Ewch i’r prif gynnwys
Dr Sophie Gilbert

Dr Sophie Gilbert

Research Associate

Ysgol y Biowyddorau

Email:
gilbertsj1@cardiff.ac.uk
Telephone:
+44 (0)29 2087 4287
Location:
Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Adeilad Syr Martin Evans, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX

My research interests encompass three areas of cartilage biology: the role of inflammatory cytokine signalling and mechanical load in cartilage degeneration and cartilage repair strategies. My current research involves delineating the role of PKR in arthritis in order to reveal new mechanisms of cytokine and mechanical load mediated cartilage degradation that may be targeted in treatment or diagnosis of arthritis. Another research priority focuses on cartilage repair with particular emphasis on investigating why repair tissue poorly integrates with the surrounding host cartilage.

I did my undergraduate degree at the University of Newcastle and then completed a PhD in 1997 at the University of Bristol investigating the role of collagen in the pathogenesis of dilated cardiomyopathy. I moved to the Connective Tissue Research Biology Labs in the School of Biosciences, Cardiff in 1997.

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My research interests encompass three areas of cartilage biology, the roles of inflammatory cytokine signalling and mechanical load in cartilage degeneration and cartilage repair strategies.

At the start of my post-doctoral research career, to identify genes involved in the onset of osteoarthritis (OA), I investigated chondrocyte gene expression in the Dunkin Hartley guinea pig model of OA. This species develops a spontaneous medial compartment knee OA that is similar in progression to human OA of the knee. Using the RNA fingerprinting technique of differential display, I detected a number of genes that were regulated in the medial compared to the lateral compartment cartilage of 8 week old Dunkin Hartley guinea pigs. Subsequent cloning and sequence analysis of one such upregulated cDNA revealed a 421bp sequence with 87% homology to the 3'UTR of human PACT, the protein activator of the interferon-inducible protein kinase, PKR. Since identifying the presence of this novel signalling pathway in osteoarthritic cartilage, I have shown that this pathway can be induced by the pro-inflammatory cytokines, TNF-a, IL-1 and oncostatin M as well as the sphingolipid second messenger, ceramide. I have since revealed a role for ceramide-mediated PKR signalling in articular cartilage degradation. Ceramide participates in a number of key signalling pathways that have been implicated in the pathogenesis of OA. TNF-α was highlighted as a potential stimulus of the ceramide pathway since it has been shown, in other cell types, to increase endogenous ceramide signalling via its receptor (TNF-R55) and is of obvious relevance to articular cartilage degeneration in arthritis. More recently, I have shown that treatment of chondrocytes with sphingomyelinase, to increase endogenous ceramide, alters chondrocyte homeostasis promoting an apparent loss of phenotype and that this may occur via activation of the MAPK-ERK signalling pathway. My current project is investigating whether over-activation of PKR with concomitant increases in ER stress, predisposes to degenerative joint disease that is mediated via pro-inflammatory and/or mechanical regulation of TNF-a.

In addition to this work, I have also been investigating the hypothesis that the combined degradative effects of mechanical loading and TNF-α stimulation of cartilage may operate synergistically through the PKR pathway. Using a loading regime of 0.5MPa for 30 minutes, which we have previously shown increases the expression and activation of MMPs, we have found that inhibiting PKR reduces load-induced cell death and load-induced activation of MMP-9. We have also investigated whether PKR is involved in the signalling pathways induced by mechanical load. To date, we have found changes in the ERK signalling pathway with mechanical load and are investigating the precise contribution of PKR in this. Although preliminary, these findings suggest that activation of the PKR signalling pathway may be mechanically regulated. Concomitant activation of PKR by mechanical load and TNF-a may represent a new degradative pathway important in the pathology of both osteo and rheumatoid arthritis.

I am also interested in why cartilage repair tissue does not integrate well with the surrounding host cartilage. Significant chondrocyte death occurs when cartilage is wounded or cut which we believe is a major inhibitory factor to successful cartilage repair. By increasing the number of viable chondrocytes at the wound edge we hypothesise that tissue integration can be enhanced. We have established a disc/ring cartilage composite model to investigate cartilage-cartilage integration. When the disc/ring composite is created using biopsy punches, apoptotic and necrotic cell death occurs at the cartilage wound edge. By pre-incubating the cartilage discs prior to creating the disc/ring composite with a pan-caspase inhibitor, we have shown that tissue integration can be significantly enhanced during cartilage repair in vitro.

I have also worked on an EU funded project on Ageing of the ECM. This study was part of the EU 5th framework and investigated changes in tendon extracellular matrix with age. An ageing colony of C57/Blk6 mice was established and biochemical changes in the Achilles tendon were investigated. Significant changes in the collagenous matrix as well as alterations in matrix turnover were key findings of the study.

Current funding

  • ARC

Collaborators

External

  • Prof Ladiges and Dr John Morton (Dept Comparative Medicine, University of Washington) – Investigating the role of PKR in arthritic disease using the P58IPK knockout mouse
  • Dr Drew Burdon (Smith & Nephew, York) – Cartilage repair strategies
  • Dr Anne Vaughan-Thomas (Liverpool University) - Effect of treatment of bovine chondrocyte cell pellets with col9a1 and col11a1 antisense oligonucleotides on matrix assembly

Internal

  • Lee Gonzalez (School of Optometry & Visual Sciences) – Mechanical testing of integrated cartilage
  • Dr D J Mason (School of Biosciences) - Molecular mechanisms of cytokine-induced cartilage degradation in arthritic disease
  • Dr EJ Blain (School of Biosciences) – Molecular mechanisms of cytokine-induced cartilage degradation in arthritic disease
  • Prof D Aeschlimann (Matrix Biology Repair Group, Dental School) - Characterising the phenotype of young and old Achilles tendon fibroblasts.

Grants

Are mechanically and TNF-a induced cartilage degradative processes mediated through PKR? 

  • Dr DJ Mason, Dr SJ Gilbert & Prof VC Duance 
  • Nov 2004 – Sept 2006 
  • Arthritis Research Campaign £81227

Does TNF-a induced activation of PKR in chondrocytes mediate cartilage destruction?

  • Dr DJ Mason, Dr SJ Gilbert & Prof VC Duance
  • Sept 2002 – July 2004
  • Arthritis Research Campaign £92149

Changes in chondrocyte gene expression in early stages of osteoarthritis.

  • Dr DJ Mason, Dr SJ Gilbert & Prof VC Duance
  • April 2000 - March 2001
  • Henry Smith's Charity £46266

Proffiliau allanol