RESEARCH - Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of RA

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Research article

Inhibition of antithrombin by hyaluronic acid may be involved in the

pathogenesis of rheumatoid arthritis

Xiaotian Chang1 , Ryo Yamada1 and Kazuhiko Yamamoto1 ,2

1Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of

Physical and Chemical Research (RIKEN), Kanagawa, Japan

2Department of Allergy and Rheumatology, Graduate School of Medicine,

University of Tokyo, Tokyo, Japan

Arthritis Res Ther 2005, 7:R268-R273 doi:10.1186/ar1487

The electronic version of this article is the complete one and can be found

online at: http://arthritis-research.com/content/7/2/R268

Published 11 January 2005

Thrombin is a key factor in the stimulation of fibrin deposition,

angiogenesis, proinflammatory processes, and proliferation of

fibroblast-like cells. Abnormalities in these processes are primary features

of rheumatoid arthritis (RA) in synovial tissues. Tissue destruction in

joints causes the accumulation of large quantities of free hyaluronic acid

(HA) in RA synovial fluid. The present study was conducted to investigate

the effects of HA and several other glycosaminoglycans on antithrombin, a

plasma inhibitor of thrombin. Various glycosaminoglycans, including HA,

chondroitin sulfate, keratan sulfate, heparin, and heparan, were incubated

with human antithrombin III in vitro. The residual activity of antithrombin

was determined using a thrombin-specific chromogenic assay. HA

concentrations ranging from 250 to 1000 μg/ml significantly blocked the

ability of antithrombin to inhibit thrombin in the presence of Ca2+ or Fe3+,

and chondroitin A, B and C also reduced this ability under the same

conditions but to a lesser extent. Our study suggests that the high

concentration of free HA in RA synovium may block antithrombin locally,

thereby deregulating thrombin activity to drive the pathogenic process of RA

under physiological conditions. The study also helps to explain why RA

occurs and develops in joint tissue, because the inflamed RA synovium is

uniquely rich in free HA along with extracellular matrix degeneration. Our

findings are consistent with those of others regarding increased coagulation

activity in RA synovium.

http://arthritis-research.com/content/7/2/R268

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