Isorhapontigenin Suppresses Interleukin-1β-Induced Inflammation and Cartilage Matrix Damage in Rat Chondrocytes

  • Yongzhuang Ma
  • Chang Tu
  • Wei Liu
  • Yifan XiaoEmail author
  • Hua WuEmail author
Original Article


Osteoarthritis (OA) is a common cause of joint pain and physical disability in the elderly. It is highly associated with local inflammatory reactions and cartilage degradation. Isorhapontigenin (ISO), a natural compound existing in various plants, has shown prominent anti-inflammatory and anti-oxidative properties in several inflammatory diseases. However, the effects of ISO on OA remain to be elucidated. Here, we investigated the effects of ISO on interleukin-1β (IL-1β)-treated rat chondrocytes and cartilage explants. Our results revealed that ISO could suppress the IL-1β-induced elevated levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX2). Besides, ISO could also inhibit the IL-1β-induced up-regulation of cartilage matrix catabolic enzymes such as matrix metalloproteinases (MMPs) and aggrecanase-2 (ADAMTS5). Moreover, the IL-1β-induced downregulation of collagen II and aggrecan could be reversed by ISO. Furthermore, ISO prevented rat cartilage explant damage induced by IL-1β. Mechanistically, ISO worked partly by suppressing mitogen-activated protein kinase (MAPK)-associated ERK and p38 pathways. Taken together, our study indicated the anti-inflammatory potential of ISO on IL-1β-treated rat chondrocytes, providing a new idea for OA treatment.


osteoarthritis isorhapontigenin iNOS COX2 MMPs ADAMTS5 



This study was supported by the grant from the National Natural Science Foundation of China (no. 51537004) to H.W.

Compliance with Ethical Standards

This study was in strict accordance with the Guidelines of Animal Care and Use Committee for Teaching and Research of Huazhong University of Science and Technology, Wuhan, China.

Conflict of Interest

The authors have no conflict of interest or financial disclosures with this research.


