Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Pharmacology
  4. Volume 17, Issue 1
  5. Article
Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

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.

© 2024 The Author(s). Published by Bentham Open.
© 2024 The Author(s). Published by Bentham Open. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmp/10.2174/0118761429261684231002062505
2024-01-01
2025-01-23

  • From This Site

    /content/journals/cmp/10.2174/0118761429261684231002062505
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmp/17/1/CMP-17-E18761429261684.html?itemId=/content/journals/cmp/10.2174/0118761429261684231002062505&mimeType=html&fmt=ahah

References

  1. NygaardG. FiresteinG.S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes.Nat. Rev. Rheumatol.202016631633310.1038/s41584‑020‑0413‑532393826
     [Google Scholar]
  2. McInnesI.B. SchettG. Cytokines in the pathogenesis of rheumatoid arthritis.Nat. Rev. Immunol.20077642944210.1038/nri209417525752
     [Google Scholar]
  3. BartokB. FiresteinG.S. Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis.Immunol. Rev.2010233123325510.1111/j.0105‑2896.2009.00859.x20193003
     [Google Scholar]
  4. PerlmanH. PopeR.M. The synovial lining micromass system: Toward rheumatoid arthritis in a dish?Arthritis Rheum.201062364364610.1002/art.2729720187157
     [Google Scholar]
  5. Müller-LadnerU. OspeltC. GayS. DistlerO. PapT. Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts.Arthritis Res. Ther.20079622310.1186/ar233718177509
     [Google Scholar]
  6. MateenS. ZafarA. MoinS. KhanA.Q. ZubairS. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.Clin. Chim. Acta201645516117110.1016/j.cca.2016.02.01026883280
     [Google Scholar]
  7. ZwerinaJ. RedlichK. SchettG. SmolenJ.S. Pathogenesis of rheumatoid arthritis: Targeting cytokines.Ann. N. Y. Acad. Sci.20051051171672910.1196/annals.1361.11616127012
     [Google Scholar]
  8. SuzukiM. TetsukaT. YoshidaS. WatanabeN. KobayashiM. MatsuiN. OkamotoT. 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.20004651232710.1016/S0014‑5793(99)01717‑210620700
     [Google Scholar]
  9. MalikS. SuchalK. KhanS.I. BhatiaJ. KishoreK. DindaA.K. AryaD.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.20173132F414F42210.1152/ajprenal.00393.201628566504
     [Google Scholar]
  10. KhansaiM. PhitakT. KlangjorhorJ. UdomrakS. FanhchaksaiK. PothacharoenP. KongtawelertP. 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.201717153210.1186/s12906‑017‑2035‑229237438
     [Google Scholar]
  11. GuanY. ZhaoX. LiuW. WangY. 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.202015148410.1186/s13018‑020‑02004‑x33087158
     [Google Scholar]
  12. NiuX. SongH. XiaoX. YangY. HuangQ. YuJ. YuJ. LiuY. HanT. ZhangD. LiW. Tectoridin ameliorates proliferation and inflammation in TNF-α-induced HFLS-RA cells via suppressing the TLR4/NLRP3/NF-κB signaling pathway.Tissue Cell20227710182610.1016/j.tice.2022.10182635623305
     [Google Scholar]
  13. ManabeN. OdaH. NakamuraK. KugaY. UchidaS. KawaguchiH. Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients.Rheumatology199938871472010.1093/rheumatology/38.8.71410501417
     [Google Scholar]
  14. NakanishiY. AkiyamaN. TsukaguchiT. FujiiT. SatohY. IshiiN. AokiM. Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1.Mol. Cancer Ther.201514370471210.1158/1535‑7163.MCT‑14‑0927‑T25589496
     [Google Scholar]
  15. LeeC.J. MoonS.J. JeongJ.H. LeeS. LeeM.H. YooS.M. LeeH.S. KangH.C. LeeJ.Y. LeeW.S. LeeH.J. KimE.K. JhunJ.Y. ChoM.L. MinJ.K. ChoY.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.20189340110.1038/s41419‑018‑0433‑029540697
     [Google Scholar]
  16. ChenJ. YuC. ZhaoY. NiuY. ZhangL. YuY. WuJ. HeJ. 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.20179189289910.1016/j.bios.2016.10.06727836589
     [Google Scholar]
  17. LiF. HuynhH. LiX. RuddyD.A. WangY. OngR. ChowP. QiuS. TamA. RakiecD.P. SchlegelR. MonahanJ.E. HuangA. FGFR-mediated reactivation of MAPK signaling attenuates antitumor effects of Imatinib in gastrointestinal stromal tumors.Cancer Discov.20155443845110.1158/2159‑8290.CD‑14‑076325673643
     [Google Scholar]
