title: Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model.
abstract: Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1/anti-IL-8. NF-kappaB was examined using a specific inhibitor and Western blotting. An RA synovial/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time- and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappaB in RA explants (p < 0.05). Finally, in the RA synovial/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis.
authors.affiliation: Dublin Academic Medical Centre, University College Dublin, Dublin, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marrelli
authors.forename: Mark
authors.initials: M
authors.lastname: Blades
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCormick
authors.forename: Paola
authors.initials: P
authors.lastname: Maderna
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Ronan
authors.initials: R
authors.lastname: Mullan
authors.forename: Oliver
authors.initials: O
authors.lastname: FitzGerald
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000276:immunology / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D018183:Transplantation Chimera; D055815:Young Adult
chemical_list: D000685:Serum Amyloid A Protein