Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis

Xiaotian Chang,Ryo Yamada,Kazuhiko Yamamoto

doi:10.1186/ar1487

Abstract

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.

Highlights

Thrombin is a multifunctional protease that can activate hemostasis and coagulation through the cleavage of fibrinogen to form fibrin clots
hyaluronic acid (HA) concentrations above 250 μg/ml considerably suppressed the inhibitory ability of antithrombin against thrombin in the presence of Ca2+ or Fe3+, and 1 mg/ml HA completely blocked antithrombin activity under the same conditions
HA after digestion with hyaluronidase inhibited antithrombin activity at relatively low concentrations (100 μg/ml) in the presence of Ca2+. This observation indicated that the inhibitory effect of HA on antithrombin was not caused by impurities in the reagent

Summary

Introduction

Thrombin is a multifunctional protease that can activate hemostasis and coagulation through the cleavage of fibrinogen to form fibrin clots. Increasing fibrin deposition is a predominant feature of rheumatoid arthritis (RA) in synovial tissue, which contributes to chronic inflammation and progressive tissue abnormalities [1]. Thrombin acts as a mitogen to stimulate the abnormal proliferation of synovial cells during RA pathogenesis. In this regard, thrombin can elevate the expression of nuclear factor-κB, interleukin-6, and granulocyte colony-stimulating factor in fibroblast-like cells of the RA synovium [2,3]. Thrombin can upregulate the transcription of vascular endothelial growth factor receptor and thereby induce the permeability, proliferation, and migration of capillary endothelial cells or their progenitors during angiogenesis [4,5,6]. Thrombin is essential for enhancing synovial thickness and inflammation during the pathogenesis of RA

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Conclusion