  18. HardingM.J. NechiporukA.V. Fgfr-Ras-MAPK signaling is required for apical constriction via apical positioning of Rho-associated kinase during mechanosensory organ formation.Development2012139173130313510.1242/dev.08227122833124
     [Google Scholar]
  19. TanY.Y. ZhouH.Q. LinY.J. YiL.T. ChenZ.G. CaoQ.D. GuoY.R. WangZ.N. ChenS.D. LiY. WangD.Y. QiaoY.K. YanY. FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells.Mil. Med. Res.202291710.1186/s40779‑022‑00366‑335093168
     [Google Scholar]
  20. ZvaiflerN.J. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases.Arthritis Res. Ther.20068321010.1186/ar196316689999
     [Google Scholar]
  21. EkwallA.K.H. EislerT. AnderbergC. JinC. KarlssonN. BrisslertM. BokarewaM.I. The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis.Arthritis Res. Ther.2011132R4010.1186/ar327421385358
     [Google Scholar]
  22. SteenvoordenM.M.C. TolboomT.C.A. van der PluijmG. LöwikC. VisserC.P.J. DeGrootJ. Gittenberger-DeGrootA.C. DeRuiterM.C. WisseB.J. HuizingaT.W.J. ToesR.E.M. Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics.Arthritis Res. Ther.200686R16510.1186/ar207317076892
     [Google Scholar]
  23. LiG.Q. ZhangY. LiuD. QianY.Y. ZhangH. GuoS.Y. SunagawaM. HisamitsuT. LiuY.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.20133721-222123110.1007/s11010‑012‑1463‑z23001847
     [Google Scholar]
  24. LefèvreS. KnedlaA. TennieC. KampmannA. WunrauC. DinserR. KorbA. SchnäkerE.M. TarnerI.H. RobbinsP.D. EvansC.H. StürzH. SteinmeyerJ. GayS. SchölmerichJ. PapT. Müller-LadnerU. NeumannE. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.Nat. Med.200915121414142010.1038/nm.205019898488
     [Google Scholar]
  25. LiL. ZhangS. LiH. ChouH. FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR.BMC Cancer201919196397410.1186/s12885‑019‑6161‑831619201
     [Google Scholar]
  26. KatohM. NakagamaH. FGF receptors: Cancer biology and therapeutics.Med. Res. Rev.201434228030010.1002/med.2128823696246
     [Google Scholar]
  27. LiY. LiuX. ZhangH. JiangT. XiaoW. ZhaoS. YuX. HanF. FGFR3 silencing by siRNA inhibits invasion of A549 cells.Oncol. Lett.20161264319432610.3892/ol.2016.527828105147
     [Google Scholar]
  28. ZuB. LiuL. WangJ. LiM. YangJ. MiR-140-3p inhibits the cell viability and promotes apoptosis of synovial fibroblasts in rheumatoid arthritis through targeting sirtuin 3.J. Orthop. Surg. Res.202116110510.1186/s13018‑021‑02236‑533530998
     [Google Scholar]
  29. QuW. JiangL. HouG. Circ-AFF2/miR-650/CNP axis promotes proliferation, inflammatory response, migration, and invasion of rheumatoid arthritis synovial fibroblasts.J. Orthop. Surg. Res.202116116510.1186/s13018‑021‑02306‑833653372
     [Google Scholar]
  30. ChungY.H. HuangY.H. ChuT.H. ChenC.L. LinP.R. HuangS.C. WuD.C. HuangC.C. HuT.H. KaoY.H. TaiM.H. BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling.Lab. Invest.2018988999101310.1038/s41374‑018‑0069‑929789683
     [Google Scholar]
  31. ChungY.H. ChengY.T. KaoY.H. TsaiW.C. HuangG.K. ChenY.T. ShenY.C. TaiM.H. ChiangP.H. MiR-26a-5p as a useful therapeutic target for upper tract urothelial carcinoma by regulating WNT5A/β-catenin signaling.Sci. Rep.2022121695510.1038/s41598‑022‑08091‑635484165
     [Google Scholar]
  32. HuangG.K. HuangC.C. KangC.H. ChengY.T. TsaiP.C. KaoY.H. ChungY.H. Genetic interference of FGFR3 impedes invasion of upper tract urothelial carcinoma cells by alleviating RAS/MAPK signal activity.Int. J. Mol. Sci.2023242177610.3390/ijms2402177636675289
     [Google Scholar]
  33. McNearneyT.A. MaY. ChenY. TaglialatelaG. YinH. ZhangW.R. WestlundK.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.20102983R584R59810.1152/ajpregu.00452.200920007519
     [Google Scholar]
  34. WięcekK. KupczykP. ChodaczekG. WoźniakM. The impact of curcumin on the inflammatory profile of SW982 cells in a rheumatoid arthritis model.J. Immunol. Res.2022202211010.1155/2022/120897035450396
     [Google Scholar]
  35. KongdangP. JaithamR. ThonghoiS. KuensaenC. PraditW. OngchaiS. Ethanolic extract of Kaempferia parviflora interrupts the mechanisms-associated rheumatoid arthritis in SW982 culture model via p38/STAT1 and STAT3 pathways.Phytomedicine20195915275510.1016/j.phymed.2018.11.01531005814
     [Google Scholar]
  36. LiuZ. ZhangD. SunC. TaoR. XuX. XuL. ChengH. XiaoM. WangY. KPNA2 contributes to the inflammatory processes in synovial tissue of patients with rheumatoid arthritis and SW982 cells.Inflammation20153862224223410.1007/s10753‑015‑0205‑226135850
     [Google Scholar]
  37. ChangJ.H. LeeK.J. KimS.K. YooD.H. KangT.Y. Validity of SW982 synovial cell line for studying the drugs against rheumatoid arthritis in fluvastatin-induced apoptosis signaling model.Indian J. Med. Res.2014139111712424604047
     [Google Scholar]
  38. ZhouL. YaoL.T. LiangZ.Y. ZhouW.X. YouL. ShaoQ.Q. HuangS. GuoJ.C. ZhaoY.P. Nuclear translocation of fibroblast growth factor receptor 3 and its significance in pancreatic cancer.Int. J. Clin. Exp. Pathol.2015811146401464826823787
     [Google Scholar]
  39. ZhaoY. SunX. LinJ. ZhangT. LiuS. YanZ. Panaxynol induces fibroblast-like synovial cell apoptosis, inhibits proliferation and invasion through TLR4/NF-kappaB pathway to alleviate rheumatoid arthritis.Int. Immunopharmacol.2021101(Pt A)108321
     [Google Scholar]
  40. ZhangQ. DuanH.X. LiR.L. SunJ.Y. LiuJ. PengW. WuC.J. GaoY.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.20211421723610.2147/JIR.S28724233542641
     [Google Scholar]
  41. WuS. JiangY. TengY. LiuX. ZhouL. LiW. Interleukin-33 promotes proliferation and inhibits apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis.Clin. Exp. Rheumatol.202139484485110.55563/clinexprheumatol/htpmp033124566
     [Google Scholar]
  42. AriiK. KumonY. IkedaY. SuehiroT. HashimotoK. Edaravone inhibits rheumatoid synovial cell proliferation and migration.Free Radic. Res.200640212112510.1080/1071576050040111616390820
     [Google Scholar]
  43. QinS. SunD. LiH. LiX. PanW. YanC. TangR. LiuX. The effect of SHH-Gli signaling pathway on the synovial fibroblast proliferation in rheumatoid arthritis.Inflammation201639250351210.1007/s10753‑015‑0273‑326552406
     [Google Scholar]
  44. ChenY.C. ChiuW.C. ChengT.T. LaiH.M. YuS.F. SuB.Y.J. HsuC.Y. KoC.H. ChenJ.F. Delayed anti-TNF therapy increases the risk of total knee replacement in patients with severe rheumatoid arthritis.BMC Musculoskelet. Disord.201718132610.1186/s12891‑017‑1685‑z28764690
     [Google Scholar]
  45. ChenY.C. KoC.H. ChenJ.F. HsuC.Y. ChiuW.C. ChengT.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.201720171710.1155/2017/165839729104376
     [Google Scholar]
  46. KurthT. HennekensC.H. BuringJ.E. GazianoJ.M. Aspirin, NSAIDs, and COX-2 inhibitors in cardiovascular disease: Possible interactions and implications for treatment of rheumatoid arthritis.Curr. Rheumatol. Rep.20046535135610.1007/s11926‑004‑0009‑015355747
     [Google Scholar]
  47. SundyJ.S. COX-2 inhibitors in rheumatoid arthritis.Curr. Rheumatol. Rep.200131869110.1007/s11926‑001‑0055‑911177775
     [Google Scholar]
  48. ChangN.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.2000267119420010.1006/bbrc.1999.190910623598
     [Google Scholar]
  49. KimW.J. KangY.J. KohE.M. AhnK.S. ChaH.S. LeeW.H. LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of pro-inflammatory cytokines and MMP-9 in macrophages.Immunology2005114227227910.1111/j.1365‑2567.2004.02004.x15667572
     [Google Scholar]
  50. Varela-ReyM. Montiel-DuarteC. Osés-PrietoJ.A. López-ZabalzaM.J. JaffrèzouJ.P. RojkindM. IraburuM.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.20025281-313313810.1016/S0014‑5793(02)03276‑312297293
     [Google Scholar]
  51. DuH. ZhangX. ZengY. HuangX. ChenH. WangS. WuJ. LiQ. ZhuW. LiH. LiuT. YuQ. WuY. JieL. 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.2019101620163210.3389/fimmu.2019.0162031396207
     [Google Scholar]
/content/journals/cmp/10.2174/0118761429261684231002062505
Loading
Targeting FGFR3 is a Useful Therapeutic Strategy for Rheumatoid Arthritis Treatment
Curr Mol Pharmacol 17, E18761429261684 (2024); https://doi.org/10.2174/0118761429261684231002062505
/content/journals/cmp/10.2174/0118761429261684231002062505
/content/journals/cmp/10.2174/0118761429261684231002062505
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Epithelial-mesenchymal transition; FGFR3; Inflammation; Rheumatoid arthritis; Synoviocytes; TNF-α

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test