دورية أكاديمية
Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice
| العنوان: | Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice |
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| المؤلفون: | Collins, John A, Kim, C James, Coleman, Ashley, Little, Abreah, Perez, Matheus M, Clarke, Emily J, Diekman, Brian, Peffers, Mandy J, Chubinskaya, Susanna, Tomlinson, Ryan E, Freeman, Theresa A, Loeser, Richard F |
| بيانات النشر: | BMJ Publishing Group Ltd |
| سنة النشر: | 2023 |
| المجموعة: | HighWire Press (Stanford University) |
| مصطلحات موضوعية: | Osteoarthritis |
| الوصف: | Objectives Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in osteoarthritis (OA). This study aimed to define the effect of Sirt6 deficiency on the development of post-traumatic and age-associated OA in mice. Methods Male cartilage-specific Sirt6 -deficient mice and Sirt6 intact controls underwent destabilisation of the medial meniscus (DMM) or sham surgery at 16 weeks of age and OA severity was analysed at 6 and 10 weeks postsurgery. Age-associated OA was assessed in mice aged 12 and 18 months of age. OA severity was analysed by micro-CT, histomorphometry and scoring of articular cartilage structure, toluidine blue staining and osteophyte formation. SIRT6-regulated pathways were analysed in human chondrocytes by RNA-sequencing, qRT-PCR and immunoblotting. Results Sirt6- deficient mice displayed enhanced DMM-induced OA severity and accelerated age-associated OA when compared with controls, characterised by increased cartilage damage, osteophyte formation and subchondral bone sclerosis. In chondrocytes, RNA-sequencing revealed that SIRT6 depletion significantly repressed cartilage extracellular matrix (eg, COL2A1 ) and anabolic growth factor (eg, insulin-like growth factor-1 ( IGF-1 )) gene expression. Gain-of-function and loss-of-function studies in chondrocytes demonstrated that SIRT6 depletion attenuated, whereas adenoviral overexpression or MDL-800-induced SIRT6 activation promoted IGF-1 signalling by increasing Aktser473 phosphorylation. Conclusions SIRT6 deficiency increases post-traumatic and age-associated OA severity in vivo. SIRT6 profoundly regulated the pro-anabolic and pro-survival IGF-1/Akt signalling pathway and suggests that preserving the SIRT6/IGF-1/Akt axis may be necessary to protect cartilage from injury-associated or age-associated OA. Targeted therapies aimed at increasing SIRT6 function could represent a novel strategy to slow or stop OA. |
| نوع الوثيقة: | text |
| وصف الملف: | text/html |
| اللغة: | English |
| العلاقة: | http://ard.bmj.com/cgi/content/short/82/11/1464Test; http://dx.doi.org/10.1136/ard-2023-224385Test |
| DOI: | 10.1136/ard-2023-224385 |
| الإتاحة: | https://doi.org/10.1136/ard-2023-224385Test http://ard.bmj.com/cgi/content/short/82/11/1464Test |
| حقوق: | Copyright (C) 2023, BMJ Publishing Group Ltd |
| رقم الانضمام: | edsbas.4DAB44D0 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1136/ard-2023-224385 |
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