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). 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.