Login Register Cart 0
Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Targeting FGFR3 is a Useful Therapeutic Strategy for Rheumatoid Arthritis Treatment

Author(s): Shan-Fu Yu, Tien-Tsai Cheng, Gong-Kai Huang, Chung-Yuan Hsu, Ying-Hsien Kao* and Yueh-Hua Chung

Volume 17, 2024

Published on: 13 October, 2023

Article ID: e18761429261684 Pages: 12

DOI: 10.2174/0118761429261684231002062505

open_access

Open Access Journals Promotions 2
Abstract

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines.

Objective: This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells.

Methods: Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells.

Results: FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9.

Conclusion: Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA.

Keywords: Epithelial-mesenchymal transition, FGFR3, Inflammation, Rheumatoid arthritis, Synoviocytes, TNF-α.

[1]
Nygaard, G.; Firestein, G.S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol., 2020, 16(6), 316-333.
[http://dx.doi.org/10.1038/s41584-020-0413-5] [PMID: 32393826]
[2]
McInnes, I.B.; Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol., 2007, 7(6), 429-442.
[http://dx.doi.org/10.1038/nri2094] [PMID: 17525752]
[3]
Bartok, B.; Firestein, G.S. Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol. Rev., 2010, 233(1), 233-255.
[http://dx.doi.org/10.1111/j.0105-2896.2009.00859.x] [PMID: 20193003]
[4]
Perlman, H.; Pope, R.M. The synovial lining micromass system: Toward rheumatoid arthritis in a dish? Arthritis Rheum., 2010, 62(3), 643-646.
[http://dx.doi.org/10.1002/art.27297] [PMID: 20187157]
[5]
Müller-Ladner, U.; Ospelt, C.; Gay, S.; Distler, O.; Pap, T. Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts. Arthritis Res. Ther., 2007, 9(6), 223.
[http://dx.doi.org/10.1186/ar2337] [PMID: 18177509]
[6]
Mateen, S.; Zafar, A.; Moin, S.; Khan, A.Q.; Zubair, S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin. Chim. Acta, 2016, 455, 161-171.
[http://dx.doi.org/10.1016/j.cca.2016.02.010] [PMID: 26883280]
[7]
Zwerina, J.; Redlich, K.; Schett, G.; Smolen, J.S. Pathogenesis of rheumatoid arthritis: Targeting cytokines. Ann. N. Y. Acad. Sci., 2005, 1051(1), 716-729.
[http://dx.doi.org/10.1196/annals.1361.116] [PMID: 16127012]
[8]
Suzuki, M.; Tetsuka, T.; Yoshida, S.; Watanabe, N.; Kobayashi, M.; Matsui, N.; Okamoto, T. The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-α- or IL-1β-stimulated rheumatoid synovial fibroblasts. FEBS Lett., 2000, 465(1), 23-27.
[http://dx.doi.org/10.1016/S0014-5793(99)01717-2] [PMID: 10620700]
[9]
Malik, S.; Suchal, K.; Khan, S.I.; Bhatia, J.; Kishore, K.; Dinda, A.K.; Arya, D.S. Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am. J. Physiol. Renal Physiol., 2017, 313(2), F414-F422.
[http://dx.doi.org/10.1152/ajprenal.00393.2016] [PMID: 28566504]
[10]
Khansai, M.; Phitak, T.; Klangjorhor, J.; Udomrak, S.; Fanhchaksai, K.; Pothacharoen, P.; Kongtawelert, P. Effects of sesamin on primary human synovial fibroblasts and SW982 cell line induced by tumor necrosis factor-alpha as a synovitis-like model. BMC Complement. Altern. Med., 2017, 17(1), 532.
[http://dx.doi.org/10.1186/s12906-017-2035-2] [PMID: 29237438]
[11]
Guan, Y.; Zhao, X.; Liu, W.; Wang, Y. Galuteolin suppresses proliferation and inflammation in TNF-α-induced RA-FLS cells by activating HMOX1 to regulate IKKβ/NF-κB pathway. J. Orthop. Surg. Res., 2020, 15(1), 484.
[http://dx.doi.org/10.1186/s13018-020-02004-x] [PMID: 33087158]
[12]
Niu, X.; Song, H.; Xiao, X.; Yang, Y.; Huang, Q.; Yu, J.; Yu, J.; Liu, Y.; Han, T.; Zhang, D.; Li, W. Tectoridin ameliorates proliferation and inflammation in TNF-α-induced HFLS-RA cells via suppressing the TLR4/NLRP3/NF-κB signaling pathway. Tissue Cell, 2022, 77, 101826.
[http://dx.doi.org/10.1016/j.tice.2022.101826] [PMID: 35623305]
[13]
Manabe, N.; Oda, H.; Nakamura, K.; Kuga, Y.; Uchida, S.; Kawaguchi, H. Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients. Rheumatology, 1999, 38(8), 714-720.
[http://dx.doi.org/10.1093/rheumatology/38.8.714] [PMID: 10501417]
[14]
Nakanishi, Y.; Akiyama, N.; Tsukaguchi, T.; Fujii, T.; Satoh, Y.; Ishii, N.; Aoki, M. Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1. Mol. Cancer Ther., 2015, 14(3), 704-712.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0927-T] [PMID: 25589496]
[15]
Lee, C.J.; Moon, S.J.; Jeong, J.H.; Lee, S.; Lee, M.H.; Yoo, S.M.; Lee, H.S.; Kang, H.C.; Lee, J.Y.; Lee, W.S.; Lee, H.J.; Kim, E.K.; Jhun, J.Y.; Cho, M.L.; Min, J.K.; Cho, Y.Y. Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis. Cell Death Dis., 2018, 9(3), 401.
[http://dx.doi.org/10.1038/s41419-018-0433-0] [PMID: 29540697]
[16]
Chen, J.; Yu, C.; Zhao, Y.; Niu, Y.; Zhang, L.; Yu, Y.; Wu, J.; He, J. A novel non-invasive detection method for the FGFR3 gene mutation in maternal plasma for a fetal achondroplasia diagnosis based on signal amplification by hemin-MOFs/PtNPs. Biosens. Bioelectron., 2017, 91, 892-899.
[http://dx.doi.org/10.1016/j.bios.2016.10.067] [PMID: 27836589]
[17]
Li, F.; Huynh, H.; Li, X.; Ruddy, D.A.; Wang, Y.; Ong, R.; Chow, P.; Qiu, S.; Tam, A.; Rakiec, D.P.; Schlegel, R.; Monahan, J.E.; Huang, A. FGFR-mediated reactivation of MAPK signaling attenuates antitumor effects of Imatinib in gastrointestinal stromal tumors. Cancer Discov., 2015, 5(4), 438-451.
[http://dx.doi.org/10.1158/2159-8290.CD-14-0763] [PMID: 25673643]
[18]
Harding, M.J.; Nechiporuk, A.V. Fgfr-Ras-MAPK signaling is required for apical constriction via apical positioning of Rho-associated kinase during mechanosensory organ formation. Development, 2012, 139(17), 3130-3135.
[http://dx.doi.org/10.1242/dev.082271] [PMID: 22833124]
[19]
Tan, Y.Y.; Zhou, H.Q.; Lin, Y.J.; Yi, L.T.; Chen, Z.G.; Cao, Q.D.; Guo, Y.R.; Wang, Z.N.; Chen, S.D.; Li, Y.; Wang, D.Y.; Qiao, Y.K.; Yan, Y. FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells. Mil. Med. Res., 2022, 9(1), 7.
[http://dx.doi.org/10.1186/s40779-022-00366-3] [PMID: 35093168]
[20]
Zvaifler, N.J. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res. Ther., 2006, 8(3), 210.
[http://dx.doi.org/10.1186/ar1963] [PMID: 16689999]
[21]
