Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts
Objective Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovi...
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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
29 April 2010
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| In: |
Arthritis & rheumatism
Year: 2010, Jahrgang: 62, Heft: 5, Pages: 1224-1235 |
| ISSN: | 1529-0131 |
| DOI: | 10.1002/art.27395 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/art.27395 Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/art.27395 
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| Verfasserangaben: | Caroline Ospelt, Joachim C. Mertens, Astrid Jüngel, Fabia Brentano, Hanna Maciejewska-Rodriguez, Lars C. Huber, Hossein Hemmatazad, Thomas Wüest, Alexander Knuth, Renate E. Gay, Beat A. Michel, Steffen Gay, Christoph Renner, and Stefan Bauer |
MARC
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| 245 | 1 | 0 | |a Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts |c Caroline Ospelt, Joachim C. Mertens, Astrid Jüngel, Fabia Brentano, Hanna Maciejewska-Rodriguez, Lars C. Huber, Hossein Hemmatazad, Thomas Wüest, Alexander Knuth, Renate E. Gay, Beat A. Michel, Steffen Gay, Christoph Renner, and Stefan Bauer |
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| 520 | |a Objective Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovial fibroblasts (RASFs) into articular cartilage. Methods Expression of FAP and DPP-4/CD26 by RASFs was analyzed using fluorescence-activated cell sorting and immunocytochemistry. Serine protease activity was measured by cleavage of fluorogenic substrates and inhibited upon treatment with L-glutamyl L-boroproline. The induction and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in RASFs were detected using real-time polymerase chain reaction. Densitometric measurements of MMPs using immunoblotting confirmed our findings on the messenger RNA level. Stromal cell-derived factor 1 (SDF-1 [CXCL12]), MMP-1, and MMP-3 protein levels were measured using enzyme-linked immunosorbent assay. The impact of FAP and DPP-4/CD26 inhibition on the invasiveness of RASFs was analyzed in the SCID mouse coimplantation model of RA using immunohistochemistry. Results Inhibition of serine protease activity of FAP and DPP-4/CD26 in vitro led to increased levels of SDF-1 in concert with MMP-1 and MMP-3, which are downstream effectors of SDF-1 signaling. Using the SCID mouse coimplantation model, inhibition of enzymatic activity in vivo significantly promoted invasion of xenotransplanted RASFs into cotransplanted human cartilage. Zones of cartilage resorption were infiltrated by FAP-expressing RASFs and marked by a significantly higher accumulation of MMP-1 and MMP-3, when compared with controls. Conclusion Our results indicate a central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in RA. | ||
| 700 | 1 | |a Mertens, Joachim C. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Jüngel, Astrid |e VerfasserIn |4 aut | |
| 700 | 1 | |a Brentano, Fabia |e VerfasserIn |4 aut | |
| 700 | 1 | |a Maciejewska-Rodriguez, Hanna |e VerfasserIn |4 aut | |
| 700 | 1 | |a Huber, Lars C. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hemmatazad, Hossein |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wüest, Thomas |e VerfasserIn |4 aut | |
| 700 | 1 | |a Knuth, Alexander |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gay, Renate E. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Michel, Beat A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gay, Steffen |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Bauer, Stefan |e VerfasserIn |0 (DE-588)1293178306 |0 (DE-627)1850504075 |4 aut | |
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