Biological Trace Element Research

, Volume 187, Issue 2, pp 367–375 | Cite as

The Importance of Se-Related Genes in the Chondrocyte of Kashin–Beck Disease Revealed by Whole Genomic Microarray and Network Analysis

  • Sen Wang
  • Guanghui Zhao
  • Wanzhen Shao
  • Huan Liu
  • Weizhuo Wang
  • Cuiyan Wu
  • Mikko J. Lammi
  • Xiong Guo


Kashin–Beck disease (KBD) is an endemic, chronic, and degenerative osteoarthropathy. Selenium (Se) deficiency plays important role in the pathogenesis of KBD. We aimed to screen Se-related gene from chondrocytes of patients with KBD. Whole-genome oligonucleotide microarrays were used to detect differentially expressed genes. qRT-PCR was used to confirm the microarray results. Comparative Toxicogenomics Database (CTD) was used to screen Se-related genes from differentially expressed genes. Gene Ontology (GO) classifications and network analysis of Se-related genes were constituted by STRING online system. Three hundred ninety-nine differentially expressed genes were obtained from microarray. Among them, 54 Se-related genes were identified by CTD. The qRT-PCR validation showed that four genes expressed similarly with the ones in the microarray transcriptional profiles. The Se-related genes were categorized into 6 cellular components, 8 molecular functions, 44 biological processes, 10 pathways, and 1 network by STRING. The Se-related gene insulin-like growth factor binding protein 2 (IGFBP2), insulin-like growth factor binding protein 3 (IGFBP3), interleukin 6 (IL6), BCL2, apoptosis regulator (BCL2), and BCL2-associated X, apoptosis regulator (BAX), which involved in many molecular functions, biological processes, and apoptosis pathway may play important roles in the pathogenesis of KBD.


Trace element Selenium Kashin–Beck disease Chondrocyte Microarray STRING 



This study was supported by grants from the National Natural Science Foundation of China (81402638, 81472924, and 81502766) and Key International Cooperation Projects from National Natural Science Foundation of China (81620108026).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12011_2018_1404_Fig2_ESM.png (1.5 mb)

The mRNA levels for IGFBP2, IL6, APOL3 and FBLN1 in chondrocytes of KBD patients and controls. The lines inside the boxes denote the medians. The boxes mark the interval between the 25 and 75 percentiles. The whiskers denote the interval between the 10 and 90 percentiles (PNG 1556 kb)

12011_2018_1404_MOESM1_ESM.tif (503 kb)
High resolution image (TIF 503 kb)
12011_2018_1404_MOESM2_ESM.docx (48 kb)
ESM 2 (DOCX 48 kb)


  1. 1.
    Wang S, Guo X, Wang W, Wang S (2012) Genome-wide study identifies the regulatory gene networks and signaling pathways from chondrocyte and peripheral blood monocyte of Kashin-Beck disease. Genes Cells 17:619–632. CrossRefPubMedGoogle Scholar
  2. 2.
    Yao Y, Pei F, Kang P (2011) Selenium, iodine, and the relation with Kashin-Beck disease. Nutrition 27:1095–1100. CrossRefPubMedGoogle Scholar
  3. 3.
    Wang S, Duan C, Zhang F, Wang X, Guo X (2016) The roles of the interaction of BCL2-antagonist/killer 1, apoptotic peptidase activating factor 1 and selenium in the pathogenesis of Kashin-Beck disease. Biol Trace Elem Res 170:17–24. CrossRefPubMedGoogle Scholar
  4. 4.
    Xiong YM, Mo XY, Zou XZ, Song RX, Sun WY, Lu W, Chen Q, Yu YX, Zang WJ (2010) Association study between polymorphisms in selenoprotein genes and susceptibility to Kashin-Beck disease. Osteoarthr Cartil 18:817–824. CrossRefPubMedGoogle Scholar
  5. 5.
    Du X, Dai XX, Xia SR, Zou XZ, Yan SW, Mo XY, Lu BG, Xiong YM (2012) SNP and mRNA expression for glutathione peroxidase 4 in Kashin-Beck disease. Br J Nutr 107:164–169. CrossRefPubMedGoogle Scholar
  6. 6.
    Wang J, Li H, Li Y, Yu J, Yang L, Feng F, Chen Z (2013) Speciation, distribution, and bioavailability of soil selenium in the Tibetan Plateau Kashin-beck disease area-a case study in Songpan County, Sichuan Province, China. Biol Trace Elem Res 156:367–375. CrossRefPubMedGoogle Scholar
  7. 7.
    Yang HJ, Zhang Y, Wang ZL, Xue SH, Li SY, Zhou XR, Zhang M, Fang Q, Wang WJ, Chen C, Deng XH, Chen JH (2017) Increased chondrocyte apoptosis in Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency. Biomed Environ Sci 30:351–362. CrossRefPubMedGoogle Scholar
  8. 8.
    Dai X, Li Y, Zhang R, Kou Y, Mo X, Cao J, Xiong Y (2016) Effects of sodium selenite on c-Jun N-terminal kinase signalling pathway induced by oxidative stress in human chondrocytes and c-Jun N-terminal kinase expression in patients with Kashin-Beck disease, an endemic osteoarthritis. Br J Nutr 115:1547–1555. CrossRefPubMedGoogle Scholar
  9. 9.
    Yu FF, Zhang YX, Zhang LH, Li WR, Guo X, Lammi MJ (2016) Identified molecular mechanism of interaction between environmental risk factors and differential expression genes in cartilage of Kashin-Beck disease. Medicine (Baltimore) 95:e5669. CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Chen J, Chu Y, Cao J, Yang Z, Guo X, Wang Z (2006) T-2 toxin induces apoptosis, and selenium partly blocks, T-2 toxin induced apoptosis in chondrocytes through modulation of the Bax/Bcl-2 ratio. Food Chem Toxicol 44:567–573. CrossRefPubMedGoogle Scholar
  11. 11.
    Zhou X, Wang Z, Chen J, Wang W, Song D, Li S, Yang H, Xue S, Chen C (2014) Increased levels of IL-6, IL-1beta, and TNF-alpha in Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency. Rheumatol Int 34:995–1004. CrossRefPubMedGoogle Scholar
  12. 12.
    Wang X, Wang S, He S, Zhang F, Tan W, Lei Y, Yu H, Li Z, Ning Y, Xiang Y, Guo X (2013) Comparing gene expression profiles of Kashin-Beck and Keshan diseases occurring within the same endemic areas of China. Sci China Life Sci 56:797–803. CrossRefPubMedGoogle Scholar
  13. 13.
    Wu SX, Wang WZ, Zhang F, Wu CY, Dennis BS, Qu CJ, Bai YD, Guo X (2014) Expression profiles of genes involved in apoptosis and selenium metabolism in articular cartilage of patients with Kashin-Beck osteoarthritis. Gene 535:124–130. CrossRefPubMedGoogle Scholar
  14. 14.
    Wang X, Ning Y, Tan W, Yu H, Li Z, Guo X (2016) Population-based comparative analysis of differentially expressed genes between Kashin-Beck disease grades I and II. Scand J Rheumatol 45:230–235. CrossRefPubMedGoogle Scholar
  15. 15.
    Davis AP, Grondin CJ, Johnson RJ, Sciaky D, King BL, McMorran R, Wiegers J, Wiegers TC, Mattingly CJ (2017) The Comparative Toxicogenomics Database: update 2017. Nucleic Acids Res 45:D972–D978. CrossRefPubMedGoogle Scholar
  16. 16.
    Liu R, Fan L, Yin L, Wang K, Miao W, Song Q, Dang X, Gao H, Bai C (2015) Comparative study of serum proteomes in Legg-Calve-Perthes disease. BMC Musculoskelet Disord 16:281. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang S, Duan C, Liu H, Shao W, Wu C, Han J, Guo X (2016) The roles of selenium, insulin-like growth factor binding protein 2 and suppressor of cytokine signaling 3 in the pathogenesis of Kashin-Beck disease. Biomarkers 21:409–415. CrossRefPubMedGoogle Scholar
  18. 18.
    Schlicht M, Matysiak B, Brodzeller T, Wen X, Liu H, Zhou G, Dhir R, Hessner MJ, Tonellato P, Suckow M, Pollard M, Datta MW (2004) Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium. BMC Genomics 5(58):58. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Le Roith D, Bondy C, Yakar S, Liu JL, Butler A (2001) The somatomedin hypothesis: 2001. Endocr Rev 22:53–74. CrossRefPubMedGoogle Scholar
  20. 20.
    Gao ZQ, Guo X, Duan C, Ma W, Xu P, Wang W, Chen JC (2012) Altered aggrecan synthesis and collagen expression profiles in chondrocytes from patients with Kashin-Beck disease and osteoarthritis. J Int Med Res 40:1325–1334. CrossRefPubMedGoogle Scholar
  21. 21.
    Kiepe D, Ulinski T, Powell DR, Durham SK, Mehls O, Tonshoff B (2002) Differential effects of insulin-like growth factor binding proteins-1, -2, -3, and -6 on cultured growth plate chondrocytes. Kidney Int 62:1591–1600. CrossRefPubMedGoogle Scholar
  22. 22.
    Patil SS, Railkar R, Swain M, Atreya HS, Dighe RR, Kondaiah P (2015) Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion. J Neuro-Oncol 123:225–235. CrossRefGoogle Scholar
  23. 23.
    Wei Z, Li HH (2015) IGFBP-3 may trigger osteoarthritis by inducing apoptosis of chondrocytes through Nur77 translocation. Int J Clin Exp Pathol 8:15599–15610PubMedPubMedCentralGoogle Scholar
  24. 24.
    Evans DS, Cailotto F, Parimi N, Valdes AM, Castano-Betancourt MC, Liu Y, Kaplan RC, Bidlingmaier M, Vasan RS, Teumer A et al (2015) Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. Ann Rheum Dis 74:1861–1867. CrossRefPubMedGoogle Scholar
  25. 25.
    Makki MS, Haseeb A, Haqqi TM (2015) MicroRNA-9 promotion of interleukin-6 expression by inhibiting monocyte chemoattractant protein-induced protein 1 expression in interleukin-1beta-stimulated human chondrocytes. Arthritis Rheumatol 67:2117–2128. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Blom AB, van Lent PL, Libregts S, Holthuysen AE, van der Kraan PM, van Rooijen N, van den Berg WB (2007) Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum 56:147–157. CrossRefPubMedGoogle Scholar
  27. 27.
    Poree B, Kypriotou M, Chadjichristos C, Beauchef G, Renard E, Legