Skip to main content

Advertisement

SpringerLink
Log in

The pathogenic role of angiogenesis in rheumatoid arthritis

  • Review Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis, and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia-inducible factors, cytokines, chemokines, matrix metalloproteinases, and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However, since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Szekanecz Z, Koch AE (2008) Vascular involvement in rheumatic diseases: ‘vascular rheumatology’. Arthritis Res Ther 10(5):224

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Szekanecz Z, Koch AE (2007) Mechanisms of disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol 3(11):635–643

    Article  CAS  PubMed  Google Scholar 

  3. Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235(4787):442–447

    Article  CAS  PubMed  Google Scholar 

  4. Lainer-Carr D, Brahn E (2007) Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat Clin Pract Rheumatol 3(8):434–442

    Article  CAS  PubMed  Google Scholar 

  5. Koch AE (1998) Angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum 41(6):951–962

    Article  CAS  PubMed  Google Scholar 

  6. Veale DJ, Fearon U (2006) Inhibition of angiogenic pathways in rheumatoid arthritis: potential for therapeutic targeting. Best Pract Res Clin Rheumatol 20(5):941–947

    Article  CAS  PubMed  Google Scholar 

  7. Szekanecz Z, Koch AE (2001) Chemokines and angiogenesis. Curr Opin Rheumatol 13(3):202–208

    Article  CAS  PubMed  Google Scholar 

  8. Auerbach W, Auerbach R (1994) Angiogenesis inhibition: a review. Pharmacol Ther 63(3):265–311

    Article  CAS  PubMed  Google Scholar 

  9. Koch AE, Distler O (2007) Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther 9(Suppl 2):S3

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Chua RA, Arbiser JL (2009) The role of angiogenesis in the pathogenesis of psoriasis. Autoimmunity 42(7):574–579

    Article  CAS  PubMed  Google Scholar 

  11. Di Stefano R, Felice F, Balbarini A (2009) Angiogenesis as risk factor for plaque vulnerability. Curr Pharm Des 15(10):1095–1106

    Article  PubMed  Google Scholar 

  12. Kushner EJ, Bautch VL (2013) Building blood vessels in development and disease. Curr Opin Hematol 20(3):231–236

    PubMed  Google Scholar 

  13. Szekanecz Z, Koch AE (2005) Endothelial cells in inflammation and angiogenesis. Curr Drug Targets Inflamm Allergy 4(3):319–323

    Article  CAS  PubMed  Google Scholar 

  14. Folkman J, Brem H (1992) Angiogenesis and inflammation. In: Gallin JI, Goldstein IM, Snyderman R (eds) Inflammation: basic principles and clinical correlates, 2nd edn. Raven Press, New York, pp 821–839

    Google Scholar 

  15. Folkman J (1997) Angiogenesis and angiogenesis inhibition: an overview. EXS 79:1–8

    CAS  PubMed  Google Scholar 

  16. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267(16):10931–10934

    CAS  PubMed  Google Scholar 

  17. Haringman JJ, Gerlag DM, Zwinderman AH, Smeets TJ, Kraan MC, Baeten D, McInnes IB, Bresnihan B, Tak PP (2005) Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64(6):834–838

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Tak PP, Breedveld FC (1997) Analysis of serial synovial biopsies as a screening method for predicting the effects of therapeutic interventions. J Clin Rheumatol 3(4):186

    Article  CAS  PubMed  Google Scholar 

  19. Tak PP, Bresnihan B (2000) The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum 43(12):2619–2633

    Article  CAS  PubMed  Google Scholar 

  20. Mulherin D, Fitzgerald O, Bresnihan B (1996) Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 39(1):115–124

    Article  CAS  PubMed  Google Scholar 

  21. Firestein GS (1996) Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum 39(11):1781–1790

    Article  CAS  PubMed  Google Scholar 

  22. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma’ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013) Tissue-resident macrophages. Nat Immunol 14(10):986–995

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Tamoutounour S, Henri S, Lelouard H, de Bovis B, de Haar C, van der Woude CJ, Woltman AM, Reyal Y, Bonnet D, Sichien D, Bain CC, Mowat AM, Reis e Sousa C, Poulin LF, Malissen B, Guilliams M (2012) CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur J Immunol 42(12):3150–3166

    Article  CAS  PubMed  Google Scholar 

  25. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90

    Article  CAS  PubMed  Google Scholar 

  26. Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, Guilliams M, Malissen B, Agace WW, Mowat AM (2013) Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol 6(3):498–510

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Jojic V, Shay T, Sylvia K, Zuk O, Sun X, Kang J, Regev A, Koller D, Best AJ, Knell J, Goldrath A, Joic V, Cohen N, Brennan P, Brenner M, Kim F, Rao TN, Wagers A, Heng T, Ericson J, Rothamel K, Ortiz-Lopez A, Mathis D, Benoist C, Bezman NA, Sun JC, Min-Oo G, Kim CC, Lanier LL, Miller J, Brown B, Merad M, Gautier EL, Jakubzick C, Randolph GJ, Monach P, Blair DA, Dustin ML, Shinton SA, Hardy RR, Laidlaw D, Collins J, Gazit R, Rossi DJ, Malhotra N, Kreslavsky T, Fletcher A, Elpek K, Bellemarte-Pelletier A, Malhotra D, Turley S (2013) Identification of transcriptional regulators in the mouse immune system. Nat Immunol 14(6):633–643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41(1):21–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, Ivanov S, Duan Q, Bala S, Condon T, van Rooijen N, Grainger JR, Belkaid Y, Ma’ayan A, Riches DW, Yokoyama WM, Ginhoux F, Henson PM, Randolph GJ (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39(3):599–610

    Article  CAS  PubMed  Google Scholar 

  30. Mills CD (1991) Molecular basis of “suppressor” macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J Immunol 146(8):2719–2723

    CAS  PubMed  Google Scholar 

  31. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686

    Article  CAS  PubMed  Google Scholar 

  32. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA (2011) IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses. Nat Immunol 12(3):231–238

    Article  CAS  PubMed  Google Scholar 

  33. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  PubMed  Google Scholar 

  34. Konisti S, Kiriakidis S, Paleolog EM (2012) Hypoxia—a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat Rev Rheumatol 8(3):153–162

    Article  CAS  PubMed  Google Scholar 

  35. Neumann E, Lefevre S, Zimmermann B, Gay S, Muller-Ladner U (2010) Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 16(10):458–468

    Article  CAS  PubMed  Google Scholar 

  36. Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233(1):233–255

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Pap T, Meinecke I, Muller-Ladner U, Gay S (2005) Are fibroblasts involved in joint destruction? Ann Rheum Dis 64(Suppl 4):iv52–iv54

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T (2006) Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology 45(6):669–675

    Article  CAS  PubMed  Google Scholar 

  39. Niedermeier M, Pap T, Korb A (2010) Therapeutic opportunities in fibroblasts in inflammatory arthritis. Best Pract Res Clin Rheumatol 24(4):527–540

    Article  PubMed  Google Scholar 

  40. Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF (1994) Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346

    Article  CAS  PubMed  Google Scholar 

  41. Szekanecz Z, Koch AE (2007) Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol 19(3):289–295

    Article  PubMed  Google Scholar 

  42. Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N (1994) Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 152(8):4149–4156

    CAS  PubMed  Google Scholar 

  43. Brouwer E, Gouw AS, Posthumus MD, van Leeuwen MA, Boerboom AL, Bijzet J, Bos R, Limburg PC, Kallenberg CG, Westra J (2009) Hypoxia inducible factor-1-alpha (HIF-1alpha) is related to both angiogenesis and inflammation in rheumatoid arthritis. Clin Exp Rheumatol 27(6):945–951

    CAS  PubMed  Google Scholar 

  44. Marrelli A, Cipriani P, Liakouli V, Carubbi F, Perricone C, Perricone R, Giacomelli R (2011) Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? Autoimmun Rev 10(10):595–598

    Article  CAS  PubMed  Google Scholar 

  45. Hu F, Mu R, Zhu J, Shi L, Li Y, Liu X, Shao W, Li G, Li M, Su Y, Cohen PL, Qiu X, Li Z (2014) Hypoxia and hypoxia-inducible factor-1alpha provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis. Ann Rheum Dis 73(5):928–936

    Article  CAS  PubMed  Google Scholar 

  46. Lu J, Kasama T, Kobayashi K, Yoda Y, Shiozawa F, Hanyuda M, Negishi M, Ide H, Adachi M (2000) Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol 164(11):5922–5927

    Article  CAS  PubMed  Google Scholar 

  47. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Shahrara S, Volin MV, Connors MA, Haines GK, Koch AE (2002) Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res 4(3):201–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Fearon U, Griosios K, Fraser A, Reece R, Emery P, Jones PF, Veale DJ (2003) Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 30(2):260–268

    CAS  PubMed  Google Scholar 

  50. Gravallese EM, Pettit AR, Lee R, Madore R, Manning C, Tsay A, Gaspar J, Goldring MB, Goldring SR, Oettgen P (2003) Angiopoietin-1 is expressed in the synovium of patients with rheumatoid arthritis and is induced by tumour necrosis factor alpha. Ann Rheum Dis 62(2):100–107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Clavel G, Bessis N, Boissier MC (2003) Recent data on the role for angiogenesis in rheumatoid arthritis. Joint Bone Spine 70(5):321–326

    Article  PubMed  Google Scholar 

  52. Daly C, Eichten A, Castanaro C, Pasnikowski E, Adler A, Lalani AS, Papadopoulos N, Kyle AH, Minchinton AI, Yancopoulos GD, Thurston G (2013) Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res 73(1):108–118

    Article  CAS  PubMed  Google Scholar 

  53. Chen Y, Donnelly E, Kobayashi H, Debusk LM, Lin PC (2005) Gene therapy targeting the Tie2 function ameliorates collagen-induced arthritis and protects against bone destruction. Arthritis Rheum 52(5):1585–1594

    Article  CAS  PubMed  Google Scholar 

  54. Honorati MC, Neri S, Cattini L, Facchini A (2006) Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthr Cartil 14(4):345–352

    Article  CAS  PubMed  Google Scholar 

  55. Shibuya H, Yoshitomi H, Murata K, Kobayashi S, Furu M, Ishikawa M, Fujii T, Ito H, Matsuda S (2015) TNFalpha, PDGF, and TGFbeta synergistically induce synovial lining hyperplasia via inducible PI3Kdelta. Mod Rheumatol 25(1):72–78

