Local expression of the serum amyloid A and formyl peptide receptor-like 1 genes in synovial tissue is associated with matrix metalloproteinase production in patients with inflammatory arthritis.
OBJECTIVE
To evaluate the regulation of acute-phase serum amyloid A (A-SAA) production in inflamed synovial tissue, and to elucidate a possible pathophysiologic role in the induction of matrix metalloproteinase (MMP) release by fibroblast-like synoviocytes (FLS).


METHODS
Synovial tissue samples were obtained by arthroscopic biopsy from the knee joints of patients with inflammatory arthritis. Primary cultures of FLS from patients with rheumatoid arthritis (RA), psoriatic arthritis, sarcoid arthritis, and undifferentiated arthritis were established. Total RNA was extracted from FLS and analyzed by reverse transcription-polymerase chain reaction (PCR) using specific primers for A-SAA and formyl peptide receptor-like 1 (FPRL1), an A-SAA receptor. Southern blot analysis confirmed the PCR products generated. Immunohistochemical analysis demonstrated the expression of A-SAA protein production by several synovial cell populations, and immunofluorescence analysis confirmed A-SAA colocalization with the macrophage marker CD68. Primary FLS cultures stimulated with recombinant human A-SAA resulted in dose-dependent MMP-1 and MMP-3 production, as measured by an enzyme-linked immunosorbent assay.


RESULTS
A-SAA messenger RNA (mRNA) and FPRL1 mRNA were present in FLS, macrophages, and endothelial cells isolated from the synovial tissue of patients with RA and other categories of inflammatory arthritis. A-SAA expression was regulated by proinflammatory cytokines and occurred in association with FPRL1 expression in FLS and endothelial cells, which is consistent with a biologic role at the sites of inflammation. Recombinant human A-SAA induced both MMP-1 and MMP-3 secretion by FLS. The mean fold increases in A-SAA-induced MMP-1 and MMP-3 production were 2.6 and 10.6, respectively, compared with 7.6-fold and 41.9-fold increases in interleukin-1 beta-induced MMP-1 and MMP-3 production.


CONCLUSIONS
The up-regulation of the A-SAA and FPRL1 genes in inflamed synovial tissue suggests an important role in the pathophysiology of inflammatory arthritis. A-SAA induces the production of MMPs. Therapeutic targeting of A-SAA, or FPRL1, may modulate pathophysiologic pathways that are associated with matrix degradation in patients with RA and other forms of progressive inflammatory arthritis.
O'Hara
Rosemary
R
St. Vincent's University Hospital, Dublin, Ireland.
Murphy
Evelyn P
EP
Whitehead
Alexander S
AS
FitzGerald
Oliver
O
Bresnihan
Barry
B
D000328:Adult; D001053:Apolipoproteins / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D002356:Cartilage / Q000201:enzymology / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D044042:Receptors, Formyl Peptide / Q000235:genetics*; D044067:Receptors, Lipoxin / Q000235:genetics*; D000685:Serum Amyloid A Protein / Q000235:genetics*; D013583:Synovial Membrane / Q000201:enzymology* / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D001053:Apolipoproteins; C105101:FPR2 protein, human; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D000685:Serum Amyloid A Protein; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1