Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence

George Batshon, Jinan Elayyan, Omar Qiq, Eli Reich, Louisa Ben-Aderet, Leonid Kandel, Amir Haze, Jürgen Steinmeyer, Veronique Lefebvre, Hong Zhang, Jennifer Elisseeff, Yves Henrotin, Ali Mobasheri, Mona Dvir-Ginzberg

Research output: Contribution to journalArticlepeer-review

Abstract

Objective Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA). Methods We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium. Results Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA. Conclusions Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult.

Original languageEnglish (US)
Pages (from-to)1370-1380
Number of pages11
JournalAnnals of the rheumatic diseases
Volume79
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • TNF-Alpha
  • chondrocytes
  • inflammation
  • osteoarthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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