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Title: Gene expression profiling and proteomic analysis of cartilage degradation in a mouse model of osteoarthritis
Author: Gardiner, Matthew David
ISNI:       0000 0004 2709 8626
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Osteoarthritis (OA) is characterised by articular cartilage degradation and changes in associated joint tissues. It is a common condition, which causes significant pain and disability. Aetiological factors include age, mechanical stress, genetic predisposition and obesity. The exact sequence of molecular events in disease initiation and progression remains unclear. Treatment options are limited to symptom control and joint replacement surgery for severe disease. The aim of this research was to perform a global analysis of the gene expression and protein profile of cartilage during the early stages of OA. The destabilisation of the medial meniscus mouse (DMM) model of OA was used to study changes in the cartilage of operated or unoperated knee joints at two, four, and eight weeks following surgery. A new method was developed to retrieve articular cartilage from the mouse knee joint. This enabled proteomic analysis of the cartilage using two-dimensional difference gel electrophoresis and tandem mass spectrometry. No significant changes were seen at two or four weeks; at eight weeks both intracellular and extracellular proteins had altered abundance including small leucine rich repeat proteoglycans (SLRPs) and proteins involved in energy production and the cytoskeleton. For whole genome expression profiling, RNA was isolated from cartilage at the same time points, amplified and hybridised to Mouse WG-6 v2.0 Expression BeadChips. Validations were performed using real-time RT-PCR. Changes in gene expression were most marked at two weeks with up-regulation of metalloproteinases and SLRPs and markedly altered expression of cytoskeletal elements. These findings demonstrate the significant alteration of key biological processes related to cartilage degeneration early in the progression of OA.
Supervisor: Nagase, Hideaki ; Nanchahal, Jagdeep Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral