Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development

Sci Rep. 2015 Dec 7;5:17602. doi: 10.1038/srep17602.

Abstract

The aim of our study was to evaluate if Sirt6, a NAD + dependent histone deacetylase, plays a protective role in cartilage degeneration by suppressing cellular senescence and inflammatory responses. The expression level of sirt6 in normal and OA human knee articular cartilage was compared by immunofluorescence and western blotting. The effect of sirt6 overexpression on replicative senescence of chondrocytes and NF-κB target genes expression was evaluated. Histological assessment of OA mice knee joint was carried out to assess the in vivo effects of sirt6 overexpression on mice chondrocytes. We found sirt6 level was significantly decreased in the articular chondrocytes of OA patients compare to normal human. SA-β-gal staining revealed that overexpression of sirt6 suppressed replicative senescence of chondrocytes. Meanwhile, the expression of NF-κB dependent genes were significantly attenuated by sirt6 overxpression. Safranin-O staining and OARSI score of knee joint cartilage in OA mice revealed that Lenti-Sirt6 intraarticular injection could protect mice chondrocytes from degeneration. These data strongly suggest that overexpression of Sirt6 can prevent OA development by reducing both the inflammatory response and chondrocytes senescence. Therefore, the development of specific activators of Sirt6 may have therapeutic potential for the treatment of OA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cellular Senescence* / drug effects
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Collagen Type II / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Interleukin-1beta / pharmacology
  • Matrix Metalloproteinase 13 / metabolism
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Osteoarthritis, Knee / genetics
  • Osteoarthritis, Knee / metabolism*
  • Osteoarthritis, Knee / pathology*
  • Protein Transport / drug effects
  • Sirtuins / metabolism*
  • Transcription Factor RelA / metabolism

Substances

  • Collagen Type II
  • Interleukin-1beta
  • NF-kappa B
  • Transcription Factor RelA
  • Sirt6 protein, mouse
  • Matrix Metalloproteinase 13
  • SIRT6 protein, human
  • Sirtuins