PT  - JOURNAL ARTICLE
AU  - M Connolly
AU  - D J Veale
AU  - U Fearon
TI  - Acute serum amyloid A regulates cytoskeletal rearrangement, cell matrix interactions and promotes cell migration in rheumatoid arthritis
AID  - 10.1136/ard.2010.142240
DP  - 2011 Jul 01
TA  - Annals of the Rheumatic Diseases
PG  - 1296--1303
VI  - 70
IP  - 7
4099  - http://ard.bmj.com/content/70/7/1296.short
4100  - http://ard.bmj.com/content/70/7/1296.full
SO  - Ann Rheum Dis2011 Jul 01; 70
AB  - Objective Serum amyloid A (A-SAA) is an acute-phase protein with cytokine-like properties implicated in the pathogenesis of rheumatoid arthritis (RA), atherosclerosis, diabetes and Alzheimer's disease. This study characterises the mechanism of A-SAA-induced cytoskeletal rearrangement and migration in synovial fibroblasts and microvascular endothelial cells (human dermal endothelial cells; HDEC). Methods Immunohistology and immunofluorescence were used to examine αvβ3 and β1-integrins, filamentous actin (F-actin) and focal adhesion expression in rheumatoid arthritis synovial tissue (RAST) and rheumatoid arthritis synovial fibroblast cells (RASFC). A-SAA-induced αvβ3 and β1-integrin binding was measured by adhesion assay. Cytoskeletal rearrangement and ρ-GTPase activation following A-SAA stimulation was examined using dual immunofluorescent staining for F-actin/vinculin staining, pull down assays and immunoblotting for Cdc42 and RhoA. Cell growth, invasion/migration, angiogenesis and actin formation were examined in the presence or absence of specific Rac1 and Cdc42 inhibitors (NSC23766 and 187-1). Results αvβ3, β1-integrin and F-actin predominantly localised to vascular endothelium and lining layer cells in RAST, compared with osteoarthritis and normal control synovial tissue. A-SAA significantly increased αvβ3 and β1 binding in RASFC. A-SAA induced cytoskeletal disassembly, loss of focal adhesions and filopodia formation in RASFC and HDEC. A-SAA significantly induced Cdc42 activation but failed to promote RhoA activation in HDEC and synovial fibroblast cells. Blockade of Rac-1 and Cdc42 inhibited A-SAA-induced cell growth, invasion/migration, actin cytoskeletal rearrangement and angiogenesis. Conclusions These data show a novel mechanism for A-SAA-induced cell migrational events in RA mediated via cytoskeletal signalling pathways.