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

Arthritis Research & Therapy

Kazuhiko Yamamoto¹  Ryo Yamada²  Xiaotian Chang² 

[1]Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

[2]Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan

关键词: thrombin;    rheumatoid arthritis;    hyaluronic acid;    glycosaminoglycan;    antithrombin;   

Others  :  1101132
DOI  :  10.1186/ar1487

 received in 2004-07-10, accepted in 2004-10-01,  发布年份 2005

【 摘 要 】

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.

【 授权许可】

   
2005 Chang et al., licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Carmassi F, de Negri F, Morale M, Song KY, Chung SI: Fibrin degradation in the synovial fluid of rheumatoid arthritis patients: a model for extravascular fibrinolysis. Semin Thromb Hemost 1996, 22:489-496.
• [2]Shin H, Kitajima I, Nakajima T, Shao Q, Tokioka T, Takasaki I, Hanyu N, Kubo T, Maruyama I: Thrombin receptor mediated signals induce expressions of interleukin 6 and granulocyte colony stimulating factor via NF-kappa B activation in synovial fibroblasts. Ann Rheum Dis 1999, 58:55-60.
• [3]Shin H, Nakajima T, Kitajima I, Shigeta K, Abeyama K, Imamura T, Okano T, Kawahara K, Nakamura T, Maruyama I: Thrombin receptor-mediated synovial proliferation in patients with rheumatoid arthritis. Clin Immunol Immunopathol 1995, 76:225-233.
• [4]Tsopanoglou NE, Maragoudakis MEJ: On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J Biol Chem 1999, 274:23969-23976.
• [5]Maragoudakis ME, Tsopanoglou NE, Andriopoulou P: Mechanism of Thrombin-induced angiogenesis. Biochem Soc Trans 2002, 30:173-177.
• [6]Narayanan S: Multifunctional roles of thrombin. Ann Clin Lab Sci 1999, 29:275-280.
• [7]Morris R, Winyard PG, Brass LF, Blake DR, Morris CJ: Thrombin in inflammation and healing' relevance to rheumatoid arthritis. Ann Rheum Dis 1994, 53:72-79.
• [8]Wiebe EM, Stafford AR, Fredenburgh JC, Weitz JI: Mechanism of catalysis of inhibition of factor IXa by antithrombin in the presence of heparin or pentasaccharide. J Biol Chem 2003, 278:35767-35774.
• [9]Lozzo RV: Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 1998, 67:609-652.
• [10]Wang JY, Roehrl MH: Glycosaminoglycans are a potential cause of rheumatoid arthritis. Proc Natl Acad Sci USA 2002, 99:14362-14367.
• [11]Jones HW, Bailey R, Zhang Z, Dunne KA, Blake DR, Cox NL, Morris CJ, Winyard PG: Inactivation of antithrombin III in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis 1998, 57:162-165.
• [12]Ohba T, Takase Y, Ohhara M, Kasukawa R: Thrombin in synovial fluid of paients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of plate derived growth factor. J Rheumatol 1996, 23:1505-1511.
• [13]Jain A, Nanchahal J, Troeberg L, Green P, Brennan F: Production of cytokines, vascular endothelial growth factor, matrix metalloproteinases, and tissue inhibitor of metalloproteinases 1 by tenosynovium demonstrates its potential for tendon destruction in rheumatoid arthritis. Arthritis Rheum 2001, 44:1754-1760.
• [14]Pitsillides AA, Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC: Hyaluronan concentration in non-inflamed and rheumatoid synovium. Br J Rheumatol 1994, 33:5-10.
• [15]Nakayama Y, Shirai Y, Yoshihara K, Uesaka S: Evaluation of glycosaminoglycans levels in normal joint fluid of the knee. J Nippon Med Sch 2000, 67:92-95.
• [16]Takei YG, Honma T, Ito A: Quantitation of hyaluronic acid in serum with automated microparticle photometric agglutination assay. J Immunoassay Immunochem 2002, 23:85-94.
• [17]Wyatt HA, Dhawan A, Cheeseman P, Mieli-Vergani G, Price JF: Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease. Arch Dis Child 2002, 86:190-193.
