Prof Victor Duance - PhD
There are three main themes to the work of my research group (i) the structure and function of the minor collagens of cartilage, in particular types III, IX, X and XI, how they change with age and in disease, as well as their importance in cartilage repair (ii) elucidation of the cell signalling pathways associated with mechanical and cytokine mediated cartilage degeneration and (iii) strategies for enhancing cartilage repair.
We have identified novel interactions of the type IX collagen with fibronectin and type XI collagen with heparan sulphate, indicating these collagens may mediate cell/matrix interactions. We believe changes in the interactions of these collagens leads to a loss of matrix integrity and predispose cartilage to mechanically-induced tissue damage resulting in diseases such as osteoarthritis. To characterise molecular mechanisms underlying cartilage degradation we are isolating genes regulated by mechanical stimulation. We have shown that mechanical stimuli up-regulates the synthesis and activation of matrix metalloproteinases (MMPs), which are mediated by thymosin ß4 which promotes disassembly of filamentous actin. Current research is aimed at elucidating the precise role of the different cytoskeletal elements in mechanotransduction mechanisms. We believe the cytoskeleton is pivotal in maintaining tissue homeostasis and that changes in the cytoskeleton may be instrumental in the catabolic phenotype that arises in these tissues with age.
We have investigated genes that are differentially regulated in the early stages of the development of osteoarthritis. One gene up-regulated is the Protein Activator of Protein Kinase R (PACT). Protein Kinase R (PKR) appears to be pivotal in cytokine signalling in chondrocytes. We have found that tumour necrosis factor alpha (TNF- a) signals via the sphingolipid, ceramide, and PKR. We are investigating this and the mechanotransduction pathways using specific inhibitors as well as antisense techniques to inhibit expression of specific genes involved.
There is currently much interest in tissue engineering to elicit more effective repair of articular cartilage. We are devising protocols to stimulate chondrocytes to maintain their phenotype and synthesise a functionally competent matrix. We are investigating strategies to promote better integration of newly synthesised cartilage matrix with existing tissue in order to facilitate a more biomechanically functional and hence longer lasting repair. We can enhance the ability of chondrocytes to migrate and are currently investigating ways of increasing the ability of these migratory chondrocytes to synthesise matrix, an essential element for effective cartilage repair.
Awarded an Adjunct Professorship at Xi’an College of Medicine, China (2010)
Current Sources of Funding
- Department of Trade and Industry/Smith & Nephew
- Arthritis Research Campaign
- EPSRC/Dorothy HodgkinPhD Award
Prof C Archer ( Swansea University) - Cartilage repair strategies.
Dr D J Mason ( School of Biosciences, Cardiff University) - Molecular mechanisms of cytokine-induced cartilage degradation in osteoarthritis.
Dr Martin Knight (Queen Mary University of London)
Dr T Chowdhury - Mechanisms of mechanotransduction
Prof. Richard Aspden ( Aberdeen) - Effect of impact loading on the chondrocyte cytoskeleton.
(Department of Optometry, Cardiff University)
Dr R D Young - Ultrastructural studies on molecular packing of heterotypic collagen fibrils.
Dr S Roberts (Orthopaedic Hospital, Oswestry) - Biochemistry of the intervertebral disc and changes in disc pathologies.
Prof D Aeschlimann (Matrix Biology Repair Group, Dental School, Cardiff University) - Characterising the phenotype of young and old Achilles tendon fibroblasts
Dr John Wardale (Astra Zeneca, Alderley Edge, Macclesfield) - The role of the chondrocyte cytoskeleton in osteoarthritis
Dr Ahmed Ali