    Article  CAS  PubMed  Google Scholar 

  56. Koyama K, Hatsushika K, Ando T, Sakuma M, Wako M, Kato R, Haro H, Sugiyama H, Hamada Y, Ogawa H, Nakao A (2007) Imatinib mesylate both prevents and treats the arthritis induced by type II collagen antibody in mice. Mod Rheumatol 17(4):306–310

    Article  CAS  PubMed  Google Scholar 

  57. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S (2010) Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum 62(2):383–391

    CAS  PubMed  Google Scholar 

  58. Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N (1987) Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329(6140):630–632

    Article  CAS  PubMed  Google Scholar 

  59. Strunk J, Bundke E, Lange U (2006) Anti-TNF-alpha antibody Infliximab and glucocorticoids reduce serum vascular endothelial growth factor levels in patients with rheumatoid arthritis: a pilot study. Rheumatol Int 26(3):252–256

    Article  CAS  PubMed  Google Scholar 

  60. Markham T, Mullan R, Golden-Mason L, Rogers S, Bresnihan B, Fitzgerald O, Fearon U, Veale DJ (2006) Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol 54(6):1003–1012

    Article  PubMed  Google Scholar 

  61. Lubberts E (2010) Th17 cytokines and arthritis. Semin Immunopathol 32(1):43–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Pickens SR, Volin MV, Mandelin AM II, Kolls JK, Pope RM, Shahrara S (2010) IL-17 contributes to angiogenesis in rheumatoid arthritis. J Immunol 184(6):3233–3241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Pickens SR, Chamberlain ND, Volin MV, Gonzalez M, Pope RM, Mandelin AM II, Kolls JK, Shahrara S (2011) Anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization. Angiogen 14(4):443–455

    Article  CAS  Google Scholar 

  64. Chen DY, Chen YM, Chen HH, Hsieh CW, Lin CC, Lan JL (2011) Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-alpha therapy. Arthritis Res Ther 13(4):R126

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Shu Q, Amin MA, Ruth JH, Campbell PL, Koch AE (2012) Suppression of endothelial cell activity by inhibition of TNFalpha. Arthritis Res Ther 14(2):R88

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Choe JY, Lee SJ, Park SH, Kim SK (2012) Tacrolimus (FK506) inhibits interleukin-1beta-induced angiopoietin-1, Tie-2 receptor, and vascular endothelial growth factor through down-regulation of JNK and p38 pathway in human rheumatoid fibroblast-like synoviocytes. Joint Bone Spine 79(2):137–143

    Article  CAS  PubMed  Google Scholar 

  67. Pickens SR, Chamberlain ND, Volin MV, Pope RM, Mandelin AM II, Shahrara S (2011) Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis Rheum 63(4):914–922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Isozaki T, Arbab AS, Haas CS, Amin MA, Arendt MD, Koch AE, Ruth JH (2013) Evidence that CXCL16 is a potent mediator of angiogenesis and is involved in endothelial progenitor cell chemotaxis: studies in mice with K/BxN serum-induced arthritis. Arthritis Rheum 65(7):1736–1746

    Article  CAS  PubMed  Google Scholar 

  69. Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y (2003) IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA 100(10):5986–5990

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Badolato R, Oppenheim JJ (1996) Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum 26(2):526–538

    Article  CAS  PubMed  Google Scholar 

  71. Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8(Suppl 2):S3

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Blue ML, Conrad P, Webb DL, Sarr T, Macaro M (1993) Interacting monocytes and synoviocytes induce adhesion molecules by a cytokine-regulated process. Lymphokine Cytokine Res 12(4):213–218

    CAS  PubMed  Google Scholar 

  73. Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, Nishimoto N (2003) Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum 48(6):1521–1529

    Article  CAS  PubMed  Google Scholar 

  74. Kayakabe K, Kuroiwa T, Sakurai N, Ikeuchi H, Kadiombo AT, Sakairi T, Matsumoto T, Maeshima A, Hiromura K, Nojima Y (2012) Interleukin-6 promotes destabilized angiogenesis by modulating angiopoietin expression in rheumatoid arthritis. Rheumatology 51(9):1571–1579

    Article  CAS  PubMed  Google Scholar 

  75. Ogami K, Yamaguchi R, Imoto S, Tamada Y, Araki H, Print C, Miyano S (2012) Computational gene network analysis reveals TNF-induced angiogenesis. BMC Syst Biol 6(Suppl 2):S12

    Article  PubMed Central  PubMed  Google Scholar 

  76. Chen Z, Kim SJ, Essani AB, Volin MV, Vila OM, Swedler W, Arami S, Volkov S, Sardin LV, Sweiss N, Shahrara S (2014) Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204530

  77. Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S, Vila O, Swedler W, Shunaigat AN, Smadi S, Sawaqed R, Perkins D, Shahrara S, Sweiss NJ (2014) Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Dev Ther 8:349–364

    CAS  Google Scholar 

  78. Huang Q, Ma Y, Adebayo A, Pope RM (2007) Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum 56(7):2192–2201

    Article  CAS  PubMed  Google Scholar 

  79. Koch AE, Kunkel SL, Burrows JC, Evanoff HL, Haines GK, Pope RM, Strieter RM (1991) Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 147(7):2187–2195

    CAS  PubMed  Google Scholar 

  80. Cho ML, Ju JH, Kim HR, Oh HJ, Kang CM, Jhun JY, Lee SY, Park MK, Min JK, Park SH, Lee SH, Kim HY (2007) Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. Immunol Lett 108(2):121–128

    Article  CAS  PubMed  Google Scholar 

  81. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089):1798–1801

    Article  CAS  PubMed  Google Scholar 

  82. Mehta VB, Hart J, Wewers MD (2001) ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J Biol Chem 276(6):3820–3826

    Article  CAS  PubMed  Google Scholar 

  83. Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, Field M, Foulis A, Liew FY, McInnes IB (1999) A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 104(10):1393–1401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Moller B, Kessler U, Rehart S, Kalina U, Ottmann OG, Kaltwasser JP, Hoelzer D, Kukoc-Zivojnov N (2002) Expression of interleukin-18 receptor in fibroblast-like synoviocytes. Arthritis Res 4:139–144

    Article  PubMed Central  PubMed  Google Scholar 

  85. Verri WA Jr, Cunha TM, Ferreira SH, Wei X, Leung BP, Fraser A, McInnes IB, Liew FY, Cunha FQ (2007) IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. Eur J Immunol 37(12):3373–3380

    Article  CAS  PubMed  Google Scholar 

  86. Marotte H, Ahmed S, Ruth JH, Koch AE (2010) Blocking ERK-1/2 reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of interleukin-18 binding protein A. Arthritis Rheum 62(3):722–731

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Volin MV, Koch AE (2011) Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. J Interferon Cytokine Res 31(10):745–751

    Article  CAS  PubMed  Google Scholar 

  88. Canetti CA, Leung BP, Culshaw S, McInnes IB, Cunha FQ, Liew FY (2003) IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4. J Immunol 171(2):1009–1015

    Article  PubMed  Google Scholar 

  89. Ruth JH, Park CC, Amin MA, Lesch C, Marotte H, Shahrara S, Koch AE (2010) Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis. Arthritis Res Ther 12(3):R118

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Amin MA, Rabquer BJ, Mansfield PJ, Ruth JH, Marotte H, Haas CS, Reamer EN, Koch AE (2010) Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases. Ann Rheum Dis 69(12):2204–2212

    Article  CAS  PubMed  Google Scholar 

  91. Park CC, Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE (2001) Evidence of IL-18 as a novel angiogenic mediator. J Immunol 167(3):1644–1653

    Article  CAS  PubMed  Google Scholar 

  92. Amin MA, Mansfield PJ, Pakozdi A, Campbell PL, Ahmed S, Martinez RJ, Koch AE (2007) Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways. Arthritis Rheum 56(6):1787–1797

    Article  CAS  PubMed  Google Scholar 

  93. Morel JC, Park CC, Kumar P, Koch AE (2001) Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFkappaB activation. Lab Invest 81(10):1371–1383

    Article  CAS  PubMed  Google Scholar 

  94. Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW (2005) IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol 175(12):8280–8286

    Article  CAS  PubMed  Google Scholar 

  95. Onodera S, Tanji H, Suzuki K, Kaneda K, Mizue Y, Sagawa A, Nishihira J (1999) High expression of macrophage migration inhibitory factor in the synovial tissues of rheumatoid joints. Cytokine 11(2):163–167

    Article  CAS  PubMed  Google Scholar 

  96. Leech M, Metz C, Hall P, Hutchinson P, Gianis K, Smith M, Weedon H, Holdsworth SR, Bucala R, Morand EF (1999) Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids. Arthritis Rheum 42(8):1601–1608

    Article  CAS  PubMed  Google Scholar 

  97. Calandra T, Bernhagen J, Mitchell RA, Bucala R (1994) The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179(6):1895–1902

    Article  CAS  PubMed  Google Scholar 

  98. Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R (1995) MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377(6544):68–71

    Article  CAS  PubMed  Google Scholar 

  99. Donnelly SC, Haslett C, Reid PT, Grant IS, Wallace WA, Metz CN, Bruce LJ, Bucala R (1997) Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 3(3):320–323

    Article  CAS  PubMed  Google Scholar 

  100. Onodera S, Kaneda K, Mizue Y, Koyama Y, Fujinaga M, Nishihira J (2000) Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J Biol Chem 275(1):444–450

    Article  CAS  PubMed  Google Scholar 

  101. Onodera S, Nishihira J, Koyama Y, Majima T, Aoki Y, Ichiyama H, Ishibashi T, Minami A (2004) Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients: common transcriptional regulatory mechanism between interleukin-8 and interleukin-1beta. Arthritis Rheum 50(5):1437–1447

    Article  CAS  PubMed  Google Scholar 

  102. Amin MA, Volpert OV, Woods JM, Kumar P, Harlow LA, Koch AE (2003) Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ Res 93(4):321–329

    Article  CAS  PubMed  Google Scholar 

  103. Nishihira J, Koyama Y, Mizue Y (1998) Identification of macrophage migration inhibitory factor (MIF) in human vascular endothelial cells and its induction by lipopolysaccharide. Cytokine 10(3):199–205

    Article  CAS  PubMed  Google Scholar 

  104. Ogawa H, Nishihira J, Sato Y, Kondo M, Takahashi N, Oshima T, Todo S (2000) An antibody for macrophage migration inhibitory factor suppresses tumour growth and inhibits tumour-associated angiogenesis. Cytokine 12(4):309–314

    Article  CAS  PubMed  Google Scholar 

  105. Leech M, Metz C, Santos L, Peng T, Holdsworth SR, Bucala R, Morand EF (1998) Involvement of macrophage migration inhibitory factor in the evolution of rat adjuvant arthritis. Arthritis Rheum 41(5):910–917

    Article  CAS  PubMed  Google Scholar 

  106. Santos LL, Dacumos A, Yamana J, Sharma L, Morand EF (2008) Reduced arthritis in MIF deficient mice is associated with reduced T cell activation: down-regulation of ERK MAP kinase phosphorylation. Clin Exp Immunol 152(2):372–380

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Singh A, Leng L, Fan J, Gajda M, Brauer R, Fingerle-Rowson G, Bucala R, Illges H (2013) Macrophage-derived, macrophage migration inhibitory factor (MIF) is necessary to induce disease in the K/BxN serum-induced model of arthritis. Rheumatol Int 33(9):2301–2308

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Szekanecz Z, Vegvari A, Szabo Z, Koch AE (2010) Chemokines and chemokine receptors in arthritis. Front Biosci (Schol Ed) 2:153–167

    Article  Google Scholar 

  109. Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D (2007) Macrophages in rheumatoid arthritis. Histol Histopathol 22(5):581–586

    CAS  PubMed  Google Scholar 

  110. Asquith DL, Bryce SA, Nibbs RJ (2015) Targeting cell migration in rheumatoid arthritis. Curr Opin Rheumatol 27(2):204–211

    Article  CAS  PubMed  Google Scholar 

  111. Park YJ, Kim JY, Park J, Choi JJ, Kim WU, Cho CS (2014) Bone erosion is associated with reduction of circulating endothelial progenitor cells and endothelial dysfunction in rheumatoid arthritis. Arthritis Rheumatol 66(6):1450–1460

    Article  CAS  PubMed  Google Scholar 

  112. Wu PF, Lu ZP, Cai BB, Tian L, Zou C, Jiang KR, Miao Y (2013) Role of CXCL12/CXCR4 signaling axis in pancreatic cancer. Chin Med J 126(17):3371–3374

    CAS  PubMed  Google Scholar 

  113. Wang H, Liu W, Wei D, Hu K, Wu X, Yao Y (2014) Effect of the LPA-mediated CXCL12–CXCR4 axis in the tumor proliferation, migration and invasion of ovarian cancer cell lines. Oncol Lett 7(5):1581–1585

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PM, Raymond E (2014) Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. Am J Transl Res 6(4):340–352

    PubMed Central  PubMed  Google Scholar 

  115. Villalvilla A, Gomez R, Roman-Blas JA, Largo R, Herrero-Beaumont G (2014) SDF-1 signaling: a promising target in rheumatic diseases. Expert Opin Ther Targets 18(9):1077–1087

    Article  CAS  PubMed  Google Scholar 

  116. Pablos JL, Santiago B, Galindo M, Torres C, Brehmer MT, Blanco FJ, Garcia-Lazaro FJ (2003) Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol 170(4):2147–2152

    Article  CAS  PubMed  Google Scholar 

  117. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, Kitamura Y, Matsushima K, Yoshida N, Nishikawa S, Kishimoto T, Nagasawa T (1998) The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393(6685):591–594

    Article  CAS  PubMed  Google Scholar 

  118. Blades MC, Ingegnoli F, Wheller SK, Manzo A, Wahid S, Panayi GS, Perretti M, Pitzalis C (2002) Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID mice. Arthritis Rheum 46(3):824–836

    Article  CAS  PubMed  Google Scholar 

  119. Madge LA, Kluger MS, Orange JS, May MJ (2008) Lymphotoxin-alpha 1 beta 2 and LIGHT induce classical and noncanonical NF-kappa B-dependent proinflammatory gene expression in vascular endothelial cells. J Immunol 180(5):3467–3477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Noort AR, van Zoest KP, Weijers EM, Koolwijk P, Maracle CX, Novack DV, Siemerink MJ, Schlingemann RO, Tak PP, Tas SW (2014) NF-kappaB-inducing kinase is a key regulator of inflammation-induced and tumour-associated angiogenesis. J Pathol 234(3):375–385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ (1999) Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 154(4):1125–1135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Rempel SA, Dudas S, Ge S, Gutierrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6(1):102–111

    CAS  PubMed  Google Scholar 

  123. Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res 6(9):3530–3535

    CAS  PubMed  Google Scholar 

  124. Matthys P, Hatse S, Vermeire K, Wuyts A, Bridger G, Henson GW, De Clercq E, Billiau A, Schols D (2001) AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor-deficient mice. J Immunol 167(8):4686–4692

