, Volume 38, Issue 4, pp 1563–1572 | Cite as

Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling Pathways

  • Zhifu Li
  • Dongdong Meng
  • Guangheng Li
  • Jianzhong Xu
  • Ke Tian
  • Yu Li


Osteoarthritis (OA) has long been a difficult to overcome joint disease for medical workers. However, there is still a lack of effective treatments for OA. In the present study, we aimed to evaluate the treatment effect of celecoxib (CLX) combined with diacerein (DC) on OA and delineate the underlying molecular mechanism. The OA model was established by using rats, and OA rats were treated with either CLX alone, DC alone, and CLX combined with DC. The results showed that, as compared with a single treatment of CLX or DC, CLX combined with DC markedly attenuated OA and inhibited the levels of inflammatory mediators interleukin-1β and nitric oxide, improved bone cartilage metabolism, and suppressed chondrocyte apoptosis. Most importantly, CLX combined with DC significantly inactivated the c-Jun N-terminal kinases (JNK) signaling pathway by the inhibition of MEKK1 and MKK7, as detected by Western blot analysis. Furthermore, the protein expression of downstream genes of JNK, including activating-transcription factor (Atf-2), matrix metalloproteinase-13 (MMP-13), and cyclooxygenase (COX-2), were also significantly inhibited by CLX combined with DC as compared with single treatments. Furthermore, CLX combined with DC also effectively inhibits p38 mitogen-activated protein kinase and nuclear factor-κB signaling pathways. Taken together, our study suggests that CLX combined with DC has satisfactory treatment effects on OA via a stronger inhibitory effect on inflammatory signaling pathway.


celecoxib diacerein JNK signaling pathway osteoarthritis 





Matrix metalloproteinase-13




Tumor necrosis factor α


C-telopeptide fragments of type II collagen


Mitogen-activated protein kinases


c-Jun N-terminal kinases


Activating-transcription factor




Mitogen-activated protein kinase


Non-steroidal anti-inflammatory drug






Enzyme-linked immune sorbent assay


Bone mineral density


Conflict of Interest

The authors declare that there are no conflicts of interest.


