Skip to main content

Advertisement

SpringerLink
Log in

Penta-acetyl Geniposide Suppresses Migration, Invasion, and Inflammation of TNF-α-Stimulated Rheumatoid Arthritis Fibroblast-Like Synoviocytes Involving Wnt/β-Catenin Signaling Pathway

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

We previously reported that penta-acetyl geniposide ((Ac)5GP, an active derivative of geniposide) showed anti-arthritic effect on adjuvant-induced arthritis (AIA) rats by promoting the apoptosis of AIA fibroblast-like synoviocyte (FLS). This study aimed to demonstrate the effects of (Ac)5GP on migration, invasion, and inflammation of TNF-α-stimulated rheumatoid arthritis (RA) FLS (MH7A cell) and to explore the involved mechanisms. MTT assay was used to determine the applied non-cytotoxic doses of (Ac)5GP (12.5, 25, 50 μM) in vitro. Results of wound-healing, transwell, and phalloidin staining assays indicated that (Ac)5GP reduced the migration, invasion, and F-actin cytoskeletal reorganization of TNF-α-stimulated MH7A. Results of ELISA and western blot assays confirmed that (Ac)5GP reduced TNF-α-induced production of pro-inflammatory cytokines (like IL-1β, IL-6, IL-8) and matrix metalloproteinases (MMPs, such as MMP-2 and MMP-9). Moreover, (Ac)5GP inhibited TNF-α-induced activation of Wnt/β-catenin pathway, evidenced by reducing the protein levels of Wnt1, p-GSK-3β (Ser9), and β-catenin and preventing β-catenin nuclear translocation. Importantly, the combination of XAV939 (an inhibitor of Wnt/β-catenin) promoted the actions of (Ac)5GP on TNF-α-induced migration, invasion, and inflammation, further revealing the involvement of Wnt/β-catenin pathway underlying the therapeutic effects of (Ac)5GP on TNF-α-stimulated MH7A. In vivo, (Ac)5GP relieved the progression and severity of rat collagen-induced arthritis, related to reducing the levels of IL-1β, IL-6, IL-8, MMP-2, and MMP-9 as well as inhibiting Wnt/β-catenin pathway in synovial tissues. Collectively, (Ac)5GP could suppress TNF-α-induced migration, invasion, and inflammation in RA FLS involving Wnt/β-catenin pathway and (Ac)5GP might be as a candidate agent for RA treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of Data and Materials

Data are available from the corresponding author on reasonable request.

References

  1. McInnes, I.B., and G. Schett. 2011. The pathogenesis of rheumatoid arthritis. The New England Journal of Medicine 365: 2205–2219.

    Article  CAS  Google Scholar 

  2. Bartok, B., and G.S. Firestein. 2010. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunological Reviews 233: 233–255.

    Article  CAS  Google Scholar 

  3. Mor, A., S.B. Abramson, and M.H. Pillinger. 2005. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clinical Immunology 115: 118–128.

    Article  CAS  Google Scholar 

  4. Christodoulou, C., and E.H. Choy. 2006. Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clinical and Experimental Medicine 6: 13–19.

    Article  CAS  Google Scholar 

  5. Sun, W., R. Qin, R. Qin, R. Wang, D. Ding, Z. Yu, Y. Liu, R. Hong, Z. Cheng, and Y. Wang. 2018. Sam68 promotes invasion, migration, and proliferation of fibroblast-like synoviocytes by enhancing the NF-kappaB/P65 pathway in rheumatoid arthritis. Inflammation 41: 1661–1670.

    Article  CAS  Google Scholar 

  6. Wang, Z., J. Li, J. Zhang, and X. Xie. 2019. Sodium tanshinone IIA sulfonate inhibits proliferation, migration, invasion and inflammation in rheumatoid arthritis fibroblast-like synoviocytes. International Immunopharmacology 73: 370–378.

