|dc.identifier.citation||Thompson, C. 2013. Interactions between primary cilia length and hedgehog signalling in response to mechanical and thermal stress. Queen Mary University of London.||en_US
|dc.description.abstract||The primary cilium is a microtubule-based organelle present on the majority of interphase
cells where it functions as a hub for numerous signalling pathways including hedgehog
signalling. Chondrocytes, the unique cellular component of articular cartilage, possess
primary cilia which are required for mechanotransduction and maintenance of a healthy
extracellular matrix. However in osteoarthritis there is an increase in primary cilia length
and prevalence associated with aberrant activation of hedgehog signalling which promotes
cartilage degradation. The aim of this thesis was therefore to examine the influence of
biophysical stimuli on chondrocyte primary cilia structure and function, relating changes in
ciliary length to perturbations in hedgehog signalling.
An in vitro mechanical loading model was established to study the influence of cyclic tensile
strain on chondrocyte primary cilia. Loading at 10% strain activated hedgehog signalling
measured by expression of Gli1 and Ptch1. Cilia progressively disassembled in response to
increasing levels of mechanical strain in a manner dependent upon tubulin deacetylation.
Cilia disassembly at 20% strain was associated with the loss of mechanosensitive hedgehog
signalling despite continued expression of hedgehog ligand (Ihh). Therefore this behaviour
may function as a protective mechanism limiting hedgehog-mediated cartilage degradation
in response to high levels of mechanical strain.
To further understand the influence the extracellular environment exerts over ciliary
function, a second in vitro model was developed investigating the effects of thermal stress.
In chondrocytes and fibroblasts, primary cilia underwent rapid resorption in response to
elevated temperature and ligand mediated hedgehog signalling was inhibited.
These studies demonstrate that regulated disassembly of the cilium in response to physical
stress modulates both cilia size and function. In particular, the findings suggest that changes
in the chondrocyte physical environment affect cilia structure and function and may
therefore be an important factor in the aetiology of cartilage disease.||en_US
|dc.description.sponsorship||Biotechnology and Biological Sciences
Research Council (BBSRC)||en_US
|dc.publisher||Queen Mary University of London||en_US
|dc.title||Interactions between primary cilia length and hedgehog signalling in response to mechanical and thermal stress.||en_US
|dc.rights.holder||The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author||