metformin against osteoarthritis through upregulation of SIRT3-mediated PINK1/Parkin-dependent mitophagy in primary chondrocytes

“…Protein acetylation in mitochondria typically promotes decreased mitochondrial integrity and function (6).The nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylase, SIRT3 (Sirtuin 3), is the major mitochondrial protein deacetylase localized to the mitochondria (7,8), thereby regulating mitochondrial antioxidant system and OXPHOS (9,10). SIRT3 protects mitochondria from oxidative stress by deacetylating superoxide dismutase (SOD2) and mitigates OA progression (11). Chen et al recently showed that SIRT3 was regulated by AMP-activated protein kinase (AMPK) activation in human chondrocytes, which reduced mtDNA 4977 deletion and improved mitochondrial functions (12).…”