OBJECTIVES: Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific Sirt1-conditional knockout (CKO) mice were analysed using an experimental OA model. METHODS: OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and Sirt1-CKO (Sirt1(flox)/(flox); Col2a1-Cre) mice generated using the Cre-loxP system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in Sirt1-CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control (Sirt1(flox)/(flox)) mice. RESULTS: The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. Sirt1-CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old Sirt1-CKO mice than in control mice. Sirt1-CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in Sirt1-CKO mice compared with control mice 2 weeks after surgery. CONCLUSIONS: Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVES: Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific Sirt1-conditional knockout (CKO) mice were analysed using an experimental OA model. METHODS: OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and Sirt1-CKO (Sirt1(flox)/(flox); Col2a1-Cre) mice generated using the Cre-loxP system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in Sirt1-CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control (Sirt1(flox)/(flox)) mice. RESULTS: The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. Sirt1-CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old Sirt1-CKO mice than in control mice. Sirt1-CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in Sirt1-CKO mice compared with control mice 2 weeks after surgery. CONCLUSIONS: Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Elizabeth W Bradley; Lomeli R Carpio; Andre J van Wijnen; Meghan E McGee-Lawrence; Jennifer J Westendorf Journal: Physiol Rev Date: 2015-10 Impact factor: 37.312