    Article  CAS  PubMed  Google Scholar 

  125. Ruth JH, Haas CS, Park CC, Amin MA, Martinez RJ, Haines GK III, Shahrara S, Campbell PL, Koch AE (2006) CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum 54(3):765–778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Katschke KJ Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE (2001) Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 44(5):1022–1032

    Article  CAS  PubMed  Google Scholar 

  127. Ruth JH, Rottman JB, Katschke KJ Jr, Qin S, Wu L, LaRosa G, Ponath P, Pope RM, Koch AE (2001) Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum 44(12):2750–2760

    Article  CAS  PubMed  Google Scholar 

  128. Shahrara S, Amin MA, Woods JM, Haines GK, Koch AE (2003) Chemokine receptor expression and in vivo signaling pathways in the joints of rats with adjuvant-induced arthritis. Arthritis Rheum 48(12):3568–3583

    Article  CAS  PubMed  Google Scholar 

  129. Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, Haas CS, Pope RM, Haines GK, Zha YY, Koch AE (2005) Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 52(6):1907–1919

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Shahrara S, Proudfoot AE, Park CC, Volin MV, Haines GK, Woods JM, Aikens CH, Handel TM, Pope RM (2008) Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol 180(5):3447–3456

    Article  CAS  PubMed  Google Scholar 

  131. Pickens SR, Chamberlain ND, Volin MV, Pope RM, Talarico NE, Mandelin AM II, Shahrara S (2012) Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis. Arthritis Rheum 64(8):2471–2481

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. Ruth JH, Volin MV, Haines GK III, Woodruff DC, Katschke KJ Jr, Woods JM, Park CC, Morel JC, Koch AE (2001) Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum 44(7):1568–1581

    Article  CAS  PubMed  Google Scholar 

  133. Garcia GE, Xia Y, Chen S, Wang Y, Ye RD, Harrison JK, Bacon KB, Zerwes HG, Feng L (2000) NF-kappaB-dependent fractalkine induction in rat aortic endothelial cells stimulated by IL-1beta, TNF-alpha, and LPS. J Leukoc Biol 67(4):577–584

    CAS  PubMed  Google Scholar 

  134. Imaizumi T, Matsumiya T, Fujimoto K, Okamoto K, Cui X, Ohtaki U, Hidemi Yoshida, Satoh K (2000) Interferon-gamma stimulates the expression of CX3CL1/fractalkine in cultured human endothelial cells. Tohoku J Exp Med 192(2):127–139

    Article  CAS  PubMed  Google Scholar 

  135. Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE (2001) Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 159(4):1521–1530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Murphy G, Knauper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I (2002) Matrix metalloproteinases in arthritic disease. Arthritis Res 4(Suppl 3):S39–S49

    Article  PubMed Central  PubMed  Google Scholar 

  137. Pap T, Shigeyama Y, Kuchen S, Fernihough JK, Simmen B, Gay RE, Billingham M, Gay S (2000) Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 43(6):1226–1232

    Article  CAS  PubMed  Google Scholar 

  138. Ahrens D, Koch AE, Pope RM, Stein-Picarella M, Niedbala MJ (1996) Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis. Arthritis Rheum 39(9):1576–1587

    Article  CAS  PubMed  Google Scholar 

  139. Freemont AJ, Hampson V, Tilman R, Goupille P, Taiwo Y, Hoyland JA (1997) Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific. Ann Rheum Dis 56(9):542–549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. Vincenti MP, Brinckerhoff CE (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 4:157–164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Brinckerhoff CE, Matrisian LM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3(3):207–214

    Article  CAS  PubMed  Google Scholar 

  142. Akhavani MA, Madden L, Buysschaert I, Sivakumar B, Kang N, Paleolog EM (2009) Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis. Arthritis Res Ther 11(3):R64

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  143. Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529–543

    Article  CAS  PubMed  Google Scholar 

  144. Kim KS, Choi HM, Lee YA, Choi IA, Lee SH, Hong SJ, Yang HI, Yoo MC (2011) Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis. Rheumatol Int 31(4):543–547

    Article  CAS  PubMed  Google Scholar 

  145. Mengshol JA, Mix KS, Brinckerhoff CE (2002) Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull’s-eye or missing the mark? Arthritis Rheum 46(1):13–20

    Article  CAS  PubMed  Google Scholar 

  146. Rabquer BJ, Pakozdi A, Michel JE, Gujar BS, Haines GK III, Imhof BA, Koch AE (2008) Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synovium. Arthritis Rheum 58(10):3020–3029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Rabquer BJ, Amin MA, Teegala N, Shaheen MK, Tsou PS, Ruth JH, Lesch CA, Imhof BA, Koch AE (2010) Junctional adhesion molecule-C is a soluble mediator of angiogenesis. J Immunol 185(3):1777–1785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Palmer G, Busso N, Aurrand-Lions M, Talabot-Ayer D, Chobaz-Peclat V, Zimmerli C, Hammel P, Imhof BA, Gabay C (2007) Expression and function of junctional adhesion molecule-C in human and experimental arthritis. Arthritis Res Ther 9(4):R65

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  149. Leinster DA, Colom B, Whiteford JR, Ennis DP, Lockley M, McNeish IA, Aurrand-Lions M, Chavakis T, Imhof BA, Balkwill FR, Nourshargh S (2013) Endothelial cell junctional adhesion molecule C plays a key role in the development of tumors in a murine model of ovarian cancer. FASEB J 27(10):4244–4253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Mojcik CF, Shevach EM (1997) Adhesion molecules: a rheumatologic perspective. Arthritis Rheum 40(6):991–1004

