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Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors

Abstract

Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as 'passive responders' to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this 'imprinted aggressor' phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.

Key Points

  • Fibroblast-like synoviocytes (FLS), normally found in the synovial intimal lining of diarthrodial joints, display an aggressive, invasive phenotype in rheumatoid arthritis (RA) and participate in joint destruction

  • FLS from patients with RA promote inflammatory cell recruitment and activation, pannus angiogenesis, cartilage degradation, and bone erosion

  • The phenotype of FLS from patients with RA is partly a passive response to the inflammatory milieu in vivo, and partly an imprinted feature that persists when the cells are cultured in vitro

  • Imprinted anomalies of FLS in RA arise, at least in part, through epigenetic modifications of the genome, such as altered microRNA expression and DNA methylation

  • Increased knowledge of the biology of FLS in RA will pave the way to novel FLS-targeted therapies with limited immunosuppressive action

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Figure 1: Roles of FLS in RA.
Figure 2: Molecular pathology of FLS in RA.
Figure 3: Imprinted anomalies of RA FLS (cultured FLS derived from patients with RA).

References

  1. Firestein, G. S. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum. 39, 1781–1790 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Müller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).

    PubMed  PubMed Central  Google Scholar 

  3. Lefèvre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233, 233–255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Edwards, J. C., Leigh, R. D. & Cambridge, G. Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts. Clin. Exp. Immunol. 108, 407–414 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Okazaki, M. et al. Molecular cloning and characterization of OB-cadherin, a new member of cadherin family expressed in osteoblasts. J. Biol. Chem. 269, 12092–12098 (1994).

    CAS  PubMed  Google Scholar 

  7. Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Valencia, X. et al. Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J. Exp. Med. 200, 1673–1679 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).

    Article  PubMed  Google Scholar 

  10. Firestein, G. S., Yeo, M. & Zvaifler, N. J. Apoptosis in rheumatoid arthritis synovium. J. Clin. Invest. 96, 1631–1638 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Imamura, F. et al. Monoclonal expansion of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 41, 1979–1986 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Matsumoto, S., Müller-Ladner, U., Gay, R. E., Nishioka, K. & Gay, S. Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J. Rheumatol. 23, 1345–1352 (1996).

    CAS  PubMed  Google Scholar 

  13. Meinecke, I. et al. Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc. Natl Acad. Sci. USA 104, 5073–5078 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Kumkumian, G. K. et al. Platelet-derived growth factor and IL-1 interactions in rheumatoid arthritis. Regulation of synoviocyte proliferation, prostaglandin production, and collagenase transcription. J. Immunol. 143, 833–837 (1989).

    CAS  PubMed  Google Scholar 

  15. Lotz, M. & Guerne, P. A. Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J. Biol. Chem. 266, 2017–2020 (1991).

    CAS  PubMed  Google Scholar 

  16. Shigeyama, Y. et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 43, 2523–2530 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Pap, T., Aupperle, K. R., Gay, S., Firestein, G. S. & Gay, R. E. Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 44, 676–681 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Guerne, P. A., Zuraw, B. L., Vaughan, J. H., Carson, D. A. & Lotz, M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J. Clin. Invest. 83, 585–592 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Crow, M. K. Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res. Ther. 12 (Suppl. 1), S5 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Palmer, C. D., Mutch, B. E., Page, T. H., Horwood, N. J. & Foxwell, B. M. Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts. Biochem. Biophys. Res. Commun. 370, 599–602 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Nikitopoulou, I. et al. Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis. J. Exp. Med. 209, 925–933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stanczyk, J., Ospelt, C., Gay, R. E. & Gay, S. Synovial cell activation. Curr. Opin. Rheumatol. 18, 262–267 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Han, Z. et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108, 73–81 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yoshizawa, T. et al. Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. J. Immunol. 183, 1360–1367 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Korb, A. et al. Differential tissue expression and activation of p38 MAPK α, β, γ, and δ isoforms in rheumatoid arthritis. Arthritis Rheum. 54, 2745–2756 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Westra, J., Limburg, P. C., de Boer, P. & van Rijswijk, M. H. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann. Rheum. Dis. 63, 1453–1459 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Inoue, T., Hammaker, D., Boyle, D. L. & Firestein, G. S. Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes. J. Immunol. 174, 4301–4306 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Guma, M. et al. Pro- and anti-inflammatory functions of the p38 pathway in rheumatoid arthritis: advantages of targeting upstream kinases MKK3 or MKK6. Arthritis Rheum. 64, 2887–2895 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cohen, S. B. et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 60, 335–344 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Genovese, M. C. et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J. Rheumatol. 38, 846–854 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Shahrara, S., Castro-Rueda, H. P., Haines, G. K. & Koch, A. E. Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues. Arthritis Res. Ther. 9, R112 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pap, T. et al. Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 50, 2794–2802 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Weisbart, R. H. et al. BRAF drives synovial fibroblast transformation in rheumatoid arthritis. J. Biol. Chem. 285, 34299–34303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Abreu, J. R. et al. The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue. Arthritis Res. Ther. 11, R121 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han, Z. et al. Jun N-terminal kinase in rheumatoid arthritis. J. Pharmacol. Exp. Ther. 291, 124–130 (1999).

