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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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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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Authors

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,

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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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