Elevation of activated protein C in synovial joints in RA and its correlation with MMP-2

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Arthritis Rheum. 2004 Jul;50(7):2151-6.

Elevation of activated protein C in synovial joints in rheumatoid

arthritis and its correlation with matrix metalloproteinase 2.

Buisson-Legendre N, S, March L, C.

Institute of Bone and Joint Research, University of Sydney, Sydney, New

South Wales, Australia.

OBJECTIVE: To investigate the involvement of the anticoagulant serine

protease activated protein C (APC) in tissue remodeling in rheumatoid

arthritis (RA). METHODS: PC/APC, matrix metalloproteinase 2 (MMP-2), and

MMP-9 were detected in synovial fluid by Western blotting, and their

antigen levels were quantified by enzyme-linked immunosorbent assay in

patients with osteoarthritis (OA) or RA. Enzymatic activity of MMP-2 was

assayed using a specific fluorogenic substrate. We developed an improved

assay to measure APC activity in synovial fluid utilizing a chromogenic

substrate following immunoprecipitation with a specific PC/APC antibody.

PC/APC and MMP-2 were localized by immunohistochemistry in RA, OA, and

normal synovial tissues. RESULTS: Synovial fluid analysis demonstrated

that APC is present in both RA and OA synovial fluid, with APC activity

being markedly higher in RA (mean +/- SEM 462 +/- 112 ng/ml versus 136

+/- 42 ng/ml; P < 0.02). A correlation (r(2) = 0.61) was found between

APC and MMP-2 activity levels in RA patients, but not in OA patients.

Immunohistochemical studies of synovial sections showed colocalization

of APC and MMP-2 in endothelial and synovial lining cells. Additionally,

APC and MMP-2 coimmunoprecipitated with an anti-PC/APC antibody.

CONCLUSION: Our results show, for the first time, that APC and MMP-2 are

coordinately up-regulated and tightly bound in RA synovial fluid and

colocalized in synovia. Their association suggests that APC may modulate

MMP-2 activity in RA.

PMID: 15248212

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