  1. 1.
    Pelletier, J.-P., J. Martel-Pelletier, and J.-P. Raynauld. 2006. Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow. Arthritis Research & Therapy 8: 206.CrossRefGoogle Scholar
  2. 2.
    Berenbaum, F. 2004. Signaling transduction: target in osteoarthritis. Current Opinion in Rheumatology 16: 616–622.PubMedCrossRefGoogle Scholar
  3. 3.
    Buckland-Wright, C. 2004. Subchondral bone changes in hand and knee osteoarthritis detected by radiography. Osteoarthritis and Cartilage 12: 10–19.CrossRefGoogle Scholar
  4. 4.
    Tinti, L., S. Niccolini, A. Lamboglia, N.A. Pascarelli, R. Cervone, and A. Fioravanti. 2011. Raloxifene protects cultured human chondrocytes from IL-1β induced damage: a biochemical and morphological study. European Journal of Pharmacology 670: 67–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Qin J., L. Shang, A.S. Ping, J. Li, X.J. Li, H. Yu, J. Magdalou, L.B. Chen, H. Wang. 2012. TNF/TNFR signal transduction pathway-mediated anti-apoptosis and anti-inflammatory effects of sodium ferulate on IL-1beta-induced rat osteoarthritis chondrocytes in vitro. Arthritis Research and Therapy 14.Google Scholar
  6. 6.
    Pacher, P., J.S. Beckman, and L. Liaudet. 2007. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87: 315–424.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Hashimoto, S., R.L. Ochs, S. Komiya, and M. Lotz. 1998. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis and Rheumatism 41: 1632–1638.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim, S.J., J.W. Ju, C.D. Oh, Y.M. Yoon, W.K. Song, J.H. Kim, Y.J. Yoo, O.S. Bang, S.S. Kang, and J.S. Chun. 2002. ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. Journal of Biological Chemistry 277: 1332–1339.PubMedCrossRefGoogle Scholar
  9. 9.
    Chowdhury, T.T., D.M. Salter, D.L. Bader, and D.A. Lee. 2008. Signal transduction pathways involving p38 MAPK, JNK, NFkappaB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression. Inflammation Research 57: 306–313.PubMedCrossRefGoogle Scholar
  10. 10.
    Dhanasekaran, D.N., and E.P. Reddy. 2008. JNK signaling in apoptosis. Oncogene 27: 6245–6251.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yoon, H.S., and H.A. Kim. 2004. Prologation of c-Jun N-terminal kinase is associated with cell death induced by tumor necrosis factor alpha in human chondrocytes. Journal of Korean Medical Science 19: 567–573.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Sylvester, J., A. Liacini, W.Q. Li, and M. Zafarullah. 2004. Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. Cellular Signalling 16: 469–476.PubMedCrossRefGoogle Scholar
  13. 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 kappaB: differential regulation of collagenase 1 and collagenase 3. Arthritis and Rheumatism 43: 801–811.PubMedCrossRefGoogle Scholar
  14. 14.
    Kuhn, K., A.R. Shikhman, and M. Lotz. 2003. Role of nitric oxide, reactive oxygen species, and p38 MAP kinase in the regulation of human chondrocyte apoptosis. Journal of Cellular Physiology 197: 379–387.PubMedCrossRefGoogle Scholar
  15. 15.
    Masuko-Hongo, K., F. Berenbaum, L. Humbert, C. Salvat, M.B. Goldring, and S. Thirion. 2004. Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis and Rheumatism 50: 2829–2838.PubMedCrossRefGoogle Scholar
  16. 16.
    Myers, L.K., A.H. Kang, A.E. Postlethwaite, E.F. Rosloniec, S.G. Morham, B.V. Shlopov, S. Goorha, and L.R. Ballou. 2000. The genetic ablation of cyclooxygenase 2 prevents the development of autoimmune arthritis. Arthritis and Rheumatism 43: 2687–2693.PubMedCrossRefGoogle Scholar
  17. 17.
    Zweers, M.C., T.N. de Boer, J. van Roon, J.W. Bijlsma, F.P. Lafeber, and S.C. Mastbergen. 2011. Celecoxib: considerations regarding its potential disease-modifying properties in osteoarthritis. Arthritis Research & Therapy 13: 239.CrossRefGoogle Scholar
  18. 18.
    Dave, M., and A.R. Amin. 2013. Yin-Yang regulation of prostaglandins and nitric oxide by PGD2 in human arthritis: reversal by celecoxib. Immunology Letters 152: 47–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Ashkavand, Z., H. Malekinejad, A. Amniattalab, A. Rezaei-Golmisheh, and B. Vishwanath. 2012. Silymarin potentiates the anti-inflammatory effects of celecoxib on chemically induced osteoarthritis in rats. Phytomedicine 19: 1200–1205.PubMedCrossRefGoogle Scholar
  20. 20.
    Dong, J., D. Jiang, Z. Wang, G. Wu, L. Miao, and L. Huang. 2013. Intra-articular delivery of liposomal celecoxib–hyaluronate combination for the treatment of osteoarthritis in rabbit model. International Journal of Pharmaceutics 441: 285–290.PubMedCrossRefGoogle Scholar