Ekwall, A.K.H.; Eisler, T.; Anderberg, C.; Jin, C.; Karlsson, N.; Brisslert, M.; Bokarewa, M.I. The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis. Arthritis Res. Ther., 2011, 13(2), R40.
[http://dx.doi.org/10.1186/ar3274] [PMID: 21385358]
[22]
Steenvoorden, M.M.C.; Tolboom, T.C.A.; van der Pluijm, G.; Löwik, C.; Visser, C.P.J.; DeGroot, J.; Gittenberger-DeGroot, A.C.; DeRuiter, M.C.; Wisse, B.J.; Huizinga, T.W.J.; Toes, R.E.M. Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics. Arthritis Res. Ther., 2006, 8(6), R165.
[http://dx.doi.org/10.1186/ar2073] [PMID: 17076892]
[23]
Li, G.Q.; Zhang, Y.; Liu, D.; Qian, Y.Y.; Zhang, H.; Guo, S.Y.; Sunagawa, M.; Hisamitsu, T.; Liu, Y.Q. PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial–mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol. Cell. Biochem., 2013, 372(1-2), 221-231.
[http://dx.doi.org/10.1007/s11010-012-1463-z] [PMID: 23001847]
[24]
Lefèvre, S.; Knedla, A.; Tennie, C.; Kampmann, A.; Wunrau, C.; Dinser, R.; Korb, A.; Schnäker, E.M.; Tarner, I.H.; Robbins, P.D.; Evans, C.H.; Stürz, H.; Steinmeyer, J.; Gay, S.; Schölmerich, J.; Pap, T.; Müller-Ladner, U.; Neumann, E. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med., 2009, 15(12), 1414-1420.
[http://dx.doi.org/10.1038/nm.2050] [PMID: 19898488]
[25]
Li, L.; Zhang, S.; Li, H.; Chou, H. FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR. BMC Cancer, 2019, 19(1), 963-974.
[http://dx.doi.org/10.1186/s12885-019-6161-8] [PMID: 31619201]
[26]
Katoh, M.; Nakagama, H. FGF receptors: Cancer biology and therapeutics. Med. Res. Rev., 2014, 34(2), 280-300.
[http://dx.doi.org/10.1002/med.21288] [PMID: 23696246]
[27]
Li, Y.; Liu, X.; Zhang, H.; Jiang, T.; Xiao, W.; Zhao, S.; Yu, X.; Han, F. FGFR3 silencing by siRNA inhibits invasion of A549 cells. Oncol. Lett., 2016, 12(6), 4319-4326.
[http://dx.doi.org/10.3892/ol.2016.5278] [PMID: 28105147]
[28]
Zu, B.; Liu, L.; Wang, J.; Li, M.; Yang, J. MiR-140-3p inhibits the cell viability and promotes apoptosis of synovial fibroblasts in rheumatoid arthritis through targeting sirtuin 3. J. Orthop. Surg. Res., 2021, 16(1), 105.
[http://dx.doi.org/10.1186/s13018-021-02236-5] [PMID: 33530998]
[29]
Qu, W.; Jiang, L.; Hou, G. Circ-AFF2/miR-650/CNP axis promotes proliferation, inflammatory response, migration, and invasion of rheumatoid arthritis synovial fibroblasts. J. Orthop. Surg. Res., 2021, 16(1), 165.
[http://dx.doi.org/10.1186/s13018-021-02306-8] [PMID: 33653372]
[30]
Chung, Y.H.; Huang, Y.H.; Chu, T.H.; Chen, C.L.; Lin, P.R.; Huang, S.C.; Wu, D.C.; Huang, C.C.; Hu, T.H.; Kao, Y.H.; Tai, M.H. BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling. Lab. Invest., 2018, 98(8), 999-1013.
[http://dx.doi.org/10.1038/s41374-018-0069-9] [PMID: 29789683]
[31]
Chung, Y.H.; Cheng, Y.T.; Kao, Y.H.; Tsai, W.C.; Huang, G.K.; Chen, Y.T.; Shen, Y.C.; Tai, M.H.; Chiang, P.H. MiR-26a-5p as a useful therapeutic target for upper tract urothelial carcinoma by regulating WNT5A/β-catenin signaling. Sci. Rep., 2022, 12(1), 6955.
[http://dx.doi.org/10.1038/s41598-022-08091-6] [PMID: 35484165]
[32]
