title: Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis.
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 mug/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.
authors.affiliation: Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan. xchang@src.riken.go.jp
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Chang
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000990:Antithrombin III / Q000037:antagonists & inhibitors*; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology* / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000494:pharmacology; D002863:Chromogenic Compounds / Q000032:analysis; D003871:Dermatan Sulfate / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology / Q000502:physiology*; D007501:Iron / Q000494:pharmacology; D007632:Keratan Sulfate / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D000990:Antithrombin III; D002118:Calcium; D002809:Chondroitin Sulfates; D002863:Chromogenic Compounds; D003871:Dermatan Sulfate; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D006820:Hyaluronic Acid; D007501:Iron; D007632:Keratan Sulfate; D013917:Thrombin
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