Skip to main content
SpringerLink
Log in

Casticin Attenuates Osteoarthritis-Related Cartilage Degeneration by Inhibiting the ROS-Mediated NF-κB Signaling Pathway in vitro and in vivo

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

Abstract

Casticin, a flavonoid isolated from Vitex trifolia, has been shown to have anti-inflammatory and antitumor effects in previous studies. Osteoarthritis (OA) is a disease based on degenerative pathological changes. The disease process is often accompanied by inflammatory pathological changes. However, there is no safe and effective drug for prevention and treatment. In the present study, we aimed to clarify the role of casticin in the murine model of destabilization of the medial meniscus (DMM). Male BALB/c mice were randomly divided into three groups: Sham, DMM-induced OA treated with vehicle, and DMM-induced OA treated with casticin. Our results indicated that the casticin treatments markedly reduced the destruction of cartilage and OARSI grades compared with those of the vehicle-treated mice. The levels of matrix metalloproteinase-13 (MMP13) in cartilage were also significantly reduced in the casticin-treated mice. Casticin also significantly regulated oxidative stress and reduced inflammation in the cartilage of mice with OA. These results suggest that casticin prevents the development of posttraumatic OA in mice. Consequently, decreased reactive oxygen species levels and suppressed proinflammatory cytokine production were confirmed in casticin-treated IL-1β-stimulated ADTC5 cells. After casticin treatment, the NF-κB signaling pathway was significantly inhibited in the cells. It can be concluded that casticin can alleviate arthritis-related cartilage degeneration by inhibiting ROS-mediated NF-κB signaling pathway in vitro and in vivo.

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

Similar content being viewed by others

References

  1. Hunter, D.J., and S. Bierma-Zeinstra. 2019. Osteoarthritis. Lancet (London, England) 393:1745–1759.

  2. Dieppe, P.A., and L.S. Lohmander. 2005. Pathogenesis and management of pain in osteoarthritis. Lancet (London, England) 365:965–973.

  3. Suri, P., D.C. Morgenroth, and D.J. Hunter. 2012. Epidemiology of osteoarthritis and associated comorbidities. PM & R : The Journal of Injury, Function, and Rehabilitation 4:s10–s19.

  4. Loeser, R.F., S.R. Goldring, C.R. Scanzello, and M.B. Goldring. 2012. Osteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism 64: 1697–1707.

    Article  Google Scholar 

  5. Zeng, C., J. Wei, Persson MSM, A. Sarmanova, M. Doherty, D. Xie, Y. Wang, X. Li, J. Li, H. Long, et al. 2018. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: A systematic review and network meta-analysis of randomised controlled trials and observational studies. British Journal of Sports Medicine 52: 642–650.

  6. Lazzaroni, M., and G. Bianchi Porro. 2004. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Alimentary Pharmacology & Therapeutics 20: 48–58.

  7. Philp, A.M., E.T. Davis, and S.W. Jones. 2017. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology (Oxford) 56: 869–881.

    CAS  Google Scholar 

  8. Lieberthal, J., N. Sambamurthy, and C.R. Scanzello. 2015. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis and Cartilage 23: 1825–1834.

    Article  CAS  Google Scholar 

  9. Goldring, M.B., M. Otero, K. Tsuchimochi, K. Ijiri, and Y. Li. 2008. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Annals of the Rheumatic Diseases 67: 75–82.

  10. Kapoor, M., J. Martel-Pelletier, D. Lajeunesse, J.P. Pelletier, and H. Fahmi. 2011. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature Reviews Rheumatology 7: 33–42.

  11. Wojdasiewicz, P., Ł.A. Poniatowski, and D. Szukiewicz. 2014. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators of Inflammation 2014: 561459.

  12. Prasadam, I., R. Crawford, and Y. Xiao. 2012. Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes -- possible pathogenic role in osteoarthritis. The Journal of Rheumatology 39: 621–634.

    Article  CAS  Google Scholar 

  13. Mengshol, J.A., M.P. Vincenti, C.I. Coon, A. Barchowsky, and C.E. Brinckerhoff. 2000. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor κB: Differential regulation of collagenase 1 and collagenase 3. Arthritis and Rheumatism 43: 801.

    Article  CAS  Google Scholar 

  14. Kobayakawa, J., F. Sato-Nishimori, M. Moriyasu, and Y. Matsukawa. 2004. G2-M arrest and antimitotic activity mediated by casticin, a flavonoid isolated from Viticis Fructus (Vitex rotundifolia Linne fil.). Cancer Letters 208: 59–64.