Huang, G.K.; Huang, C.C.; Kang, C.H.; Cheng, Y.T.; Tsai, P.C.; Kao, Y.H.; Chung, Y.H. Genetic interference of FGFR3 impedes invasion of upper tract urothelial carcinoma cells by alleviating RAS/MAPK signal activity. Int. J. Mol. Sci., 2023, 24(2), 1776.
[http://dx.doi.org/10.3390/ijms24021776] [PMID: 36675289]
[33]
McNearney, T.A.; Ma, Y.; Chen, Y.; Taglialatela, G.; Yin, H.; Zhang, W.R.; Westlund, K.N. A peripheral neuroimmune link: Glutamate agonists upregulate NMDA NR1 receptor mRNA and protein, vimentin, TNF-α, and RANTES in cultured human synoviocytes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2010, 298(3), R584-R598.
[http://dx.doi.org/10.1152/ajpregu.00452.2009] [PMID: 20007519]
[34]
Więcek, K.; Kupczyk, P.; Chodaczek, G.; Woźniak, M. The impact of curcumin on the inflammatory profile of SW982 cells in a rheumatoid arthritis model. J. Immunol. Res., 2022, 2022, 1-10.
[http://dx.doi.org/10.1155/2022/1208970] [PMID: 35450396]
[35]
Kongdang, P.; Jaitham, R.; Thonghoi, S.; Kuensaen, C.; Pradit, W.; Ongchai, S. Ethanolic extract of Kaempferia parviflora interrupts the mechanisms-associated rheumatoid arthritis in SW982 culture model via p38/STAT1 and STAT3 pathways. Phytomedicine, 2019, 59, 152755.
[http://dx.doi.org/10.1016/j.phymed.2018.11.015] [PMID: 31005814]
[36]
Liu, Z.; Zhang, D.; Sun, C.; Tao, R.; Xu, X.; Xu, L.; Cheng, H.; Xiao, M.; Wang, Y. KPNA2 contributes to the inflammatory processes in synovial tissue of patients with rheumatoid arthritis and SW982 cells. Inflammation, 2015, 38(6), 2224-2234.
[http://dx.doi.org/10.1007/s10753-015-0205-2] [PMID: 26135850]
[37]
Chang, J.H.; Lee, K.J.; Kim, S.K.; Yoo, D.H.; Kang, T.Y. Validity of SW982 synovial cell line for studying the drugs against rheumatoid arthritis in fluvastatin-induced apoptosis signaling model. Indian J. Med. Res., 2014, 139(1), 117-124.
[PMID: 24604047]
[38]
Zhou, L.; Yao, L.T.; Liang, Z.Y.; Zhou, W.X.; You, L.; Shao, Q.Q.; Huang, S.; Guo, J.C.; Zhao, Y.P. Nuclear translocation of fibroblast growth factor receptor 3 and its significance in pancreatic cancer. Int. J. Clin. Exp. Pathol., 2015, 8(11), 14640-14648.
[PMID: 26823787]
[39]
Zhao, Y.; Sun, X.; Lin, J.; Zhang, T.; Liu, S.; Yan, Z. Panaxynol induces fibroblast-like synovial cell apoptosis, inhibits proliferation and invasion through TLR4/NF-kappaB pathway to alleviate rheumatoid arthritis. Int. Immunopharmacol., 2021, 101((Pt A)), 108321.
[40]
Zhang, Q.; Duan, H.X.; Li, R.L.; Sun, J.Y.; Liu, J.; Peng, W.; Wu, C.J.; Gao, Y.X. Inducing apoptosis and suppressing inflammatory reactions in synovial fibroblasts are two important ways for Guizhi-Shaoyao-Zhimu decoction against rheumatoid arthritis. J. Inflamm. Res., 2021, 14, 217-236.
[http://dx.doi.org/10.2147/JIR.S287242] [PMID: 33542641]
[41]
Wu, S.; Jiang, Y.; Teng, Y.; Liu, X.; Zhou, L.; Li, W. Interleukin-33 promotes proliferation and inhibits apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis. Clin. Exp. Rheumatol., 2021, 39(4), 844-851.
[http://dx.doi.org/10.55563/clinexprheumatol/htpmp0] [PMID: 33124566]
[42]