    CAS  PubMed  Google Scholar 

  37. Svensson, C. I. et al. Gadd45β deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling. Arthritis Rheum. 60, 3229–3240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Luo, Y. et al. Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice. Arthritis Rheum. 63, 2949–2955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aupperle, K. et al. NF-κB regulation by IκB kinase-2 in rheumatoid arthritis synoviocytes. J. Immunol. 166, 2705–2711 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Oeckinghaus, A. & Ghosh, S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol. 1, a000034 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Okazaki, Y. et al. Effect of nuclear factor-κB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. J. Rheumatol. 32, 1440–1447 (2005).

    CAS  PubMed  Google Scholar 

  42. Zhang, H. G. et al. Gene therapy that inhibits nuclear translocation of nuclear factor κB results in tumor necrosis factor α-induced apoptosis of human synovial fibroblasts. Arthritis Rheum. 43, 1094–1105 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Pap, T. et al. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2, 59–64 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Bartok, B. et al. PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis. Am. J. Pathol. 180, 1906–1916 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Sweeney, S. E., Hammaker, D., Boyle, D. L. & Firestein, G. S. Regulation of c-Jun phosphorylation by the IκB kinase-ε complex in fibroblast-like synoviocytes. J. Immunol. 174, 6424–6430 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Sweeney, S. E., Corr, M. & Kimbler, T. B. Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β production. Arthritis Rheum. 64, 1046–1056 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Korb, A., Pavenstadt, H. & Pap, T. Cell death in rheumatoid arthritis. Apoptosis 14, 447–454 (2009).

    Article  PubMed  Google Scholar 

  48. Wakisaka, S. et al. Modulation by proinflammatory cytokines of Fas/Fas ligand-mediated apoptotic cell death of synovial cells in patients with rheumatoid arthritis (RA). Clin. Exp. Immunol. 114, 119–128 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Audo, R. et al. Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. Arthritis Rheum. 63, 904–913 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Han, Z., Boyle, D. L., Shi, Y., Green, D. R. & Firestein, G. S. Dominant-negative p53 mutations in rheumatoid arthritis. Arthritis Rheum. 42, 1088–1092 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Firestein, G. S. et al. Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am. J. Pathol. 149, 2143–2151 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cha, H. S., Rosengren, S., Boyle, D. L. & Firestein, G. S. PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes. Arthritis Rheum. 54, 587–592 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Schedel, J. et al. FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis. Arthritis Rheum. 46, 1512–1518 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Franz, J. K. et al. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum. 43, 599–607 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Maciejewska-Rodrigues, H. et al. Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J. Autoimmun. 35, 15–22 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Fassbender, H. G. & Simmling-Annefeld, M. The potential aggressiveness of synovial tissue in rheumatoid arthritis. J. Pathol. 139, 399–406 (1983).

