title: Acute-phase serum amyloid A regulates tumor necrosis factor α and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy.
abstract: OBJECTIVE
  To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis.
  
  
  METHODS
  Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen-generated biomarkers C2C and C1,2C were measured at 0-3 months in patients with inflammatory arthritis commencing anti-tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography.
  
  
  RESULTS
  Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05).
  
  
  CONCLUSIONS
  A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in vivo. The ability of A-SAA to regulate TNFα suggests that A-SAA signaling pathways may provide new therapeutic strategies for the treatment of inflammatory arthritis.
authors.affiliation: St. Vincent's University Hospital, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Ronan H
authors.initials: RH
authors.lastname: Mullan
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCormick
authors.forename: Clare
authors.initials: C
authors.lastname: Matthews
authors.forename: Owen
authors.initials: O
authors.lastname: Sullivan
authors.forename: Aisling
authors.initials: A
authors.lastname: Kennedy
authors.forename: Oliver
authors.initials: O
authors.lastname: FitzGerald
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D024043:Collagen Type II / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D033023:Foot Joints / Q000000981:diagnostic imaging; D050823:Hand Joints / Q000000981:diagnostic imaging; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D011859:Radiography; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000000981:diagnostic imaging / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D024043:Collagen Type II; D053590:Interleukin 1 Receptor Antagonist Protein; D000685:Serum Amyloid A Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases