Role of Fibroblast Activation Protein Alpha in Fibroblast-like Synoviocytes of Rheumatoid Arthritis
Fibroblast Activation Protein Alpha in Rheumatoid Arthritis
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 (qRT-PCR), 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 FAP-α 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.
2. Christodoulou C, Choy EH. Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clin Exp Med. 2006;6(1):13-9.
3. Yoshitomi H. Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes. Front Immunol. 2019;10:1395.
4. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233-55.
5. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 2013;9(1):24-33.
6. Karami J, Aslani S, Tahmasebi MN, Mousavi MJ, Sharafat Vaziri A, Jamshidi A, et al. Epigenetics in rheumatoid arthritis; fibroblast-like synoviocytes as an emerging paradigm in the pathogenesis of the disease. Immunol Cell Biol. 2020;98(3):171-86.
7. Giorello MB, Borzone FR, Labovsky V, Piccioni FV, Chasseing NA. Cancer-Associated Fibroblasts in the Breast Tumor Microenvironment. J Mammary Gland Biol Neoplasia. 2021.
8. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020.
9. Bauer S, Jendro MC, Wadle A, Kleber S, Stenner F, Dinser R, et al. Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther. 2006;8(6):R171.
10. Waldele S, Koers-Wunrau C, Beckmann D, Korb-Pap A, Wehmeyer C, Pap T, et al. Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis. Arthritis Res Ther. 2015;17:12.
11. Higashino N, Koma YI, Hosono M, Takase N, Okamoto M, Kodaira H, et al. Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma. Lab Invest. 2019;99(6):777-92.
12. Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis. 2014;5:e1155.
13. Huang Y, Simms AE, Mazur A, Wang S, Leon NR, Jones B, et al. Fibroblast activation protein-alpha promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis. 2011;28(6):567-79.
14. Ha SY, Yeo SY, Xuan YH, Kim SH. The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS One. 2014;9(6):e99955.
15. Liao Y, Ni Y, He R, Liu W, Du J. Clinical implications of fibroblast activation protein-alpha in non-small cell lung cancer after curative resection: a new predictor for prognosis. J Cancer Res Clin Oncol. 2013;139(9):1523-8.
16. Narra K, Mullins SR, Lee HO, Strzemkowski-Brun B, Magalong K, Christiansen VJ, et al. Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer. Cancer Biol Ther. 2007;6(11):1691-9.
17. Poplawski SE, Lai JH, Sanford DG, Sudmeier JL, Wu W, Bachovchin WW. Pro-soft Val-boroPro: a strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases. J Med Chem. 2011;54(7):2022-8.
18. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.
19. Muz B, Larsen H, Madden L, Kiriakidis S, Paleolog EM. Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis. Arthritis Rheum. 2012;64(9):2856-67.
20. Rosengren S, Boyle DL, Firestein GS. Acquisition, culture, and phenotyping of synovial fibroblasts. Methods Mol Med. 2007;135:365-75.
21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
22. Okondo MC, Rao SD, Taabazuing CY, Chui AJ, Poplawski SE, Johnson DC, et al. Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. Cell Chem Biol. 2018;25(3):262-7 e5.
23. Okondo MC, Johnson DC, Sridharan R, Go EB, Chui AJ, Wang MS, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017;13(1):46-53.
24. Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017;46(2):183-96.
25. Bhattaram P, Chandrasekharan U. The joint synovium: A critical determinant of articular cartilage fate in inflammatory joint diseases. Semin Cell Dev Biol. 2017;62:86-93.
26. Yoo SA, Park JH, Hwang SH, Oh SM, Lee S, Cicatiello V, et al. Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes. J Immunol. 2015;194(6):2513-21.
27. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. Cancer Res. 2016;76(14):4124-35.
28. Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2(3):187-93.
29. Juillerat-Jeanneret L, Tafelmeyer P, Golshayan D. Fibroblast activation protein-alpha in fibrogenic disorders and cancer: more than a prolyl-specific peptidase? Expert Opin Ther Targets. 2017;21(10):977-91.
30. Rettig WJ, Garin-Chesa P, Beresford HR, Oettgen HF, Melamed MR, Old LJ. Cell-surface glycoproteins of human sarcomas: differential expression in normal and malignant tissues and cultured cells. Proc Natl Acad Sci U S A. 1988;85(9):3110-4.
31. Ospelt C, Mertens JC, Jungel A, Brentano F, Maciejewska-Rodriguez H, Huber LC, et al. Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2010;62(5):1224-35.
32. Egger C, Cannet C, Gerard C, Suply T, Ksiazek I, Jarman E, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017;809:64-72.
33. Koussounadis A, Langdon SP, Um IH, Harrison DJ, Smith VA. Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. Sci Rep. 2015;5:10775.
34. Zhang T, Li H, Shi J, Li S, Li M, Zhang L, et al. p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis. Arthritis Res Ther. 2016;18(1):271.
|Issue||Vol 20 No 3 (2021)|
|Fibroblast activation protein alpha Rheumatoid arthritis Fibroblast-like synoviocytes|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|