Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes

Michal Bar Oz, Ashok Kumar, Jinan Elayyan, Eli Reich, Milana Binyamin, Leonid Kandel, Meir Liebergall, Juergen Steinmeyer, Veronique Lefebvre, Mona Dvir-Ginzberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Changes in the content of aggrecan, an essential proteoglycan of articular cartilage, have been implicated in the pathophysiology of osteoarthritis (OA), a prevalent age-related, degenerative joint disease. Here, we examined the effect of SOX9 acetylation on ACAN transactivation in the context of osteoarthritis. Primary chondrocytes freshly isolated from degenerated OA cartilage displayed lower levels of ACAN mRNA and higher levels of acetylated SOX9 compared with cells from intact regions of OA cartilage. Degenerated OA cartilage presented chondrocyte clusters bearing diffused immunostaining for SOX9 compared with intact cartilage regions. Primary human chondrocytes freshly isolated from OA knee joints were cultured in monolayer or in three-dimensional alginate microbeads (3D). SOX9 was hypo-acetylated in 3D cultures and displayed enhanced binding to a -10 kb ACAN enhancer, a result consistent with higher ACAN mRNA levels than in monolayer cultures. It also co-immunoprecipitated with SIRT1, a major deacetylase responsible for SOX9 deacetylation. Finally, immunofluorescence assays revealed increased nuclear localization of SOX9 in primary chondrocytes treated with the NAD SIRT1 cofactor, than in cells treated with a SIRT1 inhibitor. Inhibition of importin β by importazole maintained SOX9 in the cytoplasm, even in the presence of NAD. Based on these data, we conclude that deacetylation promotes SOX9 nuclear translocation and hence its ability to activate ACAN.

Original languageAmerican English
Pages (from-to)499-508
Number of pages10
JournalAging Cell
Volume15
Issue number3
DOIs
StatePublished - 1 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 The Anatomical Society and John Wiley & Sons Ltd.

Keywords

  • Acetylation
  • Aggrecan
  • Aging
  • Cartilage
  • Nucleus
  • Osteoarthritis
  • SIRT1
  • SOX9

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