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Chitosan oligosaccharides inhibit IL-1β-induced chondrocyte apoptosis via the P38 MAPK signaling pathway

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Abstract

The preventive and therapeutic effects of chitosan oligosaccharides (COS) on osteoarthritis (OA) have been rarely investigated. In this study, the protective effects of COS against IL-1β-induced chondrocyte apoptosis were evaluated and the underlying mechanisms were elucidated. Results showed that COS not only inhibited cell apoptosis in a dose-dependent manner but also ameliorated IL-1β-induced nuclear chromatin damage and mitochondrial membrane potential in chondrocytes. In IL-1β-treated chondrocytes, COS downregulated the expression of Bax and caspase-3 but upregulated the expression of Bcl-2 by inhibiting the phosphorylated p38 mitogen-activated protein kinase (MAPK). COS inhibited the mRNA expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-13 (MMP-13) and enhanced the mRNA expression of the tissue inhibitor of metalloproteinase-1 (TIMP-1). These results suggested that COS effectively inhibits the IL-1β-induced apoptosis of chondrocytes by activating the p38 MAPK signaling pathway. COS may also be used as a unique biological agent to prevent and treat OA.

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References

  1. Hao, C., Gao, L., Zhang, Y., et al.: Acetylated chitosan oligosaccharides act as antagonists against glutamate-induced PC12 cell death via Bcl-2/Bax signal pathway. Mar. Drugs 13, 1267–1289 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Urquhart, D.M., Soufan, C., Teichtahl, A.J., et al.: Factors that may mediate the relationship between physical activity and the risk for developing knee osteoarthritis. Arthritis Res. Ther. 10, 203 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zou, P., Yang, X., Wang, J., et al.: Advances in characterisation and biological activities of chitosan and chitosan oligosaccharides. Food Chem. 190, 1174–1181 (2016)

    Article  CAS  PubMed  Google Scholar 

  4. Azuma, K., Osaki, T., Minami, S., Okamoto, Y.: Anticancer and anti-inflammatory properties of chitin and chitosan oligosaccharides. J. Funct. Biomater. 6, 33–49 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liu, H.T., Li, W.M., Xu, G., et al.: Chitosan oligosaccharides attenuate hydrogen peroxide-induced stress injury in human umbilical vein endothelial cells. Pharmacol. Res. 59, 167–175 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. Fang, I.M., Yang, C.M., Yang, C.H.: Chitosan oligosaccharides prevented retinal ischemia and reperfusion injury via reduced oxidative stress and inflammation in rats. Exp. Eye Res. 130, 38–50 (2015)

    Article  CAS  PubMed  Google Scholar 

  7. Reighard, K.P., Hill, D.B., Dixon, G.A., Worley, B.V., Schoenfisch, M.H.: Disruption and eradication of P. aeruginosa biofilms using nitric oxide-releasing chitosan oligosaccharides. Biofouling 31, 775–787 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Su, Y., Hu, Y., Du, Y., et al.: Redox-responsive polymer-drug conjugates based on doxorubicin and chitosan oligosaccharide-g-stearic acid for cancer therapy. Mol. Pharm. 12, 1193–1202 (2015)

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, P., Liu, W., Peng, Y., Han, B., Yang, Y.: Toll like receptor 4 (TLR4) mediates the stimulating activities of chitosan oligosaccharide on macrophages. Int. Immunopharmacol. 23, 254–261 (2014)

    Article  CAS  PubMed  Google Scholar 

  10. Du, Y., Wang, L., Yuan, H., Hu, F.: Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells. Int. J. Biol. Macromol. 48, 215–222 (2011)

    Article  CAS  PubMed  Google Scholar 

  11. Zhao, D., Wang, J., Tan, L., Sun, C., Dong, J.: Synthesis of N-furoyl chitosan and chito-oligosaccharides and evaluation of their antioxidant activity in vitro. Int. J. Biol. Macromol. 59, 391–395 (2013)

    Article  CAS  PubMed  Google Scholar 

  12. Wang, J., Zhu, X., Liu, L., et al.: Effects of strontium on collagen content and expression of related genes in rat chondrocytes cultured in vitro. Biol. Trace Elem. Res. 153, 212–219 (2013)

    Article  CAS  PubMed  Google Scholar 

  13. Maier, R., Ganu, V., Lotz, M.: Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases. J. Biol. Chem. 268, 21527–21532 (1993)

    CAS  PubMed  Google Scholar 

  14. Bijlsma, J.W., Berenbaum, F., Lafeber, F.P.: Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011)

    Article  PubMed  Google Scholar 

  15. Wojdasiewicz, P., Poniatowski, L.A., Szukiewicz, D.: The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm. 2014, 561459 (2014)

    Article  Google Scholar 

  16. Brandt, K.D., Dieppe, P., Radin, E.: Etiopathogenesis of osteoarthritis. Med. Clin. N. Am. 93, 1–24 (2009)

    Article  PubMed  Google Scholar 

  17. Leonard, J.V., Schapira, A.H.: Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet 355, 299–304 (2000)

    Article  CAS  PubMed  Google Scholar 

  18. Santini, M.T., Cametti, C., Indovina, P.L., Morelli, G., Donelli, G.: Polylysine induces changes in membrane electrical properties of K562 cells. J. Biomed. Mater. Res. 35, 165–174 (1997)

    Article  CAS  PubMed  Google Scholar 

  19. Eichhorn, J.M., Alford, S.E., Sakurikar, N., Chambers, T.C.: Molecular analysis of functional redundancy among anti-apoptotic Bcl-2 proteins and its role in cancer cell survival. Exp. Cell Res. 322, 415–424 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, W., Zhou, J., Qu, Y., et al.: Neuroprotective effect of osthole on MPP+−induced cytotoxicity in PC12 cells via inhibition of mitochondrial dysfunction and ROS production. Neurochem. Int. 57, 206–215 (2010)

    Article  CAS  PubMed  Google Scholar 

  21. Guan, S., Jiang, B., Bao, Y.M., An, L.J.: Protocatechuic acid suppresses MPP+ −induced mitochondrial dysfunction and apoptotic cell death in PC12 cells. Food Chem. Toxicol. 44, 1659–1666 (2006)

    Article  CAS  PubMed  Google Scholar 

  22. Liu, H.T., Li, W.M., Li, X.Y., et al.: Chitosan oligosaccharides inhibit the expression of interleukin-6 in lipopolysaccharide-induced human umbilical vein endothelial cells through p38 and ERK1/2 protein kinases. Basic Clin. Pharmacol. Toxicol. 106, 362–371 (2010)

    Article  CAS  PubMed  Google Scholar 

  23. Moriue, T., Igarashi, J., Yoneda, K., et al.: Sphingosine 1-phosphate attenuates H2O2-induced apoptosis in endothelial cells. Biochem. Biophys. Res. Commun. 368, 852–857 (2008)

    Article  CAS  PubMed  Google Scholar 

  24. Weinberg, J.B., Fermor, B., Guilak, F.: Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair. Subcell. Biochem. 42, 31–62 (2007)

    Article  PubMed  Google Scholar 

  25. de Andres, M.C., Maneiro, E., Martin, M.A., Arenas, J., Blanco, F.J.: Nitric oxide compounds have different effects profiles on human articular chondrocyte metabolism. Arthritis Res. Ther. 15, R115 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhou, P., Liu, S., Peng, H.: The effect of hyaluronic acid on IL-1 beta-induced chondrocyte apoptosis in a rat model of osteoarthritis. J. Orthop. Res. 26, 1643–1648 (2008)

    Article  CAS  PubMed  Google Scholar 

  27. Maneiro, E., Lopez-Armada, M.J., de Andres, M.C., et al.: Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes. Ann. Rheum. Dis. 64, 388–395 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu, G., Chen, T., Chang, H., et al.: Nitric oxide from both exogenous and endogenous sources activates mitochondria-dependent events and induces insults to human chondrocytes. J. Cell. Biochem. 101, 1520–1531 (2007)

    Article  CAS  PubMed  Google Scholar 

  29. Zhong, H., Ding, Q., Chen, W., Luo, R.: Vorinostat, a HDAC inhibitor, showed anti-osteoarthritic activities through inhibition of iNOS and MMP expression, p38 and ERK phosphorylation and blocking NF-kappa B nuclear translocation. Int. Immunopharmacol. 17, 329–335 (2013)

    Article  CAS  PubMed  Google Scholar 

  30. Kim, S.J., Ju, J.W., Oh, C.D., et al.: ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J. Biol. Chem. 277, 1332–1339 (2002)

    Article  CAS  PubMed  Google Scholar 

  31. Kim, S.J., Hwang, S.G., Shin, D.Y., Kang, S.S., Chun, J.S.: p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NF kappa B-dependent transcription and stabilization by serine 15 phosphorylation. J. Biol. Chem. 277, 33501–33508 (2002)

    Article  CAS  PubMed  Google Scholar 

  32. He, B., Tao, H., Liu, S., et al.: Carboxymethylated chitosan protects rat chondrocytes from NOinduced apoptosis via inhibition of the p38/MAPK signaling pathway. Mol. Med. Rep. 13, 2151–2158 (2016)

  33. Zhou, Y., Liu, S.Q., Yu, L., et al.: Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling. Apoptosis 20, 1187–1199 (2015)

    Article  CAS  PubMed  Google Scholar 

  34. Mix, K.S., Mengshol, J.A., Benbow, U., et al.: A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines. Arthritis Rheum. 44, 1096–1104 (2001)

    Article  CAS  PubMed  Google Scholar 

  35. Mengshol, J.A., Mix, K.S., Brinckerhoff, C.E.: Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull’s-eye or missing the mark? Arthritis Rheum. 46, 13–20 (2002)

    Article  CAS  PubMed  Google Scholar 

  36. Meszaros, E., Malemud, C.J.: Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Ther. Adv. Chronic Dis. 3, 219–229 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  37. Omura, K., Takahashi, M., Omura, T., et al.: Changes in the concentration of plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) after total joint replacement in patients with arthritis. Clin. Rheumatol. 21, 488–492 (2002)

    Article  CAS  PubMed  Google Scholar 

  38. Kanwar, J.R., Samarasinghe, R.M., Kumar, K., et al.: Cissus quadrangularis inhibits IL-1beta induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling. Drug Des. Dev. Ther. 9, 2927–2940 (2015)

    Article  Google Scholar 

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Correspondence to Shi-Qing Liu.

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Zhang, C., Yu, L., Zhou, Y. et al. Chitosan oligosaccharides inhibit IL-1β-induced chondrocyte apoptosis via the P38 MAPK signaling pathway. Glycoconj J 33, 735–744 (2016). https://doi.org/10.1007/s10719-016-9667-1

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  • DOI: https://doi.org/10.1007/s10719-016-9667-1

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