Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts

• Verfasst von: Ospelt, Caroline [VerfasserIn]
• Verfasst von: Mertens, Joachim C. [VerfasserIn]
• Verfasst von: Jüngel, Astrid [VerfasserIn]
• Verfasst von: Brentano, Fabia [VerfasserIn]
• Verfasst von: Maciejewska-Rodriguez, Hanna [VerfasserIn]
• Verfasst von: Huber, Lars C. [VerfasserIn]
• Verfasst von: Hemmatazad, Hossein [VerfasserIn]
• Verfasst von: Wüest, Thomas [VerfasserIn]
• Verfasst von: Knuth, Alexander [VerfasserIn]
• Verfasst von: Gay, Renate E. [VerfasserIn]
• Verfasst von: Michel, Beat A. [VerfasserIn]
• Verfasst von: Gay, Steffen [VerfasserIn]
• Verfasst von: Renner, Christoph [VerfasserIn]
• Verfasst von: Bauer, Stefan [VerfasserIn]
• Titel: Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts
• Verf.angabe: 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
• E-Jahr: 2010
• Jahr: 29 April 2010
• Umfang: 12 S.
• Fussnoten: Gesehen am 19.06.2023
• Titel Quelle: Enthalten in: Arthritis & rheumatism
• Ort Quelle: Hoboken, NJ : Wiley-Blackwell, 1958
• Jahr Quelle: 2010
• Band/Heft Quelle: 62(2010), 5 vom: Mai, Seite 1224-1235
• ISSN Quelle: 1529-0131
• DOI: doi:10.1002/art.27395
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1850501734

Abstract

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.