• [18]Partsch G, Leeb B, Stancikova M, Raffayova H, Eberl G, Hitzelhammer H, Smolen JS: Low serum hyaluronan in psoriatic arthritis patients in comparison to rheumatoid arthritis patients. Clin Exp Rheumatol 1996, 14:381-386.
• [19]Skinner R, Abrahams JP, Whisstock JC, Lesk AM, Carrell RW, Wardell MR: The 2.6 A structure of antithrombin indicates a conformational change at the heparin binding site. J Mol Biol 1997, 266:601-609.
• [20]Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW: The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA 1997, 94:14683-14688.
• [21]Kobayashi K, Matsuzaka S, Yoshida Y, Miyauchi S, Wada Y, Moriya H: The effects of intraarticularly injected sodium hyaluronate on levels of intact aggrecan and nitric oxide in the joint fluid of patients with knee osteoarthritis. Osteoarthritis Cartilage 2004, 12:536-542.
• [22]Moreland LW: Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther 2003, 5:54-67. BioMed Central Full Text
• [23]Nagaya H, Yamagata T, Yamagata S, Iyoda K, Ito H, Hasegawa Y, Iwata H: Examination of synovial fluid and serum hyaluronidase activity as a joint marker in rheumatoid arthritis and osteoarthritis patients (by zymography). Ann Rheum Dis 1999, 58:186-188.
• [24]Maneiro E, de Andres MC, Fernandez-Sueiro JL, Galdo F, Blanco FJ: The biological action of hyaluronan on human osteoartritic articular chondrocytes: the importance of molecular weight. Clin Exp Rheumatol 2004, 22:307-312.
• [25]Rezaie AR: Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa. J Biol Chem 1998, 273:16824-16827.
• [26]Bedsted T, Swanson R, Chuang YJ, Bock PE, Bjork I, Olson ST: Heparin and calcium ions dramatically enhance antithrombin reactivity with factor IXa by generating new interaction exosites. Biochemistry 2003, 42:8143-8152.
• [27]Blake DR, Gallagher PJ, Potter AR, Bell MJ, Bacon PA: The effect of synovial iron on the progression of rheumatoid disease. A histologic assessment of patients with early rheumatoid synovitis. Arthritis Rheum 1984, 27:495-501.
• [28]Ahmadzadeh N, Shingu M, Nobunaga M: Iron-binding proteins and free iron in synovial fluids of rheumatoid arthritis patients. Clin Rheumatol 1989, 8:345-351.
• [29]Morris CJ, Blake DR, Wainwright AC, Steven MM: Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study. Ann Rheum Dis 1986, 45:21-26.
• [30]Telfer JF, Brock JH: Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblasts from patients with rheumatoid arthritis. Med Sci Monit 2004, 10:BR91-BR95.
• [31]Davies EV, Williams BD, Whiston RJ, Cooper AM, Campbell AK, Hallett : Altered Ca2+ signalling in human neutrophils from inflammatory sites. Ann Rheum Dis 1994, 53:446-449.
• [32]Carruthers DM, Arrol HP, Bacon PA, Young SP: Dysregulated intracellular Ca2+ stores and Ca2+ signaling in synovial fluid T lymphocytes from patients with chronic inflammatory arthritis. Arthritis Rheum 2000, 43:1257-1265.
• [33]Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, et al.: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003, 34:395-402.
• [34]Chang X, Yamada R, Sawada T, Suzuki A, Yamamoto K: The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2004, in press.
• [35]Vossenaar ER, Radstake TR, Van Der Heijden A, Van Mansum MA, Dieteren C, De Rooij DJ, Barrera P, Zendman AJ, Van Venrooij WJ: Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 2004, 63:373-381.
• [36]Chang X, Yamada R, Suzuki A, Sawada T, Yoshino S, Tokuhiro S, Yamamoto K: Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 2004, in press.
• [37]van Boven HH, Lane DA: Antithrombin and its inherited deficiency states. Semin Hematol 1997, 34:188-204.
• [38]Ishiguro K, Kojima T, Kadomatsu K, Nakayama Y, Takagi A, Suzuki M, Takeda N, Ito M, Yamamoto K, Matsushita T, et al.: Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000, 106:873-878.