    Article  CAS  PubMed  Google Scholar 

  57. Yamanishi, Y. et al. p53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis. Arthritis Res. Ther. 7, R12–R18 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Da Sylva, T. R., Connor, A., Mburu, Y., Keystone, E. & Wu, G. E. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res. Ther. 7, R844–R851 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee, S. H. et al. Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J. Immunol. 170, 2214–2220 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Tak, P. P., Zvaifler, N. J., Green, D. R. & Firestein, G. S. Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol. Today 21, 78–82 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Harty, L. C. et al. Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis. Ann. Rheum. Dis. 71, 582–588 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Karouzakis, E., Gay, R. E., Gay, S. & Neidhart, M. Epigenetic deregulation in rheumatoid arthritis. Adv. Exp. Med. Biol. 711, 137–149 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Kuchen, S. et al. The L1 retroelement-related p40 protein induces p38δ MAP kinase. Autoimmunity 37, 57–65 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. & Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-201526.

  65. Grabiec, A. M., Korchynskyi, O., Tak, P. P. & Reedquist, K. A. Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann. Rheum. Dis. 71, 424–431 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Nakamachi, Y. et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 60, 1294–1304 (2009).

    Article  PubMed  Google Scholar 

  67. Stanczyk, J. et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 63, 373–381 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Duroux-Richard, I., Jorgensen, C. & Apparailly, F. What do microRNAs mean for rheumatoid arthritis? Arthritis Rheum. 64, 11–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Karouzakis, E., Gay, R. E., Gay, S. & Neidhart, M. Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 64, 1809–1817 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Ballestar, E. An introduction to epigenetics. Adv. Exp. Med. Biol. 711, 1–11 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Bogdanos, D. P. et al. Twin studies in autoimmune disease: genetics, gender and environment. J. Autoimmun. 38, 156–169 (2012).

    Article  Google Scholar 

  72. Guma, M., Ronacher, L. M., Firestein, G. S., Karin, M. & Corr, M. JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis. Arthritis Rheum. 63, 1603–1612 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Denninger, K. et al. JNK1, but not JNK2, is required in two mechanistically distinct models of inflammatory arthritis. Am. J. Pathol. 179, 1884–1893 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, S. I., Boyle, D. L., Berdeja, A. & Firestein, G. S. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthritis Res. Ther. 14, R38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Haruta, K. et al. Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats. Inflamm. Res. 61, 551–562 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Cha, H. S. et al. A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes. J. Pharmacol. Exp. Ther. 317, 571–578 (2006).

    Article  CAS  Google Scholar 

  77. Weinblatt, M. E. et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N. Engl. J. Med. 363, 1303–1312 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Schieven, G. L. The p38α kinase plays a central role in inflammation. Curr. Top. Med. Chem. 9, 1038–1048 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Damjanov, N., Kauffman, R. S. & Spencer-Green, G. T. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum. 60, 1232–1241 (2009).

    Article  PubMed  Google Scholar 

  80. Inoue, T. et al. Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc. Natl Acad. Sci. USA 103, 5484–5489 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Hah, Y. S. et al. A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis. Arthritis Rheum. 62, 2313–2321 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Tak, P. P. et al. Inhibitor of nuclear factor κB kinase β is a key regulator of synovial inflammation. Arthritis Rheum. 44, 1897–1907 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Shi, J. et al. Epirubicin potentiates recombinant adeno-associated virus type 2/5-mediated TRAIL expression in fibroblast-like synoviocytes and augments the antiarthritic effects of rAAV2/5-TRAIL. Arthritis Rheum. 64, 1345–1354 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Lin, H. S. et al. Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br. J. Pharmacol. 150, 862–872 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kavanaugh, A. F. et al. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum. 37, 992–999 (1994).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are indebted to M. Bottini and S. Stanford for help with preparation of the figures. This work was supported, in part, by Institutional La Jolla Institute of Allergy and Immunology funds (to N. Bottini) and by NIH grants R01AI067752, R01 AI070555, and R01 AR47825 (to G. S. Firestein). This manuscript is #1556 published from the La Jolla Institute of Allergy and Immunology.

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Bottini, N., Firestein, G. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 9, 24–33 (2013). https://doi.org/10.1038/nrrheum.2012.190

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