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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:730260 |
| Date | January 2016 |
| Creators | Sacitharan, Pradeep |
| Contributors | Vincent, Tonia ; Edwards, James |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:cb519867-d184-44ff-b17f-bee1974f430b |
Page generated in 0.0021 seconds