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Naringin Protects Against Cartilage Destruction in Osteoarthritis Through Repression of NF-κB Signaling Pathway

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Abstract

Naringin was previously reported as a multifunctional agent. Recently, naringin was found to play a protective role in various inflammatory conditions. However, the role of naringin in cartilage degeneration and osteoarthritis (OA) progression is still unknown. TNF-α is reported to play a detrimental role in OA. Herein, primary murine chondrocytes were isolated and cultured with stimulation of TNF-α, in the presence or absence of naringin treatment. As a result, naringin attenuated TNF-α-mediated inflammation and catabolism in chondrocyte. Besides, surgically induced OA mice models were established. Cartilage degradation and OA severity were evaluated using Safranin-O staining, immunohistochemistry, and ELISA. Moreover, levels of inflammatory cytokines and catabolic markers in OA were analyzed. Oral administration of naringin alleviated degradation of cartilage matrix and protected against OA development in the surgically induced OA models. Furthermore, the protective function of naringin in cartilage and chondrocyte was possibly due to suppression of NF-κB signaling pathway. Collectively, this study presents naringin as a potential target for the treatment of joint degenerative diseases, including OA.

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Abbreviations

WT:

Wild type

OA:

Osteoarthritis

RA:

Rheumatoid arthritis

TNF-α:

Tumor necrosis factor α

MMP13:

Matrix metallopeptidase 13

ADAMTS:

A disintegrin and metalloproteinase with thrombospondin motifs

ACLT:

Anterior cruciate ligament transaction

References

  1. Kapoor, M., J. Martel-Pelletier, D. Lajeunesse, J.P. Pelletier, and H. Fahmi. 2011. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7: 33–42.

    Article  CAS  PubMed  Google Scholar 

  2. Johnson, K., S. Zhu, M.S. Tremblay, J.N. Payette, J. Wang, L.C. Bouchez, S. Meeusen, A. Althage, C.Y. Cho, X. Wu, and P.G. Schultz. 2012. A stem cell-based approach to cartilage repair. Science 336: 717–721.

    Article  CAS  PubMed  Google Scholar 

  3. Zhen, G., C. Wen, X. Jia, Y. Li, J.L. Crane, S.C. Mears, F.B. Askin, F.J. Frassica, W. Chang, J. Yao, J.A. Carrino, A. Cosgarea, D. Artemov, Q. Chen, Z. Zhao, X. Zhou, L. Riley, P. Sponseller, M. Wan, W.W. Lu, and X. Cao. 2013. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19: 704–712.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Cao, X., W. Lin, C. Liang, D. Zhang, F. Yang, Y. Zhang, X. Zhang, J. Feng, and C. Chen. 2015. Naringin rescued the TNF-alpha-induced inhibition of osteogenesis of bone marrow-derived mesenchymal stem cells by depressing the activation of NF-small ka. CyrillicB signaling pathway, Immunol Res 62: 357–367.

    CAS  PubMed  Google Scholar 

  5. Golechha, M., V. Sarangal, J. Bhatia, U. Chaudhry, D. Saluja, and D.S. Arya. 2014. Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress, inflammation, and cognitive impairment in rats: possible mechanisms of neuroprotection. Epilepsy Behav 41: 98–102.

    Article  PubMed  Google Scholar 

  6. Manna, K., U. Das, D. Das, S.B. Kesh, A. Khan, A. Chakraborty, and S. Dey. 2015. Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes. Free Radic Res 49: 422–439.

    Article  CAS  PubMed  Google Scholar 

  7. Kawaguchi, K., H. Maruyama, R. Hasunuma, and Y. Kumazawa. 2011. Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the Citrus flavanone naringin. Immunopharmacol Immunotoxicol 33: 723–729.

    Article  CAS  PubMed  Google Scholar 

  8. Zhao, Y.P., B. Liu, Q.Y. Tian, J.L. Wei, B. Richbourgh, and C.J. Liu. 2014. Progranulin protects against osteoarthritis through interacting with TNF-alpha and beta-Catenin signalling. Ann Rheum Dis doi: 10.1136/annrheumdis-2014-205779.

  9. Bowles, R.D., B.A. Mata, R.D. Bell, T.K. Mwangi, J.L. Huebner, V.B. Kraus, and L.A. Setton. 2014. In vivo luminescence imaging of NF-kappaB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis. Arthritis Rheumatol 66: 637–646.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Li, W., C. Wang, J. Peng, J. Liang, Y. Jin, Q. Liu, Q. Meng, K. Liu, and H. Sun. 2014. Naringin inhibits TNF-alpha induced oxidative stress and inflammatory response in HUVECs via Nox4/NF-kappa B and PI3K/Akt pathways. Curr Pharm Biotechnol 15: 1173–1182.

    Article  CAS  PubMed  Google Scholar 

  11. Chen, W.H., W.C. Lo, W.C. Hsu, H.J. Wei, H.Y. Liu, C.H. Lee, S.Y. Tina Chen, Y.H. Shieh, D.F. Williams, and W.P. Deng. 2014. Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy. Biomaterials 35: 9599–9607.

    Article  CAS  PubMed  Google Scholar 

  12. Lorenz, J., and S. Grassel. 2014. Experimental osteoarthritis models in mice. Methods Mol Biol 1194: 401–419.

    Article  PubMed  Google Scholar 

  13. Koenders, M.I., E. Lubberts, B. Oppers-Walgreen, L. van den Bersselaar, M.M. Helsen, J.K. Kolls, L.A. Joosten, and W.B. van den Berg. 2005. Induction of cartilage damage by overexpression of T cell interleukin-17A in experimental arthritis in mice deficient in interleukin-1. Arthritis Rheum 52: 975–983.

