Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are painful and debilitating diseases characterized by cartilage degeneration, swelling, and decreased function of the synovial joints. It is the leading cause of disability in the developed countries affecting one of every six people and resulting in a significant cost on health and social care systems. Cartilage degeneration can be characterized by the imbalance of a complex network of regulatory proteins. Interleukin-1 (IL-1) and Tumour Necrosis Fact or-alpha (TNF-alpha) are two major cytokines responsible for the pathogenesis of arthritis. Current pharmaceutical interventions are based on the inhibition of these pro-inflammatory pathways. This project utilizes a multidisciplinary approach characterized by the fusion of two seemingly different areas: Biomechanics and Systems Biology. The biomechanical approach will be used to monitor the degradation of cartilage explants by measuring alterations on the mechanical properties. Indentation tests will be combined with biphasic finite element models in order to measure the Young's modulus and the permeability of the tissue.
The systems biology approach will be employed to investigate the possible cross-talks of several signalling cascades that govern cartilage degeneration (i.e. TNF-alpha, IL-1, FasL). The measurements of several intracellular and extracellular protein concentrations as well as their activity state will be correlated to the alteration of the mechanical properties of the tissue by using a statistical approach such as principal component analysis and partial least squares regression. Predictive models between signalling network activities and phenotypic outcomes will be derived. The multidisciplinary approach of the project will shed light into the molecular pathways that govern cartilage degeneration. Intervention on these intracellular pathways with small molecule inhibitors can lead to new treatments of arthritis.
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