ANNUAL REVIEW master Final3a - St Vincent's University Hospital

St. Vincent’s Healthcare Group Limited - Annual Review 2007
Education & Research
Dr Monika Binecka started with us Nov 2007 as a post-doctoral fellow and is examining the role of genomic
instability in the joint and the effect of hypoxia. She has demonstrated high oxidative damage in the synovial
(A) 8-oxo DG Nuclear Staining
(B) Anaphase Bridging
Lining Layer
Endothelial cells
Fig 1: Demonstrates oxidative damage in the endothelial cells and lining layer in RA synovium (stained with
8-oxo-dG) (A) and (B) demonstrates Anaphase Bridging in primary synoviocytes and chondrocytes
tissue of patients with low pO2 levels. Currently she is examining the level of synovial infiltrate and blood
vessel stability in the tissue and relating this to patient in vivo pO2 levels. In parallel, Monika is examining the
effect of graded hypoxia on anaphase bridging, telomere lengths and proliferation in primary fibroblasts and
chondrocytes (Fig 1B).
2: Cytokines, angiogenesis and invasion
Arthroscopy and dynamic imaging (MRI/PET) will be used to determine macroscopic vascularity, microscopic
angiogenesis measures to predict cartilage degradation in arthritis patients - pre/post biologic therapy.
Recent targeted biologic therapies, including anti-TNF and IL-1 blocking drugs are effective, but may not be
effective in 30% or more patients. The increasing evidence shows that complex cytokine networks do not
operate in isolation to promote new blood vessel formation, synovial hyperplasia and joint destruction. The
effects of TNFα and IL-β‚ ?alone and in combination with novel cytokines and growth factors, including
Oncostatin M (OSM), IL-17, acute serum amyloid A (A-SAA), IL-22, GMCSF, TLRs and Angiopoietins is
being examined in the inflammatory process, lead by Dr Ursula Fearon and Dr Douglas Veale
(i)Oncostatin M, IL-17, IL-22
OSM and IL-17 work synergistically in human cells and co-culture models of disease, to promote adhesion,
angiogenesis, cell migration and matrix degradation in primary synovial cultures. Using whole tissue synovial
explants and co-culture cartilage models (which more closely reflect the in vivo environment) a dramatic
synergistic reaction between OSM and IL-17 in promoting matrix degradation and cartilage degradation was
found. Ellen Moran, a graduate PhD student is examining the role of IL-17 alone and in combination with
TNFα and OSM on cartilage degradation and matrix turnover. Ellen has demonstrated high expression of IL-
17 in the serums, synovial fluids and synovial tissue lysates of patients with inflammatory arthritis.
Furthermore the expression of IL-17 in the inflamed joint was shown to correlate with disease activity and
duration and to be regulated by anti-TNF therapy. IL-17 alone was shown to regulate MMP-1,-2, -9 and -13
production and shift MMP/TIMP ratios in explants, RA fibroblasts, cartilage and chondrocytes and cause
cartilage proteoglycan depletion. Furthermore Ellen has demonstrated that IL-17 synergistically acts with
TNFα and OSM in the regulation of MMP production and proteoglycan depletion. Preliminary work carried
out by Ellen has shown IL-17 up-regulates the production of chemotactic cytokines and chemokines by RA
fibroblasts, explants and human endothelial cells. This will be investigated further to elucidate the role of IL-
17 on cell migration in the arthritic joint.
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