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Title: Linking ageing and arthritis : the role of the longevity-related SIRT1 molecule in age-related cartilage degeneration and osteoarthritis
Author: Sacitharan, Pradeep
ISNI:       0000 0004 6495 7741
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Osteoarthritis (OA) is the most common form of arthritis worldwide and is characterised by the progressive degradation of articular cartilage. Ageing is the primary risk factor associated with OA. However, the roles of ageing-related mechanisms in cartilage homeostasis are poorly understood. The class three histone deacetylase, Silent mating type information regulation 2 homolog (SIRT1) has been extensively shown to regulate lifespan in lower organisms and signalling pathways linked to mammalian ageing. My thesis explores the role of Sirtuin 1 in cartilage homeostasis and OA. I used in vitro experiments with chondrocyte cell lines, human clinical samples, novel genetically modified cartilage specific and whole body SIRT1 deficient mice alongside molecular biological tools to investigate my research questions. Human OA cartilage showed decreased SIRT1 compared to healthy cartilage. Mice with cartilage-specific SIRT1 deletion showed greater cartilage degradation during ageing and in an experimental OA model. In vitro and in vivo studies showed SIRT1 to directly regulate autophagy in chondrocytes. More importantly, the activation of autophagy using spermidine protected against experimental OA in wild-type mice but not in cartilage-specific SIRT1 deficient mice. In addition, my data revealed whole body SIRT1 deficient mice had increased early joint inflammation in repose to injury but displayed less cartilage loss over time in an experimental OA model. Together I have shown that SIRT1 declines with age and contributes to OA due to dysregulated autophagy. However, chronic low grade inflammation caused by SIRT1 loss was protective. My data suggest these pathways can be targeted to treat OA.
Supervisor: Vincent, Tonia ; Edwards, James Sponsor: Arthritis Research UK ; Orthopaedic Research UK ; Kennedy Trust for Rheumatology Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Musculoskeletal Ageing ; Autophagy ; Inflammation ; Ageing Biology ; Osteoarthritis ; SIRT1 ; Experimental therapeutic