Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Dec;15(12):1414-20.
doi: 10.1038/nm.2050. Epub 2009 Nov 8.

Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Stephanie Lefèvre  1 , Anette Knedla, Christoph Tennie, Andreas Kampmann, Christina Wunrau, Robert Dinser, Adelheid Korb, Eva-Maria Schnäker, Ingo H Tarner, Paul D Robbins, Christopher H Evans, Henning Stürz, Jürgen Steinmeyer, Steffen Gay, Jürgen Schölmerich, Thomas Pap, Ulf Müller-Ladner, Elena Neumann
Affiliations

Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Stephanie Lefèvre et al. Nat Med. 2009 Dec.

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors have no competing interests.

Figures

Figure 1
Figure 1. Migration of RASFs
(a) Cartilage-sponge complexes with or without RASFs were implanted into SCID mice at opposite sites. OASFs, human synovium, necrotic human, bovine or murine cartilage served as controls. (b) Invasion scores show a deep invasion of RASFs in the primary and contralateral implant. Limited cartilage invasion by OASFs or into RASF-free cartilage was observed. *p<0.05; **p<0.001; NS: not significant. (c, d) Histology shows RASF invasion and pc degradation at the primary and contralaterally implanted cartilage (red arrows: invasion; blue arrows: pc degradation; mt: murine tissue; ca: cartilage; sp: sponge). (e, f) Human origin of invading cells was confirmed by species-specific antibodies against vimentin (e) or proMMP-13 (f) (red arrows). The invasion zone was not stained by murine-specific IL-1R antibodies (g), in contrast to murine vessels (black arrows). Phase contrast shows the non-stained invasion zone (green arrows).
Figure 2
Figure 2. Migratory potential of RASFs
(a) Invasion scores of cartilage after s.c., i.v., i.p. injection, implantation of whole synovium, bovine cartilage and cartilage without viable chondrocytes, showing a strong invasion in contrast to OASFs and implants without RASFs. (b) Neovascularization 7 days after implantation. I: Implant; sk: murine skin; black arrows: murine vessels. (c) Migration of human RASF out of synovial tissue into RASF-free cartilage (red arrows: invasion; blue arrow: pc degradation). (d) Invasion of implanted murine articular heads was mainly observed at the cartilage-bone junction (red arrow; blue arrow: pc cartilage degradation; ca: cartilage; b: bone; sp: sponge).
Figure 3
Figure 3. Migration and adhesion of RASF in vitro
(a) Several RASFs (black bars) were detectable in murine organs, particularly in the spleen and ear cartilage (grey bars: single RASFs; white bars: no RASFs). (b) Immunohistochemistry for human vimentin showed RASFs in the spleen (b) but not in the intestine (c). Left: hematoxylin-eosin staining; center: vimentin-stained RASFs (black arrows); right: EGFP-transduced RASFs (white arrows). (d) After collagenase treatment and injection of RASFs, invasive erosions (arrows) were detectable in the damaged articular cartilage surface (day 39 after injection; c: cartilage; b: bone; js: joint space). (e) Increased adhesion of RASFs seeded on collagenase-treated and non-treated human cartilage in comparison to OASFs and towards collagenase-digested cartilage when compared to intact cartilage. (f) Vimentin-positive RASFs are present in the murine blood, showing a remarkably high amount of human cells in this sample (n = 2); red arrows: RASFs; green arrows: murine cells. (g) y-chromosome-specific RASF-derived sry-fragment was detectable in isolated DNA out of murine blood and in the positive control. Estimated size of the sry-fragment: 601 bp. (h) No difference in expression of integrin-subunits between invading/non-invading or primary/contralaterally implanted RASF was observed by real time-PCR after LMM.
Figure 4
Figure 4. RASF-transmigration and inhibition in vitro
(a) RASFs showed an increased transmigratory and invasive potential in the TEER assay (n = 5 different primary cultures) through MDCK-C7 monolayers, comparable to Cal78 cells. HSF and OASF (n = 3 different primary cultures) showed no transmigratory behavior. p<0.05 for RASFs and Cal78 vs. HSFs and OASFs, respectively. (b) Cell adhesion was inhibited by RASF-treatment with anti-VCAM-1 antibodies. The transmigratory potential of RASFs (TEER assay) was decreased by treatment or transduction of RASFs with BB-94 (c) and TIMP-3 (d). P<0.05 for RASF transduced with BB94 and TIMP-1 vs. non-transduced RASFs.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Karouzakis E, Neidhart M, Gay RE, Gay S. Molecular and cellular basis of rheumatoid joint destruction. Immunol Lett. 2006;106:8–13. - PubMed
    1. Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1:102–10. - PubMed
    1. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2000;2:361–7. - PMC - PubMed
    1. Gravallese EM. Bone destruction in arthritis. Ann Rheum Dis. 2002;61(Suppl 2):ii84–6. - PMC - PubMed
    1. Looney RJ. B cell-targeted therapy for rheumatoid arthritis: an update on the evidence. Drugs. 2006;66:625–39. - PubMed

Publication types