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Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Abstract

Active rheumatoid arthritis originates from few joints but subsequently affects the majority of joints. Thus far, the pathways of the progression of the disease are largely unknown. As rheumatoid arthritis synovial fibroblasts (RASFs) which can be found in RA synovium are key players in joint destruction and are able to migrate in vitro, we evaluated the potential of RASFs to spread the disease in vivo. To simulate the primary joint of origin, we implanted healthy human cartilage together with RASFs subcutaneously into severe combined immunodeficient (SCID) mice. At the contralateral flank, we implanted healthy cartilage without cells. RASFs showed an active movement to the naive cartilage via the vasculature independent of the site of application of RASFs into the SCID mouse, leading to a marked destruction of the target cartilage. These findings support the hypothesis that the characteristic clinical phenomenon of destructive arthritis spreading between joints is mediated, at least in part, by the transmigration of activated RASFs.

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Figure 1: Migration of RASFs.
Figure 2: Migratory potential of RASFs.
Figure 3: Migration and adhesion of RASFs in vitro.
Figure 4: RASF transmigration and inhibition in vitro.

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References

  1. Karouzakis, E., Neidhart, M., Gay, R.E. & Gay, S. Molecular and cellular basis of rheumatoid joint destruction. Immunol. Lett. 106, 8–13 (2006).

    Article  CAS  Google Scholar 

  2. Müller-Ladner, U., Pap, T., Gay, R.E., Neidhart, M. & Gay, S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 1, 102–110 (2005).

    Article  Google Scholar 

  3. Pap, T., Muller-Ladner, U., Gay, R.E. & Gay, S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2, 361–367 (2000).

    Article  CAS  Google Scholar 

  4. Gravallese, E.M. Bone destruction in arthritis. Ann. Rheum. Dis. 61 Suppl 2, ii84–ii86 (2002).

    Article  Google Scholar 

  5. Looney, R.J. B cell–targeted therapy for rheumatoid arthritis: an update on the evidence. Drugs 66, 625–639 (2006).

    Article  CAS  Google Scholar 

  6. Ma, Y. & Pope, R.M. The role of macrophages in rheumatoid arthritis. Curr. Pharm. Des. 11, 569–580 (2005).

    Article  CAS  Google Scholar 

  7. Skapenko, A., Leipe, J., Lipsky, P.E. & Schulze-Koops, H. The role of the T cell in autoimmune inflammation. Arthritis Res. Ther. 7 Suppl 2, S4–S14 (2005).

    Article  Google Scholar 

  8. Yasuda, T. Cartilage destruction by matrix degradation products. Mod. Rheumatol. 16, 197–205 (2006).

    Article  CAS  Google Scholar 

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

    CAS  PubMed Central  Google Scholar 

  10. Buckley, C.D. et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 22, 199–204 (2001).

    Article  CAS  Google Scholar 

  11. Huber, L.C. et al. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford) 45, 669–675 (2006).

    Article  CAS  Google Scholar 

  12. Neumann, E. et al. Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10 involves the activin pathway. Gene Ther. 9, 1508–1519 (2002).

    Article  CAS  Google Scholar 

  13. 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 Central  Google Scholar 

  14. Müller-Ladner, U. et al. Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective. J. Immunol. 158, 3492–3498 (1997).

    Google Scholar 

  15. García-Vicuña, R. et al. CC and CXC chemokine receptors mediate migration, proliferation and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheum. 50, 3866–3877 (2004).

    Article  Google Scholar 

  16. Takahara, K. et al. Autocrine/paracrine role of the angiopoietin-1 and -2/Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid arthritis. Hum. Pathol. 35, 150–158 (2004).

    Article  CAS  Google Scholar 

  17. Woods, J.M. et al. A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis. Arthritis Res. Ther. 8, R113 (2006).

    Article  Google Scholar 

  18. van Beurden, H.E., Snoek, P.A., Von den Hoff, J.W., Torensma, R. & Kuijpers-Jagtman, A.M. Fibroblast subpopulations in intra-oral wound healing. Wound Repair Regen. 11, 55–63 (2003).

