Overexpression of sirtuin 6 suppresses inflammatory responses and bone destruction in mice with collagen-induced arthritis

Arthritis Rheum. 2013 Jul;65(7):1776-85. doi: 10.1002/art.37963.


Objective: Sirtuin 6 (SIRT-6) is an NAD(+) -dependent deacetylase and mono-ADP-ribosyltransferase. It is known to interfere with the NF-κB signaling pathway and thereby has an antiinflammatory function. Due to the central role of NF-κB in rheumatoid arthritis (RA) development, we undertook this study to test our hypothesis that SIRT-6 could have antiarthritic effects.

Methods: An adenovirus containing SIRT-6 complementary DNA (Ad-SIRT6) was used to deliver SIRT-6 to human RA fibroblast-like synoviocytes in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via bilateral intraarticular injections into the ankle joints.

Results: In vitro experiments demonstrated that SIRT-6 overexpression suppressed NF-κB target gene expression induced by tumor necrosis factor α. SIRT-6 overexpression inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and RANKL in bone marrow-derived macrophages. Mice with CIA had an increased incidence of disease and developed arthritis in the hind paws. In contrast, mice injected with Ad-SIRT6 showed attenuated severity of arthritis based on clinical scores, hind paw thickness, and radiographic and pathologic findings. Moreover, the injection of Ad-SIRT6 down-regulated local and systemic levels of proinflammatory cytokines. After induction of CIA, mice injected with Ad-SIRT6 showed significantly decreased arthritis severity, from the onset of clinical signs to the end of the study.

Conclusion: These results suggest that blocking the NF-κB pathway by SIRT-6 in rheumatoid joints reduces both the inflammatory response and tissue destruction. Therefore, the development of an immunoregulatory strategy based on SIRT-6 may have therapeutic potential for the treatment of RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / therapy*
  • Arthritis, Rheumatoid / immunology*
  • Cell Differentiation
  • Cells, Cultured
  • Gene Transfer Techniques
  • Humans
  • Inflammation Mediators / immunology
  • Macrophages / cytology
  • Male
  • Mice
  • Mice, Inbred DBA
  • NF-kappa B / immunology*
  • Osteoclasts / cytology
  • Signal Transduction
  • Sirtuins / genetics
  • Sirtuins / immunology
  • Sirtuins / physiology*
  • Synovial Membrane / cytology*
  • Synovial Membrane / immunology
  • Tumor Necrosis Factor-alpha / immunology
  • Up-Regulation


  • Inflammation Mediators
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Sirt6 protein, mouse
  • Sirtuins