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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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Main Authors: Ospelt, Caroline (Author) , Mertens, Joachim C. (Author) , Jüngel, Astrid (Author) , Brentano, Fabia (Author) , Maciejewska-Rodriguez, Hanna (Author) , Huber, Lars C. (Author) , Hemmatazad, Hossein (Author) , Wüest, Thomas (Author) , Knuth, Alexander (Author) , Gay, Renate E. (Author) , Michel, Beat A. (Author) , Gay, Steffen (Author) , Renner, Christoph (Author) , Bauer, Stefan (Author)
Format: Article (Journal)
Language:English
Published: 29 April 2010
In: Arthritis & rheumatism
Year: 2010, Volume: 62, Issue: 5, Pages: 1224-1235
ISSN:1529-0131
DOI:10.1002/art.27395
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 19.06.2023
Physical Description:Online Resource
ISSN:1529-0131
DOI:10.1002/art.27395

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