    Article  CAS  Google Scholar 

  15. Ling, Y., J. Zhu, M. Fan, B. Wu, L. Qin, and C. Huang. 2012. Metabolism studies of casticin in rats using HPLC-ESI-MS(n). Biomedical Chromatography 26: 1502–1508.

    Article  CAS  Google Scholar 

  16. Haïdara, K., L. Zamir, Q. Shi, and G. Batist. 2006. The flavonoid Casticin has multiple mechanisms of tumor cytotoxicity action. Cancer Letters 242: 180–190.

    Article  Google Scholar 

  17. Liou, C.J., C.Y. Cheng, K.W. Yeh, Y.H. Wu, and W.C. Huang. 2018. Protective effects of Casticin from Vitex trifolia alleviate Eosinophilic airway inflammation and oxidative stress in a murine asthma model. Frontiers in Pharmacology 9: 635.

    Article  Google Scholar 

  18. Liou, C.J., W.B. Len, S.J. Wu, C.F. Lin, X.L. Wu, and W.C. Huang. 2014. Casticin inhibits COX-2 and iNOS expression via suppression of NF-kappaB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages. Journal of Ethnopharmacology 158 (Pt a): 310–316.

    Article  CAS  Google Scholar 

  19. Lee, H., K.H. Jung, H. Lee, S. Park, W. Choi, and H. Bae. 2015. Casticin, an active compound isolated from Vitex Fructus, ameliorates the cigarette smoke-induced acute lung inflammatory response in a murine model. International Immunopharmacology 28: 1097–1101.

    Article  CAS  Google Scholar 

  20. Mesaik, M.A., S. Murad, K.M. Khan, R.B. Tareen, A. Ahmed, and M.I. Choudhary. 2009. Isolation and immunomodulatory properties of a flavonoid, casticin from Vitex agnus-castus. Phytotherapy Research 23: 1516–1520.

    Article  CAS  Google Scholar 

  21. Glasson, S.S., T.J. Blanchet, and E.A. Morris. 2007. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis and Cartilage 15: 1061–1069.

    Article  CAS  Google Scholar 

  22. Glasson, S.S., M.G. Chambers, W.B. Van Den Berg, and C.B. Little. 2010. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis and Cartilage 18 (Suppl 3): S17–S23.

    Article  Google Scholar 

  23. Vinatier, C., C. Merceron, and J. Guicheux. 2016. Osteoarthritis: From pathogenic mechanisms and recent clinical developments to novel prospective therapeutic options. Drug Discovery Today 21: 1932–1937.

    Article  CAS  Google Scholar 

  24. Kuo, C.F., J.D. Su, C.H. Chiu, C.C. Peng, C.H. Chang, T.Y. Sung, S.H. Huang, W.C. Lee, and C.C. Chyau. 2011. Anti-inflammatory effects of supercritical carbon dioxide extract and its isolated carnosic acid from Rosmarinus officinalis leaves. Journal of Agricultural and Food Chemistry 59: 3674–3685.

    Article  CAS  Google Scholar 

  25. Latourte, A., C. Cherifi, J. Maillet, H.K. Ea, W. Bouaziz, T. Funck-Brentano, M. Cohen-Solal, E. Hay, and P. Richette. 2017. Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis. Annals of the Rheumatic Diseases 76: 748–755.

    Article  CAS  Google Scholar 

  26. Zhao, Y., Y. Li, R. Qu, X. Chen, W. Wang, C. Qiu, B. Liu, X. Pan, L. Liu, K. Vasilev, J. Hayball, S. Dong, and W. Li. 2019. Cortistatin binds to TNF-alpha receptors and protects against osteoarthritis. EBioMedicine 41: 556–570.

    Article  Google Scholar 

  27. Latimer, N., J. Lord, R.L. Grant, R. O'Mahony, J. Dickson, and P.G. Conaghan. 2009. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis. BMJ 339: b2538.

    Article  Google Scholar 

  28. Wylie, J.D., J.C. Ho, S. Singh, D.R. McCulloch, and S.S. Apte. 2012. Adamts5 (aggrecanase-2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines. Journal of Orthopaedic Research 30: 226–233.

    Article  CAS  Google Scholar 

  29. Hitchon, C.A., and H.S. El-Gabalawy. 2004. Oxidation in rheumatoid arthritis. Arthritis Research & Therapy 6: 265–278.

    Article  Google Scholar 

  30. Valko, M., D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, and J. Telser. 2007. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology 39: 44–84.

    Article  CAS  Google Scholar 

  31. Griffiths, H.R. 2005. ROS as signalling molecules in T cells--evidence for abnormal redox signalling in the autoimmune disease, rheumatoid arthritis. Redox Report 10: 273–280.

    Article  CAS  Google Scholar 

  32. Henrotin, Y.E., P. Bruckner, and J.P. Pujol. 2003. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis and Cartilage 11: 747–755.

    Article  CAS  Google Scholar 

  33. Kaminskyy, V.O., and B. Zhivotovsky. 2014. Free radicals in cross talk between autophagy and apoptosis. Antioxidants & Redox Signaling 21: 86–102.

    Article  CAS  Google Scholar 

  34. Wang, Y., R. Branicky, A. Noe, and S. Hekimi. 2018. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. The Journal of Cell Biology 217: 1915–1928.

    Article  CAS  Google Scholar 

  35. Yang, C.S., J.J. Kim, S.J. Lee, J.H. Hwang, C.H. Lee, M.S. Lee, and E.K. Jo. 2013. TLR3-triggered reactive oxygen species contribute to inflammatory responses by activating signal transducer and activator of transcription-1. Journal of Immunology 190: 6368–6377.

    Article  CAS  Google Scholar 

  36. Kim, J., M. Xu, R. Xo, A. Mates, G.L. Wilson, A.W. Pearsall, and V. Grishko. 2010. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis and Cartilage 18: 424–432.

  37. Glineur, C., E. Davioud-Charvet, and B. Vandenbunder. 2000. The conserved redox-sensitive cysteine residue of the DNA-binding region in the c-Rel protein is involved in the regulation of the phosphorylation of the protein. The Biochemical Journal 352: 583–591.

  38. Janssen-Heininger, Y.M., M.E. Poynter, and P.A. Baeuerle. 2000. Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radical Biology & Medicine 28: 1317–1327.

  39. Lai, Y., X. Bai, Y. Zhao, Q. Tian, B. Liu, E.A. Lin, Y. Chen, B. Lee, C.T. Appleton, F. Beier, X.P. Yu, and C.J. Liu. 2014. ADAMTS-7 forms a positive feedback loop with TNF-alpha in the pathogenesis of osteoarthritis. Annals of the Rheumatic Diseases 73: 1575–1584.

    Article  CAS  Google Scholar 

  40. Minashima, T., K.A. Campbell, S.R. Hadley, Y. Zhang, and T. Kirsch. 2014. The role of ANK interactions with MYBBP1a and SPHK1 in catabolic events of articular chondrocytes. Osteoarthritis and Cartilage 22: 852–861.

    Article  CAS  Google Scholar 

  41. Campbell, K.A., T. Minashima, Y. Zhang, S. Hadley, Y.J. Lee, J. Giovinazzo, M. Quirno, and T. Kirsch. 2013. Annexin A6 interacts with p65 and stimulates NF-kappaB activity and catabolic events in articular chondrocytes. Arthritis and Rheumatism 65: 3120–3129.

    Article  CAS  Google Scholar 

  42. Yasuda, T. 2011. Activation of Akt leading to NF-κB up-regulation in chondrocytes stimulated with fibronectin fragment. Biomedical Research (Tokyo, Japan) 32: 209–215.

  43. Zheng, W., Z. Tao, L. Cai, C. Chen, C. Zhang, Q. Wang, X. Ying, W. Hu, and H. Chen. 2017. Chrysin attenuates IL-1β-induced expression of inflammatory mediators by suppressing NF-κB in human osteoarthritis chondrocytes. Inflammation 40: 1143–1154.

Download references

Funding

These studies were supported by the National Natural Science Foundation of China. Award Number: 81672228 and 81702199.

Author information

Author notes

  1. Jun Chu and Bo Yan contributed equally to this work.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China

    Jun Chu, Bo Yan, Jie Zhang, Xiang Ao, Zhenyu Zheng, Tao Jiang & Zhongmin Zhang

  2. Laboratory Department, Dongguan City Maternal and Child Health Hospital, Dongguan, China

    Lilan Peng

Authors
  1. Jun Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lilan Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiang Ao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhenyu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhongmin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation and data analysis were performed by Jun Chu, Tao Jiang and Bo Yan. Jun Chu, Jie Zhang and Zhenyu Zheng performed the experiments. The first draft of the manuscript was written by Zhongmin Zhang, and Lilan Peng. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhongmin Zhang.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Data Availability

The data generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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

Chu, J., Yan, B., Zhang, J. et al. Casticin Attenuates Osteoarthritis-Related Cartilage Degeneration by Inhibiting the ROS-Mediated NF-κB Signaling Pathway in vitro and in vivo. Inflammation 43, 810–820 (2020). https://doi.org/10.1007/s10753-019-01167-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01167-y

KEY WORDS

Search

Navigation