ANNUAL REVIEW master Final3a - St Vincent's University Hospital

St. Vincent’s Healthcare Group Limited - Annual Review 2007
Education & Research
Dr Bernadette Lynch (Clinical fellow) is examining the role of IL-22 in the joint. She has demonstrated high
levels of IL-22 in synovial fluid compared to serum. Currently she is examining IL-22 mRNA in synovial tissue
pre/post biologic therapy and is examining the effect of IL-22 on cytokine production, cell proliferation and
invasion and on downstream signalling pathways. Using synovial explant cultures Bernadette will examine
the of anti-IL-22 in comparison to Humira, as a potential therapeutic target. Dr Taj Saber (Clinical Fellow)
has only started with the group and will be examining the effects of IL-22 and OSM alone and in combination
on synovial invasion. Using primary fibroblasts, explants and chondrocytes Taj will examine the effect of
these two cytokines on MMP production, proteoglycan release and invasion. Furthermore she will examine
the downstream signalling pathways involved, specifically the JAK-STAT pathway.
(ii) Serum Amyloid A (A-SAA)
The role of A-SAA in the pro-inflammatory response is an on-going project theme of the unit over the past
10 years continued by Dr Ronan Mullan and Mary Connolly, graduate PhD student under the direction of Dr
Ursula Fearon, Prof Doug Veale, Prof Barry Bresnihan. Dr Ronan Mullan’s paper demonstrating that A-SAAinduces
adhesion molecule, angiogenesis and matrix metalloproteinase expression through the NFκB
pathway was published in Arthritis and Rheumatism, January 2006 and won the best Rheumatology paper
at the IJMS awards 2007. Furthermore Ronan has demonstrated increased matrix turnover in whole
cartilage explants, along with correlation of A-SAA with serum biomarkers of cartilage breakdown in patients
pre/post biologic therapy, suggesting that targeting A-SAA, or its signaling pathways, may represent a
realistic therapeutic approach. Mary Connolly continues to progress this work, specifically examining the
effect of A-SAA on cell migration and invasion, cartilage metabolism and the related transcriptional
pathways. Currently we are examining GFP tagged monocyte migration in vivo using a novel human RA
synovial tissue/SCID mouse chimera model. Mary has demonstrated high A-SAA levels in serum and
synovial fluid of RA and PsA patients. In addition A-SAA and its receptor FPRL-1 mRNA was demonstrated
in RASFC, chondrocytes, neutrophils, peripheral blood mononuclear cells, endothelial cells and synovial
tissue. Mary has also shown that A-SAA upregulates a number of MMPs and GAG in human primary
chondrocytes, synovial fibroblasts and synovial tissue. Furthermore, Mary has elucidated that A-SAA
specifically alters cytoskeletal rearrangement in RA synoviocytes producing filopodia protrusion and
migration. She has also shown that A-SAA regulates avB3, B1-integrins and viculin. Currently she is
examining the effect of A-SAA on specific cytoskeletal proteins involved in cell migration and cartilage
invasion such as PAX, FAK and the GTPases (RhoA, CDC42, RAC1).
Intact Actin
Filaments
Disassembly of actin
cytoskeleton and Induction
of filopodia formation
Fig 2 A-SAA induces disassembly of actin filaments in primary synovial fibroblast
(iii) Endothelial cell survival and blood vessel regression. One of the main interests of the group is the role
of angiogenesis in the pro-inflammatory response, with specific interest in the pathways of blood vessel
maturity and survival. This work will provide novel insights into the complex mechanisms mediating growth
factor activation within a synovial EC model. Dr Wei Gao, Jennifer Mc Cormick and Dr Catherine Sweeney
have demonstrated expression of VEGF and Ang2 in the joint, and demonstrated they have synergistic
Return to Contents
25