Expression of the SAA and FPRL1 genes in synovial tissue is associated with MMP production

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Arthritis Rheum. 2004 Jun;50(6):1788-99.

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.

O'Hara R, EP, Whitehead AS, FitzGerald O, Bresnihan B.

St. 's University Hospital, Dublin, Ireland.

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.

CONCLUSION: 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.

PMID: 15188355

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