  21. 21.
    Martel-Pelletier, J., and J.P. Pelletier. 2010. Effects of diacerein at the molecular level in the osteoarthritis disease process. Therapeutic Advances Musculoskelet Disorders 2: 95–104.CrossRefGoogle Scholar
  22. 22.
    Fidelix T.S., C.R. Macedo, L.J. Maxwell, V. Fernandes Moca Trevisani. 2014. Diacerein for osteoarthritis. Cochrane Database of Systematic Reviews 10.Google Scholar
  23. 23.
    Kikuchi, T., T. Sakuta, and T. Yamaguchi. 1998. Intra-articular injection of collagenase induces experimental osteoarthritis in mature rabbits. Osteoarthritis and Cartilage 6: 177–186.PubMedCrossRefGoogle Scholar
  24. 24.
    Kikuchi, T., H. Yamada, and M. Shimmei. 1996. Effect of high molecular weight hyaluronan on cartilage degeneration in a rabbit model of osteoarthritis. Osteoarthritis and Cartilage 4: 99–110.PubMedCrossRefGoogle Scholar
  25. 25.
    Green, L.C., D.A. Wagner, J. Glogowski, P.L. Skipper, J.S. Wishnok, and S.R. Tannenbaum. 1982. Analysis of nitrate, nitrite, and [< sup > 15</sup > N] nitrate in biological fluids. Analytical Biochemistry 126: 131–138.PubMedCrossRefGoogle Scholar
  26. 26.
    Eyre, D.R., M.A. Weis, and J.J. Wu. 2006. Articular cartilage collagen: an irreplaceable framework? European Cells & Materials 12: 57–63.Google Scholar
  27. 27.
    Legendre, F., C. Bauge, R. Roche, A.S. Saurel, and J.P. Pujol. 2008. Chondroitin sulfate modulation of matrix and inflammatory gene expression in IL-1beta-stimulated chondrocytes—study in hypoxic alginate bead cultures. Osteoarthritis and Cartilage 16: 105–114.PubMedCrossRefGoogle Scholar
  28. 28.
    Malemud, C.J. 2004. Cytokines as therapeutic targets for osteoarthritis. BioDrugs 18: 23–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Han, Z., D.L. Boyle, L. Chang, B. Bennett, M. Karin, L. Yang, A.M. Manning, and G.S. Firestein. 2001. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. Journal of Clinical Investigation 108: 73–81.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Legendre, F., P. Bogdanowicz, G. Martin, F. Domagala, S. Leclercq, J.P. Pujol, and H. Ficheux. 2007. Rhein, a diacerhein-derived metabolite, modulates the expression of matrix degrading enzymes and the cell proliferation of articular chondrocytes by inhibiting ERK and JNK-AP-1 dependent pathways. Clinical and Experimental Rheumatology 25: 546–555.PubMedGoogle Scholar
  31. 31.
    Martinez-Gonzalez, J., R. Rodriguez-Rodriguez, M. Gonzalez-Diez, C. Rodriguez, M.D. Herrera, V. Ruiz-Gutierrez, and L. Badimon. 2008. Oleanolic acid induces prostacyclin release in human vascular smooth muscle cells through a cyclooxygenase-2-dependent mechanism. Journal of Nutrition 138: 443–448.PubMedGoogle Scholar
  32. 32.
    Chen, T.H., C.F. Chang, S.C. Yu, J.C. Wang, C.H. Chen, P. Chan, and H.M. Lee. 2009. Dipyridamole inhibits cobalt chloride-induced osteopontin expression in NRK52E cells. European Journal of Pharmacology 613: 10–18.PubMedCrossRefGoogle Scholar
  33. 33.
    Chun, K.S., S.H. Kim, Y.S. Song, and Y.J. Surh. 2004. Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. Carcinogenesis 25: 713–722.PubMedCrossRefGoogle Scholar
  34. 34.
    Tsutsumi, R., H. Ito, T. Hiramitsu, K. Nishitani, M. Akiyoshi, T. Kitaori, T. Yasuda, and T. Nakamura. 2008. Celecoxib inhibits production of MMP and NO via down-regulation of NF-kappaB and JNK in a PGE2 independent manner in human articular chondrocytes. Rheumatology International 28: 727–736.PubMedCrossRefGoogle Scholar
  35. 35.
    Annamanedi, M., and A.M. Kalle. 2014. Celecoxib sensitizes Staphylococcus aureus to antibiotics in macrophages by modulating SIRT1. PLoS One 9: e99285.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Domagala, F., G. Martin, P. Bogdanowicz, H. Ficheux, and J.P. Pujol. 2006. Inhibition of interleukin-1beta-induced activation of MEK/ERK pathway and DNA binding of NF-kappaB and AP-1: potential mechanism for diacerein effects in osteoarthritis. Biorheology 43: 577–587.PubMedGoogle Scholar
  37. 37.
    Boileau, C., S.K. Tat, J.P. Pelletier, S. Cheng, and J. Martel-Pelletier. 2008. Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Research & Therapy 10: R71.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zhifu Li
    • 1
  • Dongdong Meng
    • 2
  • Guangheng Li
    • 1
  • Jianzhong Xu
    • 1
  • Ke Tian
    • 1
  • Yu Li
    • 1
  1. 1.Department of Orthopaedic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China
  2. 2.Department of EndocrinologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China

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