    Article  CAS  Google Scholar 

  7. Clevers, H., and R. Nusse. 2012. Wnt/beta-catenin signaling and disease. Cell 149: 1192–1205.

    Article  CAS  Google Scholar 

  8. Liu, X.G., Y. Zhang, W.F. Ju, C.Y. Li, and Y.C. Mu. 2019. MiR-21 relieves rheumatoid arthritis in rats via targeting Wnt signaling pathway. European Review for Medical and Pharmacological Sciences 23: 96–103.

    PubMed  Google Scholar 

  9. Rabelo Fde, S., L.M. da Mota, R.A. Lima, F.A. Lima, G.B. Barra, J.F. de Carvalho, and A.A. Amato. 2010. The Wnt signaling pathway and rheumatoid arthritis. Autoimmunity Reviews 9: 207–210.

    Article  Google Scholar 

  10. Lampropoulos, C.E., P. Orfanos, V.K. Bournia, T. Karatsourakis, C. Mavragani, D. Pikazis, M.N. Manoussakis, A.G. Tzioufas, H.M. Moutsopoulos, and P.G. Vlachoyiannopoulos. 2015. Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study. Clinical and Experimental Rheumatology 33: 216–224.

    PubMed  Google Scholar 

  11. Liu, C., L. He, J. Wang, Q. Wang, C. Sun, Y. Li, K. Jia, J. Wang, T. Xu, R. Ming, Q. Wang, and N. Lin. 2020. Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways. Journal of Ethnopharmacology 260: 113039.

    Article  CAS  Google Scholar 

  12. Shan, M., S. Yu, H. Yan, S. Guo, W. Xiao, Z. Wang, L. Zhang, A. Ding, Q. Wu, and S.F.Y. Li. 2017. A review on the phytochemistry, pharmacology, pharmacokinetics and toxicology of geniposide, a natural product. Molecules 22.

  13. Wang, F., J. Cao, J. Hao, and K. Liu. 2014. Pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats. Biopharmaceutics & Drug Disposition 35: 97–103.

    Article  Google Scholar 

  14. Cai, L., Y.R. Mu, M.M. Liu, W.J. Tang, and R. Li. 2020. Antidepressant-like effects of penta-acetyl geniposide in chronic unpredictable mild stress-induced depression rat model: Involvement of inhibiting neuroinflammation in prefrontal cortex and regulating hypothalamic-pituitaryadrenal axis. International Immunopharmacology 80: 106182.

    Article  CAS  Google Scholar 

  15. Zhang, H., T. Shi, J. Wang, R. Li, and W. Tang. 2013. Protective effect of penta-acetyl geniposide on acute liver injury induced by D-galactosamine in mice. British Journal of Pharmacology and Toxicology 4: 256–261.

    Article  Google Scholar 

  16. Cai, L., C.M. Li, W.J. Tang, M.M. Liu, W.N. Chen, Y.Y. Qiu, and R. Li. 2018. Therapeutic effect of penta-acetyl geniposide on adjuvant-induced arthritis in rats: involvement of inducing synovial apoptosis and inhibiting NF-kappaB signal pathway. Inflammation 41: 2184–2195.

    Article  CAS  Google Scholar 

  17. Mu, Y.R., M.Y. Zhou, L. Cai, M.M. Liu, and R. Li. 2020. Overexpression of aquaporin 1 in synovium aggravates rat collagen-induced arthritis through regulating beta-catenin signaling: an in vivo and in vitro study. Journal of Inflamemation Research 13: 701-712.

  18. Wang, Q.T., L.L. Zhang, H.X. Wu, and W. Wei. 2011. The expression change of beta-arrestins in fibroblast-like synoviocytes from rats with collagen-induced arthritis and the effect of total glucosides of paeony. Journal of Ethnopharmacology 133: 511–516.

    Article  CAS  Google Scholar 

  19. Mu, Y.R., L. Cai, M.Y. Zhou, M.M. Liu, Z. Li, and R. Li. 2020. Acetazolamide ameliorates the severity of collagen-induced arthritis in rats: involvement of inducing synovial apoptosis and inhibiting Wnt/beta-catenin pathway. International Immunopharmacology 90: 107214.

    Article  Google Scholar 

  20. Filer, A. 2013. The fibroblast as a therapeutic target in rheumatoid arthritis. Current Opinion in Pharmacology 13: 413–419.

    Article  CAS  Google Scholar 

  21. Feldmann, M., F.M. Brennan, M.J. Elliott, R.O. Williams, and R.N. Maini. 1995. TNF alpha is an effective therapeutic target for rheumatoid arthritis. Annals of the New York Academy of Sciences 766: 272–278.

    Article  CAS  Google Scholar 

  22. Chen, Y., Y. Wang, M. Liu, B. Zhou, and G. Yang. 2020. Diosmetin exhibits anti-proliferative and anti-inflammatory effects on TNF-alpha-stimulated human rheumatoid arthritis fibroblast-like synoviocytes through regulating the Akt and NF-kappaB signaling pathways. Phytotherapy Research 34: 1310–1319.

    Article  CAS  Google Scholar 

  23. Lefevre, S., A. Knedla, C. Tennie, A. Kampmann, C. Wunrau, R. Dinser, A. Korb, E.M. Schnaker, I.H. Tarner, P.D. Robbins, C.H. Evans, H. Sturz, J. Steinmeyer, S. Gay, J. Scholmerich, T. Pap, U. Muller-Ladner, and E. Neumann. 2009. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nature Medicine 15: 1414–1420.

    Article  CAS  Google Scholar 

  24. Karouzakis, E., R.E. Gay, S. Gay, and M. Neidhart. 2009. Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nature Reviews Rheumatology 5: 266–272.

    Article  CAS  Google Scholar 

  25. Chen, Z., W. Liu, Z. Qin, X. Liang, and G. Tian. 2020. Geniposide exhibits anticancer activity to medulloblastoma cells by downregulating microRNA-373. Journal of Biochemical and Molecular Toxicology 34: e22471.

    CAS  PubMed  Google Scholar 

  26. Ma, J., and Y. Ding. 2018. Geniposide suppresses growth, migration and invasion of MKN45 cells by down-regulation of lncRNA HULC. Experimental and Molecular Pathology 105: 252–259.

    Article  CAS  Google Scholar 

  27. Dominguez, R., and K.C. Holmes. 2011. Actin structure and function. Annual Review of Biophysics 40: 169–186.

    Article  CAS  Google Scholar 

  28. Sivalingam, S.P., J. Thumboo, S. Vasoo, S.T. Thio, C. Tse, and K.Y. Fong. 2007. In vivo pro- and anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Annals of the Academy of Medicine, Singapore 36: 96–99.

    PubMed  Google Scholar 

  29. Taneja, V. 2015. Cytokines pre-determined by genetic factors are involved in pathogenesis of rheumatoid arthritis. Cytokine 75: 216–221.

    Article  CAS  Google Scholar 

  30. Abeles, A.M., and M.H. Pillinger. 2006. The role of the synovial fibroblast in rheumatoid arthritis: cartilage destruction and the regulation of matrix metalloproteinases. Bulletin of the NYU Hospital for Joint Diseases 64: 20–24.

    PubMed  Google Scholar 

  31. Burrage, P.S., K.S. Mix, and C.E. Brinckerhoff. 2006. Matrix metalloproteinases: role in arthritis. Frontiers in Bioscience 11: 529–543.

    Article  CAS  Google Scholar 

  32. Jackson, C., M. Nguyen, J. Arkell, and P. Sambrook. 2001. Selective matrix metalloproteinase (MMP) inhibition in rheumatoid arthritis--targetting gelatinase A activation. Inflammation Research 50: 183–186.

    Article  CAS  Google Scholar 

  33. Imai, K., T. Chiba, G. Maeda, and M. Morikawa. 2009. The role of WNT in rheumatoid arthritis and its therapeutic implication. Mini Reviews in Medicinal Chemistry 9: 318–323.

    Article  CAS  Google Scholar 

  34. Miao, C.G., Y.Y. Yang, X. He, X.F. Li, C. Huang, Y. Huang, L. Zhang, X.W. Lv, Y. Jin, and J. Li. 2013. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cellular Signalling 25: 2069–2078.

    Article  CAS  Google Scholar 

  35. Sen, M., J. Reifert, K. Lauterbach, V. Wolf, J.S. Rubin, M. Corr, and D.A. Carson. 2002. Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes. Arthritis and Rheumatism 46: 2867–2877.

    Article  CAS  Google Scholar 

  36. Li, G.Q., Y.X. Fang, Y. Liu, F.R. Meng, X. Wu, C.W. Zhang, Y. Zhang, D. Liu, and B. Gao. 2019. MALAT1-driven inhibition of Wnt signal impedes proliferation and inflammation in fibroblast-like synoviocytes through CTNNB1 promoter methylation in rheumatoid arthritis. Human Gene Therapy 30: 1008–1022.

    Article  CAS  Google Scholar 

  37. Sun, J., P. Yan, Y. Chen, Y. Chen, J. Yang, G. Xu, H. Mao, and Y. Qiu. 2015. MicroRNA-26b inhibits cell proliferation and cytokine secretion in human RASF cells via the Wnt/GSK-3beta/beta-catenin pathway. Diagnostic Pathology 10: 72.

    Article  Google Scholar 

  38. Liang, J.J., H.R. Li, Y. Chen, Z. Zhou, Y.Q. Shi, L.L. Zhang, L. Xin, and D.B. Zhao. 2020. ZNRF3 regulates collagen-induced arthritis through NF-kB and Wnt pathways. Inflammation 43: 1077–1087.

    Article  CAS  Google Scholar 

  39. Tian, X.H., W.J. Hou, Y. Fang, J. Fan, H. Tong, S.L. Bai, Q. Chen, H. Xu, and Y. Li. 2013. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/beta-catenin signaling pathway. Journal of Experimental & Clinical Cancer Research 32: 100.

    Article  Google Scholar 

  40. Gul, A., B. Kunwar, M. Mazhar, K. Perveen, and S.U. Simjee. 2017. N-(2-Hydroxyphenyl)acetamide: a novel suppressor of RANK/RANKL pathway in collagen-induced arthritis model in rats. Inflammation 40: 1177–1190.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Prof. Wen-jian Tang (School of Pharmacy, Anhui Medical University) for providing penta-acetyl geniposide.

Funding

This work was supported by the National Natural Science Foundation of China (81102273, 81972040), Program for Outstanding Young Talents of Higher Education Institution of Anhui Province (gxyqZD2016045), and Open Project Program of Inflammation and Immune Mediated Diseases Laboratory of Anhui Province (IMMDL202001).

Author information

Author notes

  1. Li Cai, Yu-rong Mu, and Ming-ming Liu contributed equally to this work.

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui Province, People’s Republic of China

    Li Cai, Yu-rong Mu, Ming-ming Liu, Meng-yuan Zhou, Bo Meng, Fang-yuan Liu & Rong Li

  2. Department of Pathology, School of Basic Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui Province, People’s Republic of China

    Li Cai

Authors
  1. Li Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-rong Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming-ming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng-yuan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bo Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fang-yuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was designed by R.L.; the funding was provided by R.L. and L.C.; most of the experiments were performed by L.C., Y.M., M.L., M.Z., B.M., and F.L.; the experimental data were analyzed by L.C. and Y.M.; the writing of the manuscript was performed by L.C. and M.L.; the review and editing of the manuscript were performed by R.L. The final manuscript was read and approved by all the authors.

Corresponding author

Correspondence to Rong Li.

Ethics declarations

Ethics Approval

The study protocols were approved by the Ethical Committee on Animal Research at the School of Pharmacy of Anhui Medical University. All animal experiments complied with the ethical requirements of the ethical committee.

Consent for Publication

Not applicable

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, L., Mu, Yr., Liu, Mm. et al. Penta-acetyl Geniposide Suppresses Migration, Invasion, and Inflammation of TNF-α-Stimulated Rheumatoid Arthritis Fibroblast-Like Synoviocytes Involving Wnt/β-Catenin Signaling Pathway. Inflammation 44, 2232–2245 (2021). https://doi.org/10.1007/s10753-021-01495-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-021-01495-y

KEY WORDS

Search

Navigation