The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Roles and Prospective Therapeutic Targets

Author(s): Benjamin J. Buckley* , Umar Ali , Michael J. Kelso , Marie Ranson .

Journal Name: Current Drug Targets

Volume 20 , Issue 9 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized in its early stages by synovial hyperplasia and inflammatory cell infiltration and later by irreversible joint tissue destruction. The plasminogen activation system (PAS) is associated with a wide range of physiological and pathophysiological states involving fibrinolysis, inflammation and tissue remodeling. Various components of the PAS are implicated in the pathophysiology of RA. Urokinase plasminogen activator (uPA) in particular is a pro-inflammatory mediator that appears to play an important role in the bone and cartilage destruction associated with RA. Clinical studies have shown that uPA and its receptor uPAR are overexpressed in synovia of patients with rheumatoid arthritis. Further, genetic knockdown and antibody-mediated neutralization of uPA have been shown to be protective against induction or progression of arthritis in animal models. The pro-arthritic role of uPA is differentiated from its haemodynamic counterpart, tissue plasminogen activator (tPA), which appears to play a protective role in RA animal models. This review summarises available evidence supporting the PAS as a critical determinant of RA pathogenesis and highlights opportunities for the development of novel uPAS-targeting therapeutics.

Keywords: Rheumatoid arthritis, urokinase plasminogen activator, uPA, uPAS, plasminogen activation, drug targets.

Chaudhari K, Rizvi S, Syed BA. Rheumatoid arthritis: Current and future trends. Nat Rev Drug Discov 2016; 15(5): 305-6.
Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001.
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 388(10055): 2023-38.
Ranson M, Andronicos NM. Plasminogen binding and cancer: promises and pitfalls. Front Biosci 2003; 8: 294-304.
Carriero MV, Faranco P, Votta G, et al. Regulation of cell migration and invasion by specific modules of uPA: mechanistic insights and specific inhibitors. Curr Drug Targets 2011; 12(12): 1761-71.
Dano K, Behrendt N, Hoyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost 2005; 93(4): 676-81.
Andreasen PA, Kjoller L, Christensen L, Dufy MJ. The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer 1997; 72(1): 1-22.
Croucher DR, Saunders DN, Lobov S, Ranson M. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 2008; 8(7): 535-45.
Syrovets T, Simmet T. Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci 2004; 61(7-8): 873-5.
Ploug M, Ellis V. Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins. FEBS Lett 1994; 349(2): 163-8.
Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3(12): 932-43.
Hamilton JA. Plasminogen activator/plasmin system in arthritis and inflammation: friend or foe? Arthritis Rheum 2008; 58(3): 645-8.
Plesner T, Behrendt N, Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor. uPAR. Stem Cells 1997; 15(6): 398-408.
Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11(1): 23-36.
Huai Q, Zhou A, Lin L, et al. Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes. Nat Struct Mol Biol 2008; 15(4): 422-3.
Kriegbaum MC, Persson M, Haldager L, et al. Rational targeting of the urokinase receptor (uPAR): development of antagonists and non-invasive imaging probes. Curr Drug Targets 2011; 12(12): 1711-28.
Brommer EJ, Dooijewaard G, Dijkmans AB, Breedveld FC. Depression of tissue-type plasminogen activator and enhancement of urokinase-type plasminogen activator as an expression of local inflammation. Thromb Haemost 1992; 68(2): 180-4.
George F, Schenider NP, Arnoux D, et al. Modulation of tPA, PAI-1 and PAI-2 antigen and mRNA levels by EGF in the A431 cell line. Blood Coagul Fibrinolysis 1990; 1(6): 689-93.
Gyetko MR, Shollenberger SB, Sitrin RG. Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-gamma and tumor necrosis factor-alpha. J Leukoc Biol 1992; 51(3): 256-63.
Gyetko MR, Wilkinson CC, Sitrin RG. Monocyte urokinase expression: modulation by interleukins. J Leukoc Biol 1993; 53(5): 598-601.
Hildenbrand R, Jensen C, Wolf G, et al. Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast. Lab Invest 1998; 78(1): 59-71.
Medcalf RL, Van den Berg E, Schleuning WD. Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol 1988; 106(3): 971-8.
Weigelt B, Wessels LF, Bosma AJ, et al. No common denominator for breast cancer lymph node metastasis. Br J Cancer 2005; 93(8): 924-32.
Harris NLE, Vennin C, Conway JRW, et al. SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene 2017; 36(30): 4288-98.
Matthews H, Ranson M, Tyndall JD, Keiso MJ. Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA). Bioorg Med Chem Lett 2011; 21(22): 6760-6.
Cochran BJ, Croucher DR, Lobov S, Saunders DN, Ranson M. Dependence on endocytic receptor binding via a minimal binding motif underlies the differential prognostic profiles of serpinE1 and serpinB2 in cancer. J Biol Chem 2011; 286(27): 24467-75.
Croucher DR, Saunders DN, Stillfried GE, Ranson M. A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. Biochem J 2007; 408(Pt 2): 203-10.
Kwaan HC, Mazar AP, McMahon BJ. The apparent uPA/PAI-1 paradox in cancer: more than meets the eye. Semin Thromb Hemost 2013; 39(4): 382-91.
Belcher C, Fawthrop F, Bunning R, Doherty M. Plasminogen activators and their inhibitors in synovial fluids from normal, osteoarthritis, and rheumatoid arthritis knees. Ann Rheum Dis 1996; 55(4): 230-6.
Kim KS, Lee YA, Choi HM, Yoo MC, Yang Hi. Implication of MMP-9 and urokinase plasminogen activator (uPA) in the activation of pro-matrix metalloproteinase (MMP)-13. Rheumatol Int 2012; 32(10): 3069-75.
Jin T, Tarkowski A, Carmeliet P, Bokarewa M. Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis. Arthritis Res Ther 2003; 5(1): R9-R17.
Kikuchi H, Shimada W, Nonaka T, Ueshima S, Tanaka S. Significance of serine proteinase and matrix metalloproteinase systems in the destruction of human articular cartilage. Clin Exp Pharmacol Physiol 1996; 23(10-11): 885-9.
Saxne T, Lecander I, Geborek P. Plasminogen activators and plasminogen activator inhibitors in synovial fluid. Difference between inflammatory joint disorders and osteoarthritis. J Rheumatol 1993; 20(1): 91-6.
Braat EA, Jie AF, Ronday HK, Beekman B, Rijken DC. Urokinase-mediated fibrinolysis in the synovial fluid of rheumatoid arthritis patients may be affected by the inactivation of single chain urokinase type plasminogen activator by thrombin. Ann Rheum Dis 2000; 59(4): 315-8.
Busso N, Péclat V, So A, Sappino AP. Plasminogen activation in synovial tissues: differences between normal, osteoarthritis, and rheumatoid arthritis joints. Ann Rheum Dis 1997; 56(9): 550-7.
Pianon M, Punzi L, Stefani MP. Interleukin-1 beta, plasminogen activator and inhibitor of plasminogen activator in synovial fluid of rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Agents Actions 1994; 41(1-2): 88-9.
Cerinic MM, Generini S, Partsch G, et al. Synoviocytes from osteoarthritis and rheumatoid arthritis produce plasminogen activators and plasminogen activator inhibitor-1 and display u-PA receptors on their surface. Life Sci 1998; 63(6): 441-53.
Montuori N, Visconte V, Rossi G, Ragno P. Soluble and cleaved forms of the urokinase-receptor: degradation products or active molecules? Thromb Haemost 2005; 93(2): 192-8.
Ronday HK, Smits HH, Van Muijen GN, et al. Difference in expression of the plasminogen activation system in synovial tissue of patients with rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1996; 35(5): 416-23.
Wallberg-Jonsson S, Rantapää-Dahlqvist S, Nordmark L, Rånby M. Mobilization of fibrinolytic enzymes in synovial fluid and plasma of rheumatoid arthritis and spondyloarthropathy and their relation to radiological destruction. J Rheumatol 1996; 23(10): 1704-9.
Szekanecz Z, Haines GK, Koch AE. Differential expression of the urokinase receptor (CD87) in arthritic and normal synovial tissues. J Clin Pathol 1997; 50(4): 314-9.
Slot O, Brünner N, Locht H, Oxholm P, Stephens RW. Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: increased concentrations in rheumatoid arthritis. Ann Rheum Dis 1999; 58(8): 488-92.
Slot O, Brunner N, Stephens RW. Marker of erosive progression in RA. Ann Rheum Dis 2000; 59(8): 656.
Huang CM, Chen CL, Tsai JJ, Tsai CH, Tsai FJ. Association between urokinase gene 3′-UTR T/C polymorphism and Chinese patients with rheumatoid arthritis in Taiwan. Clin Exp Rheumatol 2004; 22(2): 219-22.
Chu SC, Yang SF, Lue KH. Urokinase-type plasminogen activator, receptor, and inhibitor correlating with gelatinase-B (MMP-9) contribute to inflammation in gouty arthritis of the knee. J Rheumatol 2006; 33(2): 311-7.
Baran M, Möllers LN, Andersson S, et al. Survivin is an essential mediator of arthritis interacting with urokinase signalling. J Cell Mol Med 2009; 13(9b): 3797-808.
Koga T1, Okada A, Kawashiri S, Soluble urokinase plasminogen activator receptor as a useful biomarker to predict the response to adalimumab in patients with rheumatoid arthritis in a Japanese population. Clin Exp Rheumatol 2011; 29(5): 811-5.
Dimitroulas T, Douglas KM, Panoulas VF, et al. Derangement of hemostasis in rheumatoid arthritis: association with demographic, inflammatory and metabolic factors. Clin Rheumatol 2013; 32(9): 1357-64.
Urano T, Castellino FJ, Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin. J Thromb Haemost 2018.
So AK, Varisco PA, Kemkes-Matthes B, et al. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. J Thromb Haemost 2003; 1(12): 2510-5.
Gálvez J, Sola J, Ortuño G, et al. Microscopic rice bodies in rheumatoid synovial fluid sediments. J Rheumatol 1992; 19(12): 1851-8.
Busso N, Hamilton JA. Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis. Arthritis Rheum 2002; 46(9): 2268-79.
Kannan K, Ortmann RA, Kimpel D. Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology 2005; 12(3): 167-81.
Asquith DL, Miller AM, McInnes IB, Liew FY. Animal models of rheumatoid arthritis. Eur J Immunol 2009; 39(8): 2040-4.
Bevaart L, Vervoordeldonk MJ, Tak PP. Evaluation of therapeutic targets in animal models of arthritis: how does it relate to rheumatoid arthritis? Arthritis Rheum 2010; 62(8): 2192-205.
Luross JA, Williams NA. The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 2001; 103(4): 407-16.
Wooley PH, Luthra HS, Griffiths MM. Type II collagen-induced arthritis in mice. IV. Variations in immunogenetic regulation provide evidence for multiple arthritogenic epitopes on the collagen molecule. J Immunol 1985; 135(4): 2443-51.
Brunsberg U, Gustafsson K, Jansson L, et al. Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol 1994; 24(7): 1698-702.
Holmdahl R1, Andersson ME, Goldschmidt TJ, Collagen induced arthritis: an experimental model for rheumatoid arthritis with involvement of both DTH and immune complex mediated mechanisms. Clin Exp Rheumatol 1989; 7(Suppl. 3): S51-5.
Song H1, Qiao F, Atkinson C, Holers VM, Tomlinson S. A complement C3 inhibitor specifically targeted to sites of complement activation effectively ameliorates collagen-induced arthritis in DBA/1J mice. J Immunol 2007; 179(11): 7860-7.
Cho YG, Cho ML, Min SY, Kim HY. Type II collagen autoimmunity in a mouse model of human rheumatoid arthritis. Autoimmun Rev 2007; 7(1): 65-70.
Brackertz D, Mitchell GF, Mackay IR. Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum 1977; 20(3): 841-50.
van den Berg WB, van de Putte LB, Zwarts WA, Joosten LA. Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice. J Clin Invest 1984; 74(5): 1850-9.
Frey O, Petrow KP, Gajda M, et al. The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4(+)CD25(+)T cells. Arthritis Res Ther 2005; 7(2): R291-301.
McNamee K, Williams R, Seed M. Animal models of rheumatoid arthritis: How informative are they? Eur J Pharmacol 2015; 759: 278-86.
Li J, Guo Y, Holmadhai R. NY T. Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models. Arthritis Rheum 2005; 52(8): 2541-8.
Hegen M, Keith JC Jr, Collins M, Nickerson-Nutter CL. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis 2008; 67(11): 1505-15.
Bendele A. Animal models of rheumatoid arthritis. J Musculoskelet Neuronal Interact 2001; 1(4): 377-85.
Wengner AM, Höpken UE, Petrow PK, et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum 2007; 56(10): 3271-83.
Busso N, Péclat V, Van Ness K, et al. Exacerbation of antigen-induced arthritis in urokinase-deficient mice. J Clin Invest 1998; 102(1): 41-50.
Yang YH, Carmeliet P, Hamilton JA. Tissue-type plasminogen activator deficiency exacerbates arthritis. J Immunol 2001; 167(2): 1047-52.
Cook AD, Braine EL, Campbell IK, Hamilton JA. Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis. Am J Pathol 2002; 160(3): 917-26.
Van Ness K, Chobaz-Peclat V, Castellicci M, So A, Busso N. Plasminogen activator inhibitor type‐1 deficiency attenuates murine antigen‐induced arthritis. Rheumatology 2002; 41(2): 136-41.
Guo Y, Li J, Hagstrom E, Ny T. Protective effects of plasminogen in a mouse model of Staphylococcus aureus–induced arthritis. Arthritis Rheum 2008; 58(3): 764-72.
Li J, Ny A, Leonardsson G, et al. The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis. Am J Pathol 2005; 166(3): 783-92.
Cook AD, De Nardo CM, Braine EL, et al. Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement. Arthritis Res Ther 2010; 12(2): R37.
Thornton S, Raghu H, Cruz C, et al. Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells. Blood Adv 2017; 1(9): 545-56.
Almholt K, Hebsgaard JB, Nansen A, et al. Antibody-mediated neutralization of uPA proteolytic function reduces disease progression in mouse arthritis models. J Immunol 2018; 200(3): 957-65.
Apparailly F, Bouquet C, Millet V, et al. Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis. Gene Ther 2002; 9(3): 192-200.
Salvi R, Paclat V, So A, Busso N, et al. Enhanced expression of genes involved in coagulation and fibrinolysis in murine arthritis. Arthritis Res 2000; 2(6): 504-12.
De Nardo CM, Lenzo JC, Pobjoy J, Hamilton JA, Cook AD. Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models. Arthritis Res Ther 2010; 12(5): R199.
Klak M, Anakkala N, Wang W, et al. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis. Scand J Infect Dis 2010; 42(5): 351-8.
Serrati S, Margheri F, Chilla A, et al. Reduction of in vitro invasion and in vivo cartilage degradation in a SCID mouse model by loss of function of the fibrinolytic system of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2011; 63(9): 2584-94.
Raghu H, Jone A, Cruz C, et al. Plasminogen is a joint-specific positive or negative determinant of arthritis pathogenesis in mice. Arthritis Rheumatol 2014; 66(6): 1504-16.
Wang Y, Kristan J, Hao L, et al. A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol 2000; 164(8): 4340-7.
Ji H, Ohmura K, Mahmood U, et al. Arthritis critically dependent on innate immune system players. Immunity 2002; 16(2): 157-68.
Wong PK, Quinn JM, Sims NA, et al. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 2006; 54(1): 158-68.
Fischetti F, Durigutto P, Macor P, et al. Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats. Arthritis Rheum 2007; 56(4): 1187-97.
Nandakumar KS, Holmdahl R. Antibody-induced arthritis: disease mechanisms and genes involved at the effector phase of arthritis. Arthritis Res Ther 2006; 8(6): 223.
Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12(8): 472-85.
Hamilton JA, Slywka J. Stimulation of human synovial fibroblast plasminogen activator production by mononuclear cell supernatants. J Immunol 1981; 126(3): 851-5.
Yoshida E, Tsuchiya K, Sugiki M, et al. Modulation of the receptor for urokinase-type plasminogen activator in macrophage-like U937 cells by inflammatory mediators. Inflammation 1996; 20(3): 319-26.
Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 1996; 39(1): 115-24.
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7(6): 429-42.
Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR. Macrophages in rheumatoid arthritis. Arthritis Res 2000; 2(3): 189-202.
Kinne RW, Stuhlmuller B, Burmester BR. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res Ther 2007; 9(6): 224.
Barrera P, Blom A, van Lent PL, et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 2000; 43(9): 1951-9.
Li J, Hsu HC, Yang P, et al. Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum 2012; 64(4): 1098-109.
Van Lent PL, Holthuysen A, Rooijen NV, De Putte LB, Berg Den WBV. Local removal of phagocytic synovial lining cells by clodronate-liposomes decreases cartilage destruction during collagen type II arthritis. Ann Rheum Dis 1998; 57(7): 408-13.
Haringman JJ, Gerlag DM, Zwinderman AH, et al. Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005; 64(6): 834-8.
Maccioni M, Zeder-Lutz G, Huang H, et al. Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med 2002; 195(8): 1071-7.
Christensen AD, Haase C, Cook AD, Hamilton JA. K/BxN serum-transfer arthritis as a model for human inflammatory arthritis. Front Immunol 2016; 7: 213.
Ohshima S, Saeki Y. Toru Mima, Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 1998; 95(14): 8222-6.
Lawlor KE, Campbell IK, O’donnell K, Wu L, Wicks IP. Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis. Arthritis Rheum 2001; 44(2): 442-50.
Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10(13): 4025-31.
Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995; 9(7): 794-807.
Bugge TH, Kombrinck KW, Flick MJ, et al. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996; 87(4): 709-19.
Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8(9): 1895-902.
Zhu W, He X, Xia Z, Zhai J, Weng X. Hemophilic arthropathy in a patient with multi-joint replacement: A case report and literature review. Medicine 2018; 97(29): e11163.
Lund IK, Jögi A, Rønø B, et al. Antibody-mediated targeting of the urokinase-type plasminogen activator proteolytic function neutralizes fibrinolysis in vivo. J Biol Chem 2008; 283(47): 32506-15.
Atkinson SM, Usher PA, Kvist PH, et al. Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice. Arthritis Res Ther 2012; 14(3): R134.
Pass J, Jögi A, Lund IK, et al. Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: inhibitory effects on receptor-mediated uPA activity in vitro and in vivo. Thromb Haemost 2007; 97(6): 1013-22.
Jögi A1, Pass J, Høyer-Hansen G, Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice. J Thromb Haemost 2007; 5(9): 1936-44.
Pisetsky DS. Advances in the Treatment of rheumatoid arthritis: costs and challenges. N C Med J 2017; 78(5): 337-40.
Koike T. Treatment of rheumatoid arthritis by molecular-targeted agents: efficacy and limitations. J Orthop Sci 2015; 20(6): 951-7.
Krishnan E, Fries JF. Reduction in long-term functional disability in rheumatoid arthritis from 1977 to 1998: a longitudinal study of 3035 patients. Am J Med 2003; 115(5): 371-6.
Borenstein DG, Hassett AL, Pisetsky D. Pain management in rheumatology research, training, and practice. Clin Exp Rheumatol 2017; 35 Suppl 107(5): 2-7.
Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73(3): 492-509.
O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013; 369(4): 307-18.
Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295(19): 2275-85.
Buckley BJ, Aboelela A, Minaei E, et al. 6-Substituted hexamethylene amiloride (HMA) derivatives as potent and selective inhibitors of the human urokinase plasminogen activator for use in cancer. J Med Chem 2018; 61(18): 8299-320.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [970 - 981]
Pages: 12
DOI: 10.2174/1389450120666181204164140

Article Metrics

PDF: 32