    Article  Google Scholar 

  19. Clark, R.A.F., An, J.C., Greiling, D., Khan, A. & Schwarzbauer, J.E. Fibroblast migration on fibronectin requires three distinct functional domains. J. Invest. Dermatol. 121, 695–705 (2003).

    Article  CAS  Google Scholar 

  20. Blaney Davidson, E.N. et al. Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor β–induced osteophytes. Arthritis Rheum. 56, 4065–4073 (2007).

    Article  CAS  Google Scholar 

  21. Zak, J., Schneider, S.W., Eue, I., Ludwig, T. & Oberleithner, H. High-resistance MDCK-C7 monolayers used for measuring invasive potency of tumour cells. Pflugers Arch. 440, 179–183 (2000).

    Article  CAS  Google Scholar 

  22. Hutchings, H., Ortega, N. & Plouet, J. Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration and survival through integrin ligation. FASEB J. 17, 1520–1522 (2003).

    Article  CAS  Google Scholar 

  23. Hubbell, J.A. Matrix-bound growth factors in tissue repair. Swiss Med. Wkly. 137 Suppl 155, 72S–76S (2007).

    CAS  Google Scholar 

  24. Hall, H. & Hubbell, J.A. Matrix-bound siwth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating αvβ3-integrin and activating VEGF-R2. Microvasc. Res. 68, 169–178 (2004).

    Article  CAS  Google Scholar 

  25. Cazes, A. et al. Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration and sprouting and alters actin cytoskeleton. Circ. Res. 99, 1207–1215 (2006).

    Article  CAS  Google Scholar 

  26. Felix, R. et al. Synthesis of membrane- and matrix-bound colony-stimulating factor-1 by cultured osteoblasts. J. Cell. Physiol. 166, 311–322 (1996).

    Article  CAS  Google Scholar 

  27. Nicosia, R.F. & Tuszynski, G.P. Matrix-bound thrombospondin promotes angiogenesis in vitro. J. Cell Biol. 124, 183–193 (1994).

    Article  CAS  Google Scholar 

  28. Saint-Geniez, M., Kurihara, T. & D'Amore, P.A. Absence of cell and matrix-bound VEGF isoforms is associated with abnormal lens development. Invest. Ophthalmol. Vis. Sci. 50, 311–321 (2009).

    Article  Google Scholar 

  29. el-Gabalawy, H. et al. Synovial distribution of α d/CD18, a novel leukointegrin. Comparison with other integrins and their ligands. Arthritis Rheum. 39, 1913–1921 (1996).

    Article  CAS  Google Scholar 

  30. Morales-Ducret, J. et al. α4/β1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J. Immunol. 149, 1424–1431 (1992).

    CAS  Google Scholar 

  31. Müller-Ladner, U. et al. Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid arthritis synovium. J. Rheumatol. 24, 1873–1880 (1997).

    Google Scholar 

  32. Schedel, J. et al. Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis. Scand. J. Immunol. 60, 514–523 (2004).

    Article  CAS  Google Scholar 

  33. Giancotti, F.G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    Article  CAS  Google Scholar 

  34. Owsianik, W.D. et al. Radiological articular involvement in the dominant hand in rheumatoid arthritis. Ann. Rheum. Dis. 39, 508–10 (1980).

    Article  CAS  Google Scholar 

  35. Ishikawa, H., Ohno, O. & Hirohata, K. An electron microscopic study of the synovial-bone junction in rheumatoid arthritis. Rheumatol. Int. 4, 1–8 (1984).

    Article  CAS  Google Scholar 

  36. Bromley, M., Bertfield, H., Evanson, J.M. & Woolley, D.E. Bidirectional erosion of cartilage in the rheumatoid knee joint. Ann. Rheum. Dis. 44, 676–681 (1985).

    Article  CAS  Google Scholar 

  37. Bresnihan, B. Pathogenesis of joint damage in rheumatoid arthritis. J. Rheumatol. 26, 717–719 (1999).

    CAS  Google Scholar 

  38. Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  Google Scholar 

  39. Müller-Ladner, U. et al. Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum. 42, 490–497 (1999).

    Article  Google Scholar 

  40. Neumann, E. et al. Identification of differentially expressed genes in rheumatoid arthritis by a combination of complementary DNA array and RNA arbitrarily primed-polymerase chain reaction. Arthritis Rheum. 46, 52–63 (2002).

    Article  CAS  Google Scholar 

  41. Lechman, E.R. et al. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J. Immunol. 163, 2202–2208 (1999).

    CAS  Google Scholar 

  42. Judex, M. et al. 'Inverse wrap'—an improved implantation technique for virus-transduced synovial fibroblasts in the SCID-mouse model for RA. Mod. Rheumatol. 11, 145–150 (2001).

    Article  CAS  Google Scholar 

  43. Clements, K.M., Bee, Z.C., Crossingham, G.V., Adams, M.A. & Sharif, M. How severe must repetitive loading be to kill chondrocytes in articular cartilage? Osteoarthritis Cartilage 9, 499–507 (2001).

    Article  CAS  Google Scholar 

  44. Knedla, A. et al. The therapeutic use of osmotic minipumps in the SCID mouse model for rheumatoid arthritis. Ann. Rheum. Dis. 68, 124–129 (2009).

    Article  CAS  Google Scholar 

  45. Hashimoto, A. et al. Laser-mediated microdissection for analysis of gene expression in synovial tissue. Mod. Rheumatol. 17, 185–190 (2007).

    Article  CAS  Google Scholar 

  46. Judex, M., Neumann, E., Gay, S. & Muller-Ladner, U. Laser-mediated microdissection as a tool for molecular analysis in arthritis. Methods Mol. Med. 101, 93–105 (2004).

    CAS  Google Scholar 

  47. Lechner, S. et al. Gene expression pattern of laser microdissected colonic crypts of adenomas with low grade dysplasia. Gut 52, 1148–1153 (2003).

    Article  CAS  Google Scholar 

  48. Little, C.B. et al. ADAMTS-1–knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo. Arthritis Rheum. 52, 1461–1472 (2005).

    Article  CAS  Google Scholar 

  49. van der Laan, W.H. et al. Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cell surface-targeted plasmin inhibitor. Arthritis Rheum. 43, 1710–1718 (2000).

    Article  CAS  Google Scholar 

  50. Hajiioannou, J.K. et al. In vitro enzymatic treatment and carbon dioxide laser beam irradiation of morphologic cartilage specimens. Arch. Otolaryngol. Head Neck Surg. 132, 1363–1370 (2006).

    Article  Google Scholar 

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Acknowledgements

This study was funded by a start-up grant of the German Society of Rheumatology, by research grants of the German Research Foundation (Deutsche Forschungsgemeinschaft: NE1174/3-1, MU1383/14-1, FOR 696), by the Swiss National Fond 32000-116842 and by the Sixth Framework Programme Autocure and Seventh Framework Programme Masterswitch of the EU initiatives. We wish to thank S. Benninghoff, B. Riepl, S. Brückmann and C. Schreiyäck for technical assistance.

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S.L., experiment selection, design and performance, manuscript preparation; A. Knedla, SCID mouse surgery and evaluation; C.T., detection and evaluation of RASFs in mice; A. Kampmann, LMM and evaluation of integrins; C.W., TEER assay and evaluation; R.D., collagenase injection and evaluation; A. Korb, TEER adhesion assay and evaluation; E.-M.S., TEER assay and evaluation; I.H.T., SCID mouse surgery; P.D.R. and C.H.E., preparation of adenoviral vectors; H.S., orthopedic surgery and collection for research; J. Steinmeyer, tissue preparation for experiments; S.G., project design and experimental design; J. Schölmerich, project and experimental design; T.P., project and experimental design, TEER and adhesion assay; U.M.-L., project development and design, experimental design and manuscript preparation; E.N., project development and coordination, study and experimental design and performance and manuscript preparation,

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Correspondence to Elena Neumann.

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Lefèvre, S., Knedla, A., Tennie, C. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 15, 1414–1420 (2009). https://doi.org/10.1038/nm.2050

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