Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice

Ann Rheum Dis. 2023 Nov;82(11):1464-1473. doi: 10.1136/ard-2023-224385. Epub 2023 Aug 7.


Objectives: Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in osteoarthritis (OA). This study aimed to define the effect of Sirt6 deficiency on the development of post-traumatic and age-associated OA in mice.

Methods: Male cartilage-specific Sirt6-deficient mice and Sirt6 intact controls underwent destabilisation of the medial meniscus (DMM) or sham surgery at 16 weeks of age and OA severity was analysed at 6 and 10 weeks postsurgery. Age-associated OA was assessed in mice aged 12 and 18 months of age. OA severity was analysed by micro-CT, histomorphometry and scoring of articular cartilage structure, toluidine blue staining and osteophyte formation. SIRT6-regulated pathways were analysed in human chondrocytes by RNA-sequencing, qRT-PCR and immunoblotting.

Results: Sirt6-deficient mice displayed enhanced DMM-induced OA severity and accelerated age-associated OA when compared with controls, characterised by increased cartilage damage, osteophyte formation and subchondral bone sclerosis. In chondrocytes, RNA-sequencing revealed that SIRT6 depletion significantly repressed cartilage extracellular matrix (eg, COL2A1) and anabolic growth factor (eg, insulin-like growth factor-1 (IGF-1)) gene expression. Gain-of-function and loss-of-function studies in chondrocytes demonstrated that SIRT6 depletion attenuated, whereas adenoviral overexpression or MDL-800-induced SIRT6 activation promoted IGF-1 signalling by increasing Aktser473 phosphorylation.

Conclusions: SIRT6 deficiency increases post-traumatic and age-associated OA severity in vivo. SIRT6 profoundly regulated the pro-anabolic and pro-survival IGF-1/Akt signalling pathway and suggests that preserving the SIRT6/IGF-1/Akt axis may be necessary to protect cartilage from injury-associated or age-associated OA. Targeted therapies aimed at increasing SIRT6 function could represent a novel strategy to slow or stop OA.

Keywords: arthritis, experimental; biological therapy; chondrocytes; osteoarthritis; osteoarthritis, knee.

Publication types

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

MeSH terms

  • Aged
  • Animals
  • Cartilage, Articular* / metabolism
  • Chondrocytes / metabolism
  • Disease Models, Animal
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice
  • Osteoarthritis* / genetics
  • Osteoarthritis* / metabolism
  • Osteophyte*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA / metabolism
  • Sirtuins* / genetics
  • Sirtuins* / metabolism


  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-akt
  • RNA
  • Sirtuins
  • SIRT6 protein, human
  • Sirt6 protein, mouse