  1. 1.
    Mathiessen, A., and P.G. Conaghan. 2017. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Research & Therapy 19 (1): 18.CrossRefGoogle Scholar
  2. 2.
    Aicher, W.K., and B. Rolauffs. 2014. The spatial organisation of joint surface chondrocytes: review of its potential roles in tissue functioning, disease and early, preclinical diagnosis of osteoarthritis. Annals of the Rheumatic Diseases 73 (4): 645–653.CrossRefGoogle Scholar
  3. 3.
    Troeberg, L., and H. Nagase. 2012. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochimica et Biophysica Acta 1824 (1): 133–145.CrossRefGoogle Scholar
  4. 4.
    Glyn-Jones, S., A.J.R. Palmer, R. Agricola, A.J. Price, T.L. Vincent, H. Weinans, and A.J. Carr. 2015. Osteoarthritis. Lancet 386 (9991): 376–387.CrossRefGoogle Scholar
  5. 5.
    Bonnet, C.S., and D.A. Walsh. 2005. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 44 (1): 7–16.CrossRefGoogle Scholar
  6. 6.
    Dodge, G.R., and A.R. Poole. 1989. Immunohistochemical detection and immunochemical analysis of type II collagen degradation in human normal, rheumatoid, and osteoarthritic articular cartilages and in explants of bovine articular cartilage cultured with interleukin 1. The Journal of Clinical Investigation 83 (2): 647–661.CrossRefGoogle Scholar
  7. 7.
    Le Maitre, C.L., et al. 2007. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochemical Society Transactions 35 (Pt 4): 652–655.Google Scholar
  8. 8.
    Goldring, S.R., and M.B. Goldring. 2004. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clinical Orthopaedics and Related Research (427 Suppl): S27–S36.Google Scholar
  9. 9.
    Chabane, N., N. Zayed, H. Afif, L. Mfuna-Endam, M. Benderdour, C. Boileau, J. Martel-Pelletier, J.P. Pelletier, N. Duval, and H. Fahmi. 2008. Histone deacetylase inhibitors suppress interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Osteoarthritis and Cartilage 16 (10): 1267–1274.CrossRefGoogle Scholar
  10. 10.
    Wang, Q.L., M. Lin, and G.T. Liu. 2001. Antioxidative activity of natural isorhapontigenin. Japanese Journal of Pharmacology 87 (1): 61–66.CrossRefGoogle Scholar
  11. 11.
    Yeo, S.C.M., P.S. Fenwick, P.J. Barnes, H.S. Lin, and L.E. Donnelly. 2017. Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism. British Journal of Pharmacology 174 (13): 2043–2059.CrossRefGoogle Scholar
  12. 12.
    Kawakami, S., Y. Kinoshita, H. Maruki-Uchida, K. Yanae, M. Sai, and T. Ito. 2014. Piceatannol and its metabolite, isorhapontigenin, induce SIRT1 expression in THP-1 human monocytic cell line. Nutrients 6 (11): 4794–4804.CrossRefGoogle Scholar
  13. 13.
    Liu, Y., and G. Liu. 2004. Isorhapontigenin and resveratrol suppress oxLDL-induced proliferation and activation of ERK1/2 mitogen-activated protein kinases of bovine aortic smooth muscle cells. Biochemical Pharmacology 67 (4): 777–785.CrossRefGoogle Scholar
  14. 14.
    Oh, J.S., I.A. Cho, K.R. Kang, J.S. You, S.J. Yu, G.J. Lee, Y.S. Seo, C.S. Kim, D.K. Kim, S.G. Kim, Y.W. Seo, H.J. Im, and J.S. Kim. 2016. Biochanin-A antagonizes the interleukin-1beta-induced catabolic inflammation through the modulation of NFkappaB cellular signaling in primary rat chondrocytes. Biochemical and Biophysical Research Communications 477 (4): 723–730.CrossRefGoogle Scholar
  15. 15.
    Chen, P., S. Zhu, Y. Wang, Q. Mu, Y. Wu, Q. Xia, X. Zhang, H. Sun, J. Tao, H. Hu, P. Lu, and H. Ouyang. 2014. The amelioration of cartilage degeneration by ADAMTS-5 inhibitor delivered in a hyaluronic acid hydrogel. Biomaterials 35 (9): 2827–2836.CrossRefGoogle Scholar
  16. 16.
    Wojdasiewicz, P., L.A. Poniatowski, and D. Szukiewicz. 2014. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators of Inflammation 2014: 561459.CrossRefGoogle Scholar
  17. 17.
    Su, S.C., K. Tanimoto, Y. Tanne, R. Kunimatsu, N. Hirose, T. Mitsuyoshi, Y. Okamoto, and K. Tanne. 2014. Celecoxib exerts protective effects on extracellular matrix metabolism of mandibular condylar chondrocytes under excessive mechanical stress. Osteoarthritis and Cartilage 22 (6): 845–851.CrossRefGoogle Scholar
  18. 18.
    Dragos, D., M. Gilca, L. Gaman, A. Vlad, L. Iosif, I. Stoian, and O. Lupescu. 2017. Phytomedicine in joint disorders. Nutrients 9 (1): 70.Google Scholar
  19. 19.
    Abbas, A.M. 2016. Cardioprotective effect of resveratrol analogue isorhapontigenin versus omega-3 fatty acids in isoproterenol-induced myocardial infarction in rats. Journal of Physiology and Biochemistry 72 (3): 469–484.CrossRefGoogle Scholar
  20. 20.
    Dai, Y., S.C.M. Yeo, P.J. Barnes, L.E. Donnelly, L.C. Loo, and H.S. Lin. 2018. Pre-clinical pharmacokinetic and metabolomic analyses of isorhapontigenin, a dietary resveratrol derivative. Frontiers in Pharmacology 9: 753.CrossRefGoogle Scholar
  21. 21.
    Roos, E.M., and N.K. Arden. 2016. Strategies for the prevention of knee osteoarthritis. Nature Reviews Rheumatology 12 (2): 92–101.CrossRefGoogle Scholar
  22. 22.
    Attur, M., I. Belitskaya-Lévy, C. Oh, S. Krasnokutsky, J. Greenberg, J. Samuels, S. Smiles, S. Lee, J. Patel, H. al-Mussawir, G. McDaniel, V.B. Kraus, and S.B. Abramson. 2011. Increased interleukin-1beta gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis and Rheumatism 63 (7): 1908–1917.CrossRefGoogle Scholar
  23. 23.
    Wang, P., et al. 2018. Histone deacetylase-4 and histone deacetylase-8 regulate interleukin-1beta-induced cartilage catabolic degradation through MAPK/JNK and ERK pathways. International Journal of Molecular Medicine 41 (4): 2117–2127.Google Scholar
  24. 24.
    Cao, M., et al. 1997. Nitric oxide inhibits the synthesis of type-II collagen without altering Col2A1 mRNA abundance: prolyl hydroxylase as a possible target. The Biochemical Journal 324 (Pt 1): 305–310.CrossRefGoogle Scholar
  25. 25.
    Takada, K., et al. 2013. Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis. Biomedical Reports 1 (2): 315–319.CrossRefGoogle Scholar
  26. 26.
    Dumond, H., N. Presle, P. Pottie, S. Pacquelet, B. Terlain, P. Netter, A. Gepstein, E. Livne, and J.Y. Jouzeau. 2004. Site specific changes in gene expression and cartilage metabolism during early experimental osteoarthritis. Osteoarthritis and Cartilage 12 (4): 284–295.CrossRefGoogle Scholar
  27. 27.
    Vo, N.V., R.A. Hartman, T. Yurube, L.J. Jacobs, G.A. Sowa, and J.D. Kang. 2013. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. The Spine Journal 13 (3): 331–341.CrossRefGoogle Scholar
  28. 28.
    Saklatvala, J. 2007. Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. Current Drug Targets 8 (2): 305–313.CrossRefGoogle Scholar
  29. 29.
    Sondergaard, B.C., N. Schultz, S.H. Madsen, A.C. Bay-Jensen, M. Kassem, and M.A. Karsdal. 2010. MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation—divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation. Osteoarthritis and Cartilage 18 (3): 279–288.CrossRefGoogle Scholar
  30. 30.
    Cargnello, M., and P.P. Roux. 2011. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiology and Molecular Biology Reviews 75 (1): 50–83.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Orthopedics, Tongji HospitalTongji Medical College, Huazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Department of Pathology and Pathophysiology, School of MedicineJianghan UniversityWuhanPeople’s Republic of China

Personalised recommendations