Objective: To investigate the effects of 3 mycotoxins, deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, in the presence and absence of selenium (Se) on the metabolism of tissue-engineered cartilage to mimic conditions found in Kashin-Beck disease (KBD) environments. Materials and Methods: Chondrocytes were seeded onto bone matrix gelatin (BMG) to construct engineered cartilage. The 3 toxins were added to the culture media for 3 weeks followed by immunhistochemical analyses of collagens type II and X, aggrecan, matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3), MMP inhibitors 1 and 3 (TIMP-1 and TIMP-3) and α2 macroglobulin (α2M). Results: Type II collagen was decreased while type X collagen was increased in response to DON, NIV and T-2 toxin. Aggrecan was reduced by all 3 mycotoxins. Compared with the control, the 3 toxins decreased the expression of α2M, TIMP-1 and TIMP-3, and increased the expression of MMP-1 and MMP-3. Se could partially inhibit the effects of DON, NIV and T-2 toxins. Conclusion: Under the low Se condition, the 3 mycotoxins produced procatabolic changes in cartilage resulting in the loss of aggrecan and type II collagen and promoted a hypertrophic phenotype of chondrocytes characterized by increasing type-X-collagen expression, enhancing the expression of MMPs, while weakening the TIMPs. Se could partially block the effects mentioned above. These results support the hypothesis that the combination of mycotoxin stress and Se deficiency would be the causative factors for KBD.

Keywords:
Mycotoxins, Kashin-Beck disease, Aggrecan, Collagen, Matrix metalloproteinases, Selenium deficiency
1.
Bai, C., S.M. Lv, Z.L. Wang, L. Xue (1996) Empirical study of seven trace elements and KBD pathogenetic condition. Chin J Control Endem Dis 15: 64–70.
2.
Bao, B.J., G.X. Gou, M.L. Bao, B.R. Ding, R.G. Xiao, L.Y. Zhang (1997) Study on the content of hair Se and blood GSH-Px activity of people in endemic goiter, Keshan disease and Kashin-Beck disease areas in Henan province. Trace Elem Sci 4: 16–18.
3.
Bi, H.Y., S.Y. Zhang, Y. Luo, J.L. Feng, S.X. Wu, K.Y. Kuang (2001) A comparative investigation on the role of fungi and their toxins in food from diseased area of Shaanxi province in both causes of Keshan disease and Kashin-Beck disease (in Chinese). J Xi’an Med Univ 22: 308–311.
4.
Billinghurst, R.C., L. Dahlberg, M. Ionescu, A. Reiner, R. Bourne, C. Rorabeck (1997) Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest 99: 1534–1545.
5.
Cao, J.L., S.Y. Li, Z.L. Shi, Y. Yue, J. Sun, J.H. Chen (2008) Articular cartilage metabolism in patients with Kashin-Beck disease: an endemic osteoarthropathy in China. Osteoarthritis Cartilage 16: 680–688.
6.
Cao, J.L., Y.M. Xiong, S.Y. Zhang, D.X. Mo (1995) The experimental study of effect of mycotoxin DON, T-2 and NIV on the cultural chondrocytes. Chin J Control Endem Dis 10: 69–71.
7.
Chen, J.H., J.L. Cao, Y.L. Chu, Z.T. Yang, Z.L. Shi, H.L. Wang (2006) Protective effect of selenium against T-2 toxin-induced inhibition of chondrocyte aggrecan and collagen II synthesis. Nan Fang Yi Ke Da Xue Xue Bao 26: 381–385.
8.
Chen, J.H., Z.L. Wang, H.J. Yang, S.H. Xue, D.Q. Song, L. Dong (2010) Histopathology of chondronecrosis in knee articular cartilage of rat at T-2 toxin and selenium deficiency conditions. Chin J Control Endem Dis 25: 98–101.
9.
Christopher, B.L., T.M. Clare, B.G. Suzanne, E.L. Kate, J.F. Pamela, M.S. Susan (2007) Recent studies identifying aggrecanase-2 (ADAMTS-5) as the predominant aggrecanase in mouse cartilage have not distinguished aggrecanolysis in the IGD from aggrecanolysis in the CS-2 domain. J Clin Invest 17: 1–10.
10.
Chu, R.Q., J.L. Cao, J.F. Zhang, L. Xie, Y. Yue, X.P. Hu (2003) The effect of nivalenol on metabolism of cultured chondrocytes and the protection of selenium. J Nanjing Med Univ 17: 97–105.
11.
Guo, X., T. Aigner, P. Lammi, M.J. Lammi, J.R. Zhang, J.M. Wang, F.Q. Zhang (1998) A study on abnormal chondrocyte differentiation and abnormal expression of collagen types in articular cartilage from patients with Kaschin-Beck disease. Chin J Pathol 27: 19–22.
12.
Guo, X., S.Y. Zhang, D.X. Mo (1993) The effects of low selenium on KBD. Chin J Control Endem Dis 8: 82–84.
13.
Li, Q.W., X.M. Li, H.S. Hou (2005) Study on the correlation of severe-degree osteoarthritis and DON levels in food. Chin J Control Endem Dis 20: 333–335.
14.
Li, S.Y., J.L. Cao, Z.L. Shi, J.H. Chen, Z.T. Zhang, H.E. Clare (2008) Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect. J Zhejiang Univ-Sci B 9: 22–33.
15.
Li, X.D., L. Jin, B. Gary, C.T. Laurencin, D.G. Anderson (2006) Demineralized bone matrix gelatin as scaffold for osteochondral tissue engineering. Biomaterials 27: 2426–2433.
16.
Liang, L.J. (2008) Selenium element and health. J Med Theory Pract 21: 287–288.
17.
Little, C.B., C.E. Hughes, C.L. Curtis, M.J. Janusz, R. Bohne, W.G. Wang (2002) Matrix metalloproteinases are involved in C-terminal and interglobular domain processing of cartilage aggrecan in late stage cartilage degradation. Matrix Biol 21: 271–288.
18.
Luo, Y., J.S. Zheng, J. Yang, F. Liu, Z.S. Ze, S.Y. Zhang (1992) Determination of fusarium mycotoxins in corn and wheat from Kaschin Beck disease areas. Chin J Control Endem Dis 7: 71–75.
19.
Mo, D.X. (1996) Effects of T-2 toxin moniliformin and selenium on osteo-chondrosis of the Chinese minipig. Chin J Control Endem Dis 11: 130–133.
20.
Mwale, F., C. Billinghurst, W. Wu, M. Alini, C. Webber, A. Reiner, M. Ionescu, J. Poole, A.R. Poole (2000) Selective assembly and remodelling of collagens II and IX associated with expression of the chondrocyte hypertrophic phenotype. Dev Dyn 218: 648–662.
21.
Mwale, F., D. Stachura, P. Roughley, J. Antoniou (2006) Limitations of using aggrecan and type X collagen as markers of chondrogenesis in mesenchymal stem cell differentiation. J Orthop Res 24: 1791–1798.
22.
Mwale, F., E. Tchetina, C.W. Wu, A.R. Poole (2002) The assembly and remodeling of the extracellular matrix in the growth plate in relationship to mineral deposition and cellular hypertrophy: an in situ study of collagens II and IX and proteoglycan. J Bone Miner Res 17: 275–283.
23.
Peng, S.Q., X.L. Yu, B.Z. Wang, Y. Yang, Z.F. Zheng, J.S. Yang (1993) Injurious effect of fusarial toxin on articular chondrocytes and protective effect of selenium. Chin J Control Endem Dis 8: 258–259.
24.
Poole, A.R., S. Laverty, F. Mwale (2000) Endochondral bone formation and development in the axial and appendicular skeleton; in Henderson, J.E., Goltzman, D. (eds): The Osteoporosis Primer. Cambridge, Cambridge University Press, pp 3–17.
25.
Ren, F.L., X. Guo, R.J. Zhang, S.J. Wang, H. Zuo, Z.T. Zhang (2007) Effects of selenium and iodine deficiency on bone, cartilage growth plate and chondrocyte differentiation in two generations of rats. Osteoarthritis Cartilage 15: 1171–1177.
26.
Stone, R. (2009) A medical mystery in middle China. Science 325: 392–393.
27.
Tchetina, E., F. Mwale, A.R. Poole (2003) Distinct phases of coordinated early and late gene expression in growth plate chondrocytes in relationship to cell proliferation, matrix assembly, remodeling, and cell differentiation. J Bone Miner Res 18: 844–851.
28.
Wang, H.Y., Z. Chen (2008) The pair matching study for the relation between KBD and selenium. Chin J Control Endem Dis 23: 59–60.
29.
Wang, Z.L, J.H. Chen, Y.M. Xiong, W.J. Liu, X.W. Tan, Z.T. Yang (2003) The prevalent growth and decline studies on results of national Kaschin-Beck disease surveillance in Shaanxi province from 1992 to 2002. Chin J Control Endem Dis 18: 137–139.
30.
Wang, Z.L. (2005) Synchronous study on the four kinds of etiological hypotheses of Kashin-Beck disease. J Xi’an Jiaotong Univ Med Sci 26: 1–7.
31.
Xie, L., J.L. Cao, Y. Yue, J.H. Zhu, Z.T. Zhang, F.J. Zhang (2003) Study on the effect of T-2 toxin and selenium on CD44 expression in the cultured human fetal chondrocytes in vitro. Acad J Xi’an Jiaotong Univ 15: 78–81.
32.
Xiong, Y.M., Z.L. Wang, X.X. Dai, Q. Chen, Z.L. Yang, X.W. Tan (2003) Relationship of human parvovirus B19 with selenium and Kaschin-Beck disease. Chin J Control Endem Dis 22: 16–20.
33.
Yang, J.B., L. Li, D.J. Sun, B. Gao (1994) Observation on mycotoxin-problem of fusarium produced in maize of the Kashin-Beck disease endemic area. Chin J Endemiol 13: 321–322.
34.
Yang, J.B., D.J. Sun, Z.W. Wang (1995) Determination of T-2 toxin in the staple food from the sick families in Kaschin-Beck disease (KBD) areas. Chin J Endemiol 14: 146–149.
35.
Yang, Z.T., X. Guo, J.H. Chen, Z.L. Wang, J.L. Cao, Y.M. Xiong (2008) Effects of T-2 toxin on NO production and iNOS expression in chondrocytes. Shaanxi Med J 37: 1115–1117.
36.
Yue, Y., J.L. Cao, S.Y. Li, L. Xie, J. Sun, Z.T. Zhang (2005) The effect on proteoglycan metabolism of deoxynivalenol and selenium in the cultured human fetal chondrocytes in vitro. Acad J Xi’an Jiaotong Univ 17: 151–154.
37.
Zhang, A., J.L. Cao, B. Yang, J.H. Chen, Z.T. Zhang, S.Y. Li (2010) Effects of moniliformin and selenium on human articular cartilage metabolism and their potential relationships to the pathogenesis of Kaschin-Beck disease. J Zhejiang Univ-Sci B 11: 200–208.
38.
Zhang, B.J., L.S. Yang, W.Y. Wang, Y.H. Li, H.R. Guo (2009) Selenium in the environment and its relationship with Kaschin-Beck disease in Rangtang county, Sichuan province. Prog Geogr 28: 886–891.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.