    Article  CAS  PubMed  Google Scholar 

  14. Gosset, M., F. Berenbaum, S. Thirion, and C. Jacques. 2008. Primary culture and phenotyping of murine chondrocytes. Nat Protoc 3: 1253–1260.

    Article  CAS  PubMed  Google Scholar 

  15. Tang, W., Y. Lu, Q.Y. Tian, Y. Zhang, F.J. Guo, G.Y. Liu, N.M. Syed, Y. Lai, E.A. Lin, L. Kong, J. Su, F. Yin, A.H. Ding, A. Zanin-Zhorov, M.L. Dustin, J. Tao, J. Craft, Z. Yin, J.Q. Feng, S.B. Abramson, X.P. Yu, and C.J. Liu. 2011. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332: 478–484.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Shuang, F., S.X. Hou, J.L. Zhu, Y. Liu, Y. Zhou, C.L. Zhang, and J.G. Tang. 2015. Establishment of a rat model of lumbar facet joint osteoarthritis using intraarticular injection of urinary plasminogen activator. Sci Rep 5: 9828.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Hu, W., W. Zhang, F. Li, F. Guo, and A. Chen. 2014. Bortezomib prevents the expression of MMP-13 and the degradation of collagen type 2 in human chondrocytes. Biochem Biophys Res Commun 452: 526–530.

    Article  CAS  PubMed  Google Scholar 

  18. Emery P., J. Vencovsky, A. Sylwestrzak, P. Leszczynski, W. Porawska, A. Baranauskaite, V. Tseluyko, V.M. Zhdan, B. Stasiuk, R. Milasiene, A.A. Barrera Rodriguez, S.Y. Cheong, and J. Ghil. 2015. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis doi: 10.1136/annrheumdis-2015-207588

  19. Jani M., H. Chinoy, R.B. Warren, C. Em Griffiths, D. Plant, B. Fu, A.W. Morgan, A.G. Wilson, J.D. Isaacs, K.L. Hyrich, and A. Barton. 2015. Clinical utility of random anti-TNF drug level testing and measurement of anti-drug antibodies on long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol doi: 10.1002/art.39169.

  20. Zhang, D., and Y. Zhou. 2014. The protective effects of Donepezil (DP) against cartilage matrix destruction induced by TNF-alpha. Biochem Biophys Res Commun 454: 115–118.

    Article  CAS  PubMed  Google Scholar 

  21. Buckland, J. 2013. Osteoarthritis: positive feedback between ADAMTS-7 and TNF in OA. Nat Rev Rheumatol 9: 566.

    Article  PubMed  Google Scholar 

  22. Chan, B.Y., E.S. Fuller, A.K. Russell, S.M. Smith, M.M. Smith, M.T. Jackson, M.A. Cake, R.A. Read, J.F. Bateman, P.N. Sambrook, and C.B. Little. 2011. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage 19: 874–885.

    Article  CAS  PubMed  Google Scholar 

  23. Vasheghani, F., Y. Zhang, Y.H. Li, M. Blati, H. Fahmi, B. Lussier, P. Roughley, D. Lagares, H. Endisha, B. Saffar, D. Lajeunesse, W.K. Marshall, Y.R. Rampersaud, N.N. Mahomed, R. Gandhi, J.P. Pelletier, J. Martel-Pelletier, and M. Kapoor. 2015. PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis 74: 569–578.

    Article  PubMed Central  PubMed  Google Scholar 

  24. 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. Ann Rheum Dis 73: 1575–1584.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Chtourou, Y., B. Aouey, M. Kebieche, and H. Fetoui. 2015. Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-kappaB and P53 signaling pathways. Chem Biol Interact 239: 76–86.

    Article  CAS  PubMed  Google Scholar 

  26. Hui W., D.A. Young, A.D. Rowan, X. Xu, T.E. Cawston, and C.J. Proctor. 2014. Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Ann Rheum Dis doi: 10.1136/annrheumdis-2014-206295.

  27. Lianxu, C., J. Hongti, and Y. Changlong. 2006. NF-kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis Cartilage 14: 367–376.

    Article  CAS  PubMed  Google Scholar 

  28. Saito, T., A. Fukai, A. Mabuchi, T. Ikeda, F. Yano, S. Ohba, N. Nishida, T. Akune, N. Yoshimura, T. Nakagawa, K. Nakamura, K. Tokunaga, U.I. Chung, and H. Kawaguchi. 2010. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 16: 678–686.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported partly by the Natural Science Foundation of Shandong Province (ZR2011CM022 to Ruifeng Li), Foundation of Shandong Province Outstanding Young Scientist Research Award (BS2014YY048 to Yunpeng Zhao), and a scientific research grant from Qilu Hospital of Shandong University (26010175616073 to Yunpeng Zhao).

Conflict of Interest

We herein declare that we have no conflict of interest.

Contributors

All authors made substantial contributions to design, execution, and reporting of the manuscript and approved the final version.

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Correspondence to Yunpeng Zhao or Weiwei Li.

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Yunpeng Zhao and Zhong Li contributed equally to this work.

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Zhao, Y., Li, Z., Wang, W. et al. Naringin Protects Against Cartilage Destruction in Osteoarthritis Through Repression of NF-κB Signaling Pathway. Inflammation 39, 385–392 (2016). https://doi.org/10.1007/s10753-015-0260-8

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