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

2010 ◽  
Vol 62 (5) ◽  
pp. 1224-1235 ◽  
Author(s):  
Caroline Ospelt ◽  
Joachim C. Mertens ◽  
Astrid Jüngel ◽  
Fabia Brentano ◽  
Hanna Maciejewska-Rodriguez ◽  
...  
Rheumatology ◽  
2021 ◽  
Author(s):  
Daphne N Dorst ◽  
Mark Rijpkema ◽  
Mijke Buitinga ◽  
Birgitte Walgreen ◽  
Monique M A Helsen ◽  
...  

Abstract Objective Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.


2016 ◽  
Vol 21 (11) ◽  
pp. 1915-1923 ◽  
Author(s):  
Premarani Sinnathurai ◽  
Wendy Lau ◽  
Ana Julia Vieira de Ribeiro ◽  
William W. Bachovchin ◽  
Helen Englert ◽  
...  

2015 ◽  
Vol 56 (5) ◽  
pp. 778-783 ◽  
Author(s):  
P. Laverman ◽  
T. van der Geest ◽  
S. Y. A. Terry ◽  
D. Gerrits ◽  
B. Walgreen ◽  
...  

2011 ◽  
Vol 63 (2) ◽  
pp. 373-381 ◽  
Author(s):  
Joanna Stanczyk ◽  
Caroline Ospelt ◽  
Emmanuel Karouzakis ◽  
Andrew Filer ◽  
Karim Raza ◽  
...  

Author(s):  
Mohammad Javad Mousavi ◽  
Elham Farhadi ◽  
Mohammad Vodjgani ◽  
Jafar Karami ◽  
Mohammad Naghi Tahmasebi ◽  
...  

Fibroblast-like synoviocytes (FLSs) have been introduced in recent years as a key player in the pathogenesis of rheumatoid arthritis (RA), but the exact mechanisms of their transformation and intracellular pathways have not yet been determined. This study aimed to investigate the role of fibroblast activation protein-alpha (FAP-α) in the regulation of genes involved in the transformation and pathogenic activity of RA FLSs. Synovial FLSs were isolated from RA patients and non-arthritic individuals (n=10 in both groups) and characterized; using immunocytochemistry and flow cytometry analysis. FLSs were divided into un-treated and Talabostat-treated groups to evaluate the FAP-α effect on the selected genes involved in cell cycle regulation (p21, p53, CCND1), apoptosis (Bcl-2, PUMA), and inflammatory and destructive behavior of FLSs (IL-6, TGF-β1, MMP-2, MMP-9, P2RX7). Gene expression analysis was performed by quantitative real-time polymerase chain reaction (qRTPCR), and immunoblotting was carried out to evaluate FAP-α protein levels. The basal level of FAP-α protein in RA patients was significantly higher than non-arthritic control individuals. However, no differences were observed between RA and non-arthritic FLSs, at the baseline mRNA levels of all the genes. Talabostat treatment significantly reduced FAPα protein levels in both RA and non-arthritic FLSs, however, had no effect on mRNA expressions except an upregulated TGF-β1 expression in non-arthritic FLSs. A significantly higher protein level of FAP-α in FLSs of RA patients compared with that of healthy individuals may point to the pathogenic role of this protein in RA FLSs. However, more investigations are necessary to address the mechanisms mediating the FAP-α pathogenic role in RA FLSs.


Sign in / Sign up

Export Citation Format

Share Document