    Article  CAS  PubMed  Google Scholar 

  151. McMurray RW (1996) Adhesion molecules in autoimmune disease. Semin Arthritis Rheum 25(4):215–233

    Article  CAS  PubMed  Google Scholar 

  152. Hosaka S, Shah MR, Pope RM, Koch AE (1996) Soluble forms of P-selectin and intercellular adhesion molecule-3 in synovial fluids. Clin Immunol Immunopathol 78(3):276–282

    Article  CAS  PubMed  Google Scholar 

  153. Koch AE, Shah MR, Harlow LA, Lovis RM, Pope RM (1994) Soluble intercellular adhesion molecule-1 in arthritis. Clin Immunol Immunopathol 71:208–215

    Article  CAS  PubMed  Google Scholar 

  154. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ (1995) Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376(6540):517–519

    Article  CAS  PubMed  Google Scholar 

  155. Schimmer RC, Schrier DJ, Flory CM, Dykens J, Tung DK, Jacobson PB, Friedl HP, Conroy MC, Schimmer BB, Ward PA (1997) Streptococcal cell wall-induced arthritis: requirements for neutrophils, P-selectin, intercellular adhesion molecule-1, and macrophage-inflammatory protein-2. J Immunol 159:4103–4108

    CAS  PubMed  Google Scholar 

  156. Kakimoto K, Nakamura T, Ishii K, Takashi T, Iigou H, Yagita H, Okumura K, Onoue K (1992) The effect of anti-adhesion molecule antibody on the development of collagen-induced arthritis. Cell Immunol 142(2):326–337

    Article  CAS  PubMed  Google Scholar 

  157. Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik JP, Cylwik B, Skowronski J, Chwiecko J (2002) Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis 61(9):804–809

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Shahrara S, Huang Q, Mandelin AM II, Pope RM (2008) TH-17 cells in rheumatoid arthritis. Arthritis Res Ther 10(4):R93

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  159. Kim SJ, Chen Z, Chamberlain ND, Volin MV, Swedler W, Volkov S, Sweiss N, Shahrara S (2013) Angiogenesis in rheumatoid arthritis is fostered directly by Toll-like receptor 5 ligation and indirectly through interleukin-17 induction. Arthritis Rheum 65(8):2024–2036

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Pickens SR, Chamberlain ND, Volin MV, Mandelin AM II, Agrawal H, Matsui M, Yoshimoto T, Shahrara S (2011) Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum 63(8):2289–2298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76(2):301–314

    Article  CAS  PubMed  Google Scholar 

  162. Lasky LA (1992) Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science 258(5084):964–969

    Article  CAS  PubMed  Google Scholar 

  163. Bevilacqua MP, Stengelin S, Gimbrone MA Jr, Seed B (1989) Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 243(4895):1160–1165

    Article  CAS  PubMed  Google Scholar 

  164. Maruotti N, Cantatore FP, Ribatti D (2014) Putative effects of potentially anti-angiogenic drugs in rheumatic diseases. Eur J Clin Pharmacol 70(2):135–140

    Article  CAS  PubMed  Google Scholar 

  165. Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB (2004) Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 50(2):650–659

    Article  CAS  PubMed  Google Scholar 

  166. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, Aelion JA, Lee SH, Codding CE, Kellner H, Ikawa T, Hugot S, Mpofu S (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72(6):863–869

    Article  CAS  PubMed  Google Scholar 

  167. Genovese MC, Greenwald M, Cho CS, Berman A, Jin L, Cameron GS, Benichou O, Xie L, Braun D, Berclaz PY, Banerjee S (2014) A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol 66(7):1693–1704

    Article  CAS  PubMed  Google Scholar 

  168. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, Deodhar A, Newmark R, Feng J, Erondu N, Nirula A (2014) Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 370(24):2295–2306

    Article  PubMed  CAS  Google Scholar 

  169. Yao HP, Qian Y, Shao XT, Xu ZR, Cheng LF, Feng L, Wu NP, Yang YM (2010) Construction of a recombinant adenovirus vector expressing IL-18BP/IL-4 fusion gene and the anti-inflammatory effect induced by this gene on lipopolysaccharide-stimulated synovial fibroblasts. Inflamm Res 59(2):97–104

    Article  CAS  PubMed  Google Scholar 

  170. Mistry P, Reid J, Pouliquen I, McHugh S, Abberley L, DeWall S, Taylor A, Tong X, Rocha Del Cura M, McKie E (2014) Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin-18 mAb GSK1070806 in healthy and obese subjects. Int J Clin Pharmacol Ther 52(10):867–879

    Article  CAS  PubMed  Google Scholar 

  171. Tak PP, Bacchi M, Bertolino M (2006) Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis. Eur J Drug Metab Pharmacokinet 31(2):109–116

    Article  CAS  PubMed  Google Scholar 

  172. Greven D, Leng L, Bucala R (2010) Autoimmune diseases: MIF as a therapeutic target. Expert Opin Ther Targets 14(3):253–264