Arii, K.; Kumon, Y.; Ikeda, Y.; Suehiro, T.; Hashimoto, K. Edaravone inhibits rheumatoid synovial cell proliferation and migration. Free Radic. Res., 2006, 40(2), 121-125.
[http://dx.doi.org/10.1080/10715760500401116] [PMID: 16390820]
[43]
Qin, S.; Sun, D.; Li, H.; Li, X.; Pan, W.; Yan, C.; Tang, R.; Liu, X. The effect of SHH-Gli signaling pathway on the synovial fibroblast proliferation in rheumatoid arthritis. Inflammation, 2016, 39(2), 503-512.
[http://dx.doi.org/10.1007/s10753-015-0273-3] [PMID: 26552406]
[44]
Chen, Y.C.; Chiu, W.C.; Cheng, T.T.; Lai, H.M.; Yu, S.F.; Su, B.Y.J.; Hsu, C.Y.; Ko, C.H.; Chen, J.F. Delayed anti-TNF therapy increases the risk of total knee replacement in patients with severe rheumatoid arthritis. BMC Musculoskelet. Disord., 2017, 18(1), 326.
[http://dx.doi.org/10.1186/s12891-017-1685-z] [PMID: 28764690]
[45]
Chen, Y.C.; Ko, C.H.; Chen, J.F.; Hsu, C.Y.; Chiu, W.C.; Cheng, T.T. Anti-TNF-alpha-Adalimumab therapy had time lag of improvement in synovial hypertrophy compared to rapid response in power Doppler synovial vascularity. Mediators Inflamm., 2017, 2017, 1-7.
[http://dx.doi.org/10.1155/2017/1658397] [PMID: 29104376]
[46]
Kurth, T.; Hennekens, C.H.; Buring, J.E.; Gaziano, J.M. Aspirin, NSAIDs, and COX-2 inhibitors in cardiovascular disease: Possible interactions and implications for treatment of rheumatoid arthritis. Curr. Rheumatol. Rep., 2004, 6(5), 351-356.
[http://dx.doi.org/10.1007/s11926-004-0009-0] [PMID: 15355747]
[47]
Sundy, J.S. COX-2 inhibitors in rheumatoid arthritis. Curr. Rheumatol. Rep., 2001, 3(1), 86-91.
[http://dx.doi.org/10.1007/s11926-001-0055-9] [PMID: 11177775]
[48]
Chang, N.S. TGF-beta-induced matrix proteins inhibit p42/44 MAPK and JNK activation and suppress TNF-mediated IkappaBalpha degradation and NF-kappaB nuclear translocation in L929 fibroblasts. Biochem. Biophys. Res. Commun., 2000, 267(1), 194-200.
[http://dx.doi.org/10.1006/bbrc.1999.1909] [PMID: 10623598]
[49]
Kim, W.J.; Kang, Y.J.; Koh, E.M.; Ahn, K.S.; Cha, H.S.; Lee, W.H. LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of pro-inflammatory cytokines and MMP-9 in macrophages. Immunology, 2005, 114(2), 272-279.
[http://dx.doi.org/10.1111/j.1365-2567.2004.02004.x] [PMID: 15667572]
[50]
Varela-Rey, M.; Montiel-Duarte, C.; Osés-Prieto, J.A.; López-Zabalza, M.J.; Jaffrèzou, J.P.; Rojkind, M.; Iraburu, M.J. p38 MAPK mediates the regulation of α1(I) procollagen mRNA levels by TNF-α and TGF-β in a cell line of rat hepatic stellate cells. FEBS Lett., 2002, 528(1-3), 133-138.
[http://dx.doi.org/10.1016/S0014-5793(02)03276-3] [PMID: 12297293]
[51]
Du, H.; Zhang, X.; Zeng, Y.; Huang, X.; Chen, H.; Wang, S.; Wu, J.; Li, Q.; Zhu, W.; Li, H.; Liu, T.; Yu, Q.; Wu, Y.; Jie, L. A novel phytochemical, DIM, inhibits proliferation, migration, invasion and TNF-alpha induced inflammatory cytokine production of synovial fibroblasts from rheumatoid arthritis patients by targeting MAPK and AKT/mTOR signal pathway. Front. Immunol., 2019, 10, 1620-1632.
[http://dx.doi.org/10.3389/fimmu.2019.01620] [PMID: 31396207]

Rights & Permissions Print Cite
Article Metrics
33
1
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy