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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Molecular and cellular basis of rheumatoid joint destruction. Immunol. Lett. 106, 8–13 (2006).

  2. 2.

    , , , & Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 1, 102–110 (2005).

  3. 3.

    , , & Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2, 361–367 (2000).

  4. 4.

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

  5. 5.

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

  6. 6.

    & The role of macrophages in rheumatoid arthritis. Curr. Pharm. Des. 11, 569–580 (2005).

  7. 7.

    , , & The role of the T cell in autoimmune inflammation. Arthritis Res. Ther. 7 Suppl 2, S4–S14 (2005).

  8. 8.

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

  9. 9.

    , , & Are fibroblasts involved in joint destruction? Ann. Rheum. Dis. 64 Suppl 4, iv52–iv54 (2005).

  10. 10.

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

  11. 11.

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

  12. 12.

    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).

  13. 13.

    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).

  14. 14.

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

  15. 15.

    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).

  16. 16.

    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).

  17. 17.

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

  18. 18.

    , , , & Fibroblast subpopulations in intra-oral wound healing. Wound Repair Regen. 11, 55–63 (2003).

  19. 19.

    , , , & Fibroblast migration on fibronectin requires three distinct functional domains. J. Invest. Dermatol. 121, 695–705 (2003).

  20. 20.

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

  21. 21.

    , , , & High-resistance MDCK-C7 monolayers used for measuring invasive potency of tumour cells. Pflugers Arch. 440, 179–183 (2000).

  22. 22.

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

  23. 23.

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

  24. 24.

    & 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).

  25. 25.

    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).

  26. 26.

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

  27. 27.

    & Matrix-bound thrombospondin promotes angiogenesis in vitro. J. Cell Biol. 124, 183–193 (1994).

  28. 28.

    , & Absence of cell and matrix-bound VEGF isoforms is associated with abnormal lens development. Invest. Ophthalmol. Vis. Sci. 50, 311–321 (2009).

  29. 29.

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

  30. 30.

    et al. α41 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).

  31. 31.

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

  32. 32.

    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).

  33. 33.

    & Integrin signaling. Science 285, 1028–1032 (1999).

  34. 34.

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

  35. 35.

    , & An electron microscopic study of the synovial-bone junction in rheumatoid arthritis. Rheumatol. Int. 4, 1–8 (1984).

  36. 36.

    , , & Bidirectional erosion of cartilage in the rheumatoid knee joint. Ann. Rheum. Dis. 44, 676–681 (1985).

  37. 37.

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

  38. 38.

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

  39. 39.

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

  40. 40.

    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).

  41. 41.

    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).

  42. 42.

    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).

  43. 43.

    , , , & How severe must repetitive loading be to kill chondrocytes in articular cartilage? Osteoarthritis Cartilage 9, 499–507 (2001).

  44. 44.

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

  45. 45.

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

  46. 46.

    , , & Laser-mediated microdissection as a tool for molecular analysis in arthritis. Methods Mol. Med. 101, 93–105 (2004).

  47. 47.

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

  48. 48.

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

  49. 49.

    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).

  50. 50.

    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).

Download references

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.

Author information

Affiliations

  1. Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff-Clinic, Bad Nauheim, Germany.

    • Stephanie Lefèvre
    • , Anette Knedla
    • , Christoph Tennie
    • , Andreas Kampmann
    • , Robert Dinser
    • , Ingo H Tarner
    • , Ulf Müller-Ladner
    •  & Elena Neumann
  2. Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.

    • Christina Wunrau
    •  & Thomas Pap
  3. Department of Internal Medicine D, Nephrology and Rheumatology, University Hospital Muenster, Muenster, Germany.

    • Adelheid Korb
  4. Department of Dermatology, University Hospital Muenster, Muenster, Germany.

    • Eva-Maria Schnäker
  5. Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Paul D Robbins
  6. Center for Molecular Orthopedics, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher H Evans
  7. Department of Orthopedics and Orthopedic Surgery, University Hospital Giessen and Marburg, Giessen, Germany.

    • Henning Stürz
  8. Department of Orthopedics and Experimental Orthopedics, University Hospital Giessen and Marburg, Giessen, Germany.

    • Jürgen Steinmeyer
  9. Center for Experimental Rheumatology, Zürich Center for Integrative Human Physiology, USZ, Zürich, Switzerland.

    • Steffen Gay
  10. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.

    • Jürgen Schölmerich

Authors

  1. Search for Stephanie Lefèvre in:

  2. Search for Anette Knedla in:

  3. Search for Christoph Tennie in:

  4. Search for Andreas Kampmann in:

  5. Search for Christina Wunrau in:

  6. Search for Robert Dinser in:

  7. Search for Adelheid Korb in:

  8. Search for Eva-Maria Schnäker in:

  9. Search for Ingo H Tarner in:

  10. Search for Paul D Robbins in:

  11. Search for Christopher H Evans in:

  12. Search for Henning Stürz in:

  13. Search for Jürgen Steinmeyer in:

  14. Search for Steffen Gay in:

  15. Search for Jürgen Schölmerich in:

  16. Search for Thomas Pap in:

  17. Search for Ulf Müller-Ladner in:

  18. Search for Elena Neumann in:

Contributions

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,

Corresponding author

Correspondence to Elena Neumann.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.2050

Further reading