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

Abstract

ObjectiveSirtuin 6 (SIRT-6) is an NAD(+)-dependent deacetylase and mono-ADP-ribosyltransferase. It is known to interfere with the NF-B signaling pathway and thereby has an antiinflammatory function. Due to the central role of NF-B in rheumatoid arthritis (RA) development, we undertook this study to test our hypothesis that SIRT-6 could have antiarthritic effects. MethodsAn 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. ResultsIn vitro experiments demonstrated that SIRT-6 overexpression suppressed NF-B target gene expression induced by tumor necrosis factor . 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. ConclusionThese results suggest that blocking the NF-B 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.