Overexpression of Sirtuin 6 Suppresses Inflammatory Responses and Bone Destruction in Mice With Collagen‐Induced Arthritis

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.