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

Arthritis Rheum. 2012 Apr;64(4):1035-45. doi: 10.1002/art.33455. Epub 2011 Nov 10.


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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism*
  • Collagen Type II / metabolism
  • Disease Progression*
  • Female
  • Follow-Up Studies
  • Foot Joints / diagnostic imaging
  • Hand Joints / diagnostic imaging
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Male
  • Matrix Metalloproteinases / metabolism
  • Middle Aged
  • Radiography
  • Serum Amyloid A Protein / metabolism*
  • Synovial Fluid / metabolism
  • Synovial Membrane / diagnostic imaging
  • Synovial Membrane / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism


  • Antirheumatic Agents
  • Collagen Type II
  • Interleukin 1 Receptor Antagonist Protein
  • Serum Amyloid A Protein
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Matrix Metalloproteinases