Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis.
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.
Chang
Xiaotian
X
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan. xchang@src.riken.go.jp
Yamada
Ryo
R
Yamamoto
Kazuhiko
K
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
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
Ann Rheum Dis. 1986 Jan;45(1):21-6
3954454
Arthritis Rheum. 1984 May;27(5):495-501
6202303
Ann Rheum Dis. 1994 Jan;53(1):72-9
8311562
Br J Rheumatol. 1994 Jan;33(1):5-10
8162458
Ann Rheum Dis. 1994 Jul;53(7):446-9
7944616
Clin Immunol Immunopathol. 1995 Sep;76(3 Pt 1):225-33
7554443
Clin Exp Rheumatol. 1996 Jul-Aug;14(4):381-6
8871836
J Rheumatol. 1996 Sep;23(9):1505-11
8877916
Semin Thromb Hemost. 1996;22(6):489-96
9122713
J Mol Biol. 1997 Feb 28;266(3):601-9
9067613
Semin Hematol. 1997 Jul;34(3):188-204
9241705
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14683-8
9405673
Ann Rheum Dis. 1998 Mar;57(3):162-5
9640132
J Biol Chem. 1998 Jul 3;273(27):16824-7
9642241
Annu Rev Biochem. 1998;67:609-52
9759499
Ann Rheum Dis. 1999 Jan;58(1):55-60
10343541
Ann Rheum Dis. 1999 Mar;58(3):186-8
10364918
J Biol Chem. 1999 Aug 20;274(34):23969-76
10446165
Ann Clin Lab Sci. 1999 Oct-Dec;29(4):275-80
10528826
Rheumatology (Oxford). 2005 Jan;44(1):40-50
15466895
Rheumatology (Oxford). 2005 Mar;44(3):293-8
15561738
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14362-7
12391302
J Nippon Med Sch. 2000 Apr;67(2):92-5
10754597
Arthritis Rheum. 2000 Jun;43(6):1257-65
10857784
J Clin Invest. 2000 Oct;106(7):873-8
11018075
Arthritis Rheum. 2001 Aug;44(8):1754-60
11508425
J Immunoassay Immunochem. 2002;23(1):85-94
11848103
Arch Dis Child. 2002 Mar;86(3):190-3
11861239
Biochem Soc Trans. 2002 Apr;30(2):173-7
12023846
Arthritis Res Ther. 2003;5(2):54-67
12718745
Biochemistry. 2003 Jul 15;42(27):8143-52
12846563
Nat Genet. 2003 Aug;34(4):395-402
12833157
J Biol Chem. 2003 Sep 12;278(37):35767-74
12832413
Ann Rheum Dis. 2004 Apr;63(4):373-81
15020330
Clin Exp Rheumatol. 2004 May-Jun;22(3):307-12
15144124
Osteoarthritis Cartilage. 2004 Jul;12(7):536-42
15219568
Med Sci Monit. 2004 Apr;10(4):BR91-5
15039637
Clin Rheumatol. 1989 Sep;8(3):345-51
2805610