Skip to main content


Log in

Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

  • Published:
Inflammation Aims and scope Submit manuscript


Oridonin, an active diterpenoid compound from Rabdosia rubescens, has anti-tumor effects. Rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), a pathological hallmark of RA, exhibits “tumor-like” phenotype. Here, we investigated the effects of oridonin on the proliferation and apoptosis of RAFLS. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis and mitochondrial membrane potential were detected by flow cytometry. Western blot analysis was performed to examine the phosphorylation of extra-cellular regulated kinases (ERK1/2), C-Jun N-Terminal Kinase (JNK), and p38 mitogen-activated protein kinases and the expression of apoptosis-related proteins. Oridonin inhibited cell proliferation and induced cell apoptosis in interleukin-1β (IL-1β)-treated FLS. z-VAD-fmk, a pan-caspase inhibitor, significantly (P < 0.05) attenuated oridonin-induced apoptosis of FLS. Oridonin suppressed IL-1β-mediated phosphorylation of ERK1/2 and JNK in a dose-dependent manner. Meanwhile, oridonin alone dose-dependently suppressed FLS proliferation, triggered cell apoptosis, and reduced mitochondrial membrane potential (ΔΨm) through activating caspase-3, caspase-9, and PARP, leading to translocation of cytochrome c into cytoplasm. z-VAD-fmk significantly (P < 0.05) inhibited oridonin-induced apoptosis. The accumulation of cellular reactive oxygen species (ROS) was about sevenfold increase in oridonin-treated cells. Pretreatment of N-acetylcysteine (NAC), an inhibitor of ROS, significantly attenuated oridonin-triggered apoptosis, indicating the involvement of ROS production in oridonin-induced mitochondrial apoptosis. Oridonin inhibits cell proliferation, induces cell apoptosis, and decreases the phosphorylation of ERK1/2 and JNK in IL-1β-exposed RAFLS. Oridonin induces mitochondrial apoptosis by enhancing the production of ROS in FLS.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others


  1. Bottini, N., and G.S. Firestein. 2013. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology 9: 24–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Firestein, G.S. 1996. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis and Rheumatism 39: 1781–1790.

    Article  CAS  PubMed  Google Scholar 

  3. Lefèvre, S., A. Knedla, C. Tennie, A. Kampmann, C. Wunrau, R. Dinser, A. Korb, E.M. Schnäker, I.H. Tarner, P.D. Robbins, C.H. Evans, H. Stürz, J. Steinmeyer, S. Gay, J. Schölmerich, T. Pap, U. Müller-Ladner, and E. Neumann. 2009. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nature Medicine 15: 1414–1420.

    Article  PubMed  PubMed Central  Google Scholar 

  4. McInnes, I.B., B.P. Leung, and F.Y. Liew. 2000. Cell-cell interactions in synovitis. Interactions between T lymphocytes and synovial cells. Arthritis Research 2: 374–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Okamoto, H., D. Hoshi, A. Kiire, H. Yamanaka, and N. Kamatani. 2008. Molecular targets of rheumatoid arthritis. Inflammation & Allergy Drug Targets 7: 53–66.

    Article  CAS  PubMed  Google Scholar 

  6. Okamoto, H., T.P. Cujec, H. Yamanaka, and N. Kamatani. 2008. Molecular aspects of rheumatoid arthritis: role of transcription factors. FEBS Journal 275: 4463–4470.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Korb, A., H. Pavenstädt, and T. Pap. 2009. Cell death in rheumatoid arthritis. Apoptosis 14: 447–454.

    Article  PubMed  Google Scholar 

  9. Negroni, A., S. Cucchiara, and L. Stronati. 2015. Apoptosis, necrosis, and necroptosis in the gut and intestinal homeostasis. Mediators of Inflammation 2015: 250762.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li, H., and A. Wan. 2013. Apoptosis of rheumatoid arthritis fibroblast-like synoviocytes: possible roles of nitric oxide and the thioredoxin 1. Mediators of Inflammation 2013: 953462.

    PubMed  PubMed Central  Google Scholar 

  11. Balaban, R.S., S. Nemoto, and T. Finkel. 2005. Mitochondria, oxidants, and aging. Cell 120: 483–495.

    Article  CAS  PubMed  Google Scholar 

  12. Nishioka, K., T. Hasunuma, T. Kato, T. Sumida, and T. Kobata. 1998. Apoptosis in rheumatoid arthritis: a novel pathway in the regulation of synovial tissue. Arthritis and Rheumatism 41: 1–9.

    Article  CAS  PubMed  Google Scholar 

  13. Phillips, D.C., H.K. Dias, G.D. Kitas, and H.R. Griffiths. 2010. Aberrant reactive oxygen and nitrogen species generation in rheumatoid arthritis (RA): causes and consequences for immune function, cell survival, and therapeutic intervention. Antioxidants and Redox Signaling 12: 743–785.

    Article  CAS  PubMed  Google Scholar 

  14. Osawa, K., H. Yasuda, T. Maruyama, H. Morita, and K. Takeya. 1994. Antibacteria trichorabdal diterpenes from Rabdosia trichocarpa. Phytochemistry 36: 1287–1291.

    Article  CAS  PubMed  Google Scholar 

  15. Han, Q.B., M.L. Li, S.H. Li, Y.K. Mou, Z.W. Lin, and H.D. Sun. 2003. Ent-kaurane diterpenoids from Isodon rubescens var lushanensis. Chemical and Pharmaceutical Bulletin 51: 790–793.

    Article  CAS  PubMed  Google Scholar 

  16. Bao, R., Y. Shu, X. Wu, H. Weng, Q. Ding, Y. Cao, M. Li, J. Mu, W. Wu, Q. Ding, et al. 2014. Oridonin induces apoptosis and cell cycle arrest of gallbladder cancer cells via the mitochondrial pathway. BMC Cancer. 14: 217.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kuo, L.M., C.Y. Kuo, C.Y. Lin, M.F. Hung, J.J. Shen, and T.L. Hwang. 2014. Intracellular glutathione depletion by oridonin leads to apoptosis in hepatic stellate cells. Molecules 19: 3327–3344.

    Article  PubMed  Google Scholar 

  18. Neff, L., M. Zeisel, J. Sibilia, M. Schöller-Guinard, J.P. Klein, and D. Wachsmann. 2001. NF-kappaB and the MAP kinases/AP-1 pathways are both involved in interleukin-6 and interleukin-8 expression in fibroblast-like synoviocytes stimulated by protein I/II, a modulin from oral streptococci. Cellular Microbiology 3: 703–712.

    Article  CAS  PubMed  Google Scholar 

  19. Turner-Brannen, E., K.Y. Choi, D.N. Lippert, J.P. Cortens, R.E. Hancock, H. El-Gabalawy, and N. Mookherjee. 2011. Modulation of interleukin-1β-induced inflammatory responses by a synthetic cationic innate defence regulator peptide, IDR-1002, in synovial fibroblasts. Arthritis Research and Therapy 13: R129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shih, K.S., J.H. Wang, Y.W. Wu, C.M. Teng, C.C. Chen, and C.R. Yang. 2012. Aciculatin inhibits granulocyte colony-stimulating factor production by human interleukin 1β-stimulated fibroblast-like synoviocytes. PloS One 7: e42389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jin, S., J.N. Shen, J. Wang, G. Huang, and J.G. Zhou. 2007. Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. Cancer Biology and Therapy 6: 261–268.

    Article  CAS  PubMed  Google Scholar 

  22. Lee, H.H., S. Lee, K. Lee, Y.S. Shin, H. Kang, and H. Cho. 2015. Anti-cancer effect of Cordyceps militaris in human colorectal carcinoma RKO cells via cell cycle arrest and mitochondrial apoptosis. Daru 23: 35.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sun, K.W., Y.Y. Ma, T.P. Guan, Y.J. Xia, C.M. Shao, L.G. Chen, Y.J. Ren, H.B. Yao, Q. Yang, and X.J. He. 2012. Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway. World Journal of Gastroenterology 18: 7166–7174.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Scorrano, L., and S.J. Korsmeyer. 2003. Mechanisms of cytochrome c release by proapoptotic bcl-2 family members. Biochemical and Biophysical Research Communications 304: 437–444.

    Article  CAS  PubMed  Google Scholar 

  25. Kim, H.E., F. Du, M. Fang, and X. Wang. 2005. Formation of apoptosome is initiated by cytochrome c-induced datp hydrolysis and subsequent nucleotide exchange on apaf-1. Proceedings of the National academy of Sciences of the United States of America 102: 17545–17550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zeng, R., Y. Chen, S. Zhao, and G.H. Cui. 2012. Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1. Acta Pharmacologica Sinica 33: 91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Meunier, J., and T. Hayashi. 2010. Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB. Journal of Pharmacol and Experimental Therapeutics 332: 388–397.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Cai-hong Shang.


Below is the link to the electronic supplementary material.


(DOC 69 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shang, Ch., Zhang, Qq. & Zhou, Jh. Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Inflammation 39, 873–880 (2016).

Download citation

  • Published:

  • Issue Date:

  • DOI: