摘要
类风湿性关节炎（RA）是一种慢性和进行性炎性疾病，其早期阶段是滑膜增生和炎性细胞浸润，后来是不可逆的关节组织破坏。纤溶酶原激活系统（PAS）涉及广泛的生理和病理生理状态，涉及纤维蛋白溶解，炎症和组织重塑。 PAS的各种组分涉及RA的病理生理学。尿激酶纤溶酶原激活物（uPA）特别是促炎介质，其似乎在与RA相关的骨和软骨破坏中起重要作用。临床研究表明，uPA及其受体uPAR在类风湿性关节炎患者的滑膜中过度表达。此外，已显示基因敲除和抗体介导的uPA中和对动物模型中的关节炎的诱导或进展具有保护作用。 uPA的促关节炎作用与其血液动力学对应物组织纤溶酶原激活物（tPA）不同，后者似乎在RA动物模型中起保护作用。本综述总结了支持PAS作为RA发病机制的关键决定因素的现有证据，并突出了开发新型uPAS靶向治疗药物的机会。
关键词: 类风湿性关节炎，尿激酶纤溶酶原激活物，uPA，uPAS，纤溶酶原激活，药物靶点。
图形摘要
[1]
Chaudhari K, Rizvi S, Syed BA. Rheumatoid arthritis: Current and future trends. Nat Rev Drug Discov 2016; 15(5): 305-6.
[2]
Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001.
[4]
Ranson M, Andronicos NM. Plasminogen binding and cancer: promises and pitfalls. Front Biosci 2003; 8: 294-304.
[5]
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.
[6]
Dano K, Behrendt N, Hoyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost 2005; 93(4): 676-81.
[7]
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.
[8]
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.
[9]
Syrovets T, Simmet T. Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci 2004; 61(7-8): 873-5.
[10]
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.
[11]
Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3(12): 932-43.
[12]
Hamilton JA. Plasminogen activator/plasmin system in arthritis and inflammation: friend or foe? Arthritis Rheum 2008; 58(3): 645-8.
[13]
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.
[14]
Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11(1): 23-36.
[15]
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.
[16]
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.
[17]
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.
[18]
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.
[19]
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.
[20]
Gyetko MR, Wilkinson CC, Sitrin RG. Monocyte urokinase expression: modulation by interleukins. J Leukoc Biol 1993; 53(5): 598-601.
[21]
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.
[22]
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.
[23]
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.
[24]
Harris NLE, Vennin C, Conway JRW, et al. SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene 2017; 36(30): 4288-98.
[25]
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.
[26]
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.
[27]
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.
[28]
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.
[29]
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.
[30]
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.
[31]
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.
[32]
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.
[33]
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.
[34]
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.
[35]
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.
[36]
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.
[37]
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.
[38]
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.
[39]
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.
[40]
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.
[41]
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.
[42]
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.
[43]
Slot O, Brunner N, Stephens RW. Marker of erosive progression in RA. Ann Rheum Dis 2000; 59(8): 656.
[44]
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.
[45]
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.
[46]
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.
[47]
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.
[48]
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.
[49]
Urano T, Castellino FJ, Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin. J Thromb Haemost 2018.
[50]
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.
[51]
Gálvez J, Sola J, Ortuño G, et al. Microscopic rice bodies in rheumatoid synovial fluid sediments. J Rheumatol 1992; 19(12): 1851-8.
[52]
Busso N, Hamilton JA. Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis. Arthritis Rheum 2002; 46(9): 2268-79.
[53]
Kannan K, Ortmann RA, Kimpel D. Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology 2005; 12(3): 167-81.
[54]
Asquith DL, Miller AM, McInnes IB, Liew FY. Animal models of rheumatoid arthritis. Eur J Immunol 2009; 39(8): 2040-4.
[55]
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.
[56]
Luross JA, Williams NA. The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 2001; 103(4): 407-16.
[57]
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.
[58]
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.
[59]
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.
[60]
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.
[61]
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.
[62]
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.
[63]
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.
[64]
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.
[65]
McNamee K, Williams R, Seed M. Animal models of rheumatoid arthritis: How informative are they? Eur J Pharmacol 2015; 759: 278-86.
[66]
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.
[67]
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.
[68]
Bendele A. Animal models of rheumatoid arthritis. J Musculoskelet Neuronal Interact 2001; 1(4): 377-85.
[69]
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.
[70]
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.
[71]
Yang YH, Carmeliet P, Hamilton JA. Tissue-type plasminogen activator deficiency exacerbates arthritis. J Immunol 2001; 167(2): 1047-52.
[72]
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.
[73]
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.
[74]
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.
[75]
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.
[76]
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.
[77]
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.
[78]
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.
[79]
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.
[80]
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.
[81]
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.
[82]
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.
[83]
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.
[84]
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.
[85]
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.
[86]
Ji H, Ohmura K, Mahmood U, et al. Arthritis critically dependent on innate immune system players. Immunity 2002; 16(2): 157-68.
[87]
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.
[88]
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.
[89]
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.
[90]
Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12(8): 472-85.
[91]
Hamilton JA, Slywka J. Stimulation of human synovial fibroblast plasminogen activator production by mononuclear cell supernatants. J Immunol 1981; 126(3): 851-5.
[92]
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.
[93]
Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 1996; 39(1): 115-24.
[94]
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7(6): 429-42.
[95]
Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR. Macrophages in rheumatoid arthritis. Arthritis Res 2000; 2(3): 189-202.
[96]
Kinne RW, Stuhlmuller B, Burmester BR. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res Ther 2007; 9(6): 224.
[97]
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.
[98]
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.
[99]
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.
[100]
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.
[101]
Maccioni M, Zeder-Lutz G, Huang H, et al. Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med 2002; 195(8): 1071-7.
[102]
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.
[103]
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.
[104]
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.
[105]
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.
[106]
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.
[107]
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.
[108]
Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8(9): 1895-902.
[109]
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.
[110]
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.
[111]
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.
[112]
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.
[113]
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.
[114]
Pisetsky DS. Advances in the Treatment of rheumatoid arthritis: costs and challenges. N C Med J 2017; 78(5): 337-40.
[115]
Koike T. Treatment of rheumatoid arthritis by molecular-targeted agents: efficacy and limitations. J Orthop Sci 2015; 20(6): 951-7.
[116]
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.
[117]
Borenstein DG, Hassett AL, Pisetsky D. Pain management in rheumatology research, training, and practice. Clin Exp Rheumatol 2017; 35 Suppl 107(5): 2-7.
[118]
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.
[119]
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.
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