title: Overexpression of sirtuin 6 suppresses inflammatory responses and bone destruction in mice with collagen-induced arthritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Chonbuk National University, Jeonbuk, Republic of Korea.
authors.forename: Hwa-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Sun-O
authors.initials: SO
authors.lastname: Ka
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Lee
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000107:Acetylation; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000276:immunology*; D010010:Osteoclasts / Q000166:cytology; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C501860:Sirt6 protein, mouse; D037761:Sirtuins