    Article  CAS  PubMed  Google Scholar 

  173. Cournia Z, Leng L, Gandavadi S, Du X, Bucala R, Jorgensen WL (2009) Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screening. J Med Chem 52(2):416–424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Fruehauf S (2013) Current clinical indications for plerixafor. Transfus Med Hemother 40(4):246–250

    Article  PubMed Central  PubMed  Google Scholar 

  175. Kuhne MR, Mulvey T, Belanger B, Chen S, Pan C, Chong C, Cao F, Niekro W, Kempe T, Henning KA, Cohen LJ, Korman AJ, Cardarelli PM (2013) BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res 19(2):357–366

    Article  CAS  PubMed  Google Scholar 

  176. Coxon A, Bready J, Min H, Kaufman S, Leal J, Yu D, Lee TA, Sun JR, Estrada J, Bolon B, McCabe J, Wang L, Rex K, Caenepeel S, Hughes P, Cordover D, Kim H, Han SJ, Michaels ML, Hsu E, Shimamoto G, Cattley R, Hurh E, Nguyen L, Wang SX, Ndifor A, Hayward IJ, Falcon BL, McDonald DM, Li L, Boone T, Kendall R, Radinsky R, Oliner JD (2010) Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody. Mol Cancer Ther 9(10):2641–2651

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  177. Weeraratne DK, Lofgren J, Dinnogen S, Swanson SJ, Zhong ZD (2013) Development of a biosensor-based immunogenicity assay capable of blocking soluble drug target interference. J Immunol Methods 396(1–2):44–55

    Article  CAS  PubMed  Google Scholar 

  178. Hah YS, Koh YJ, Lim HS, Kim HO, Cheon YH, Noh HS, Jang KY, Lee SY, Lee GM, Koh GY, Lee SI (2013) Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis. Arthritis Res Ther 15(4):R85

    Article  PubMed Central  PubMed  Google Scholar 

  179. Dorman G, Cseh S, Hajdu I, Barna L, Konya D, Kupai K, Kovacs L, Ferdinandy P (2010) Matrix metalloproteinase inhibitors: a critical appraisal of design principles and proposed therapeutic utility. Drugs 70(8):949–964

    Article  CAS  PubMed  Google Scholar 

  180. Thabet MM, Huizinga TW (2006) Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs 7(11):1014–1019

    CAS  PubMed  Google Scholar 

  181. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290(23):3073–3080

    Article  CAS  PubMed  Google Scholar 

  182. Prater EF, Day A, Patel M, Menter A (2014) A retrospective analysis of 72 patients on prior efalizumab subsequent to the time of voluntary market withdrawal in 2009. J Drugs Dermatol 13(6):712–718

    CAS  PubMed  Google Scholar 

  183. Jones R (2000) Rovelizumab (ICOS Corp). IDrugs Investig Drugs J 3(4):442–446

    CAS  Google Scholar 

  184. Kavanaugh AF, Davis LS, Nichols LA, Norris SH, Rothlein R, Scharschmidt LA, Lipsky PE (1994) Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum 37(7):992–999

    Article  CAS  PubMed  Google Scholar 

  185. Kavanaugh AF, Davis LS, Jain RI, Nichols LA, Norris SH, Lipsky PE (1996) A phase I/II open label study of the safety and efficacy of an anti-ICAM-1 (intercellular adhesion molecule-1; CD54) monoclonal antibody in early rheumatoid arthritis. J Rheumatol 23(8):1338–1344

    CAS  PubMed  Google Scholar 

  186. Kavanaugh AF, Schulze-Koops H, Davis LS, Lipsky PE (1997) Repeat treatment of rheumatoid arthritis patients with a murine anti-intercellular adhesion molecule 1 monoclonal antibody. Arthritis Rheum 40(5):849–853

    Article  CAS  PubMed  Google Scholar 

  187. Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, Galea I (2011) Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 10:CD007621

    PubMed  Google Scholar 

  188. Podar K, Zimmerhackl A, Fulciniti M, Tonon G, Hainz U, Tai YT, Vallet S, Halama N, Jager D, Olson DL, Sattler M, Chauhan D, Anderson KC (2011) The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br J Haematol 155(4):438–448

    Article  CAS  PubMed  Google Scholar 

  189. Mitroulis I, Alexaki VI, Kourtzelis I, Ziogas A, Hajishengallis G, Chavakis T (2015) Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 147:123–135

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by awards from the National Institutes of Health AR056099 and AR065778, funding provided by Department of Defense PR093477 and Arthritis Foundation Innovative Research Grant. We apologize to colleagues whose studies were not cited because of space limitation.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, MSB 835 S Wolcott Ave., E807-E809, Chicago, IL, 60612, USA

    Hatem A. Elshabrawy, Zhenlong Chen, Shalini Ravella, Shanti Virupannavar & Shiva Shahrara

  2. Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, 60515, USA

    Michael V. Volin

Authors
  1. Hatem A. Elshabrawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenlong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael V. Volin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shalini Ravella
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shanti Virupannavar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shiva Shahrara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiva Shahrara.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elshabrawy, H.A., Chen, Z., Volin, M.V. et al. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18, 433–448 (2015). https://doi.org/10.1007/s10456-015-9477-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-015-9477-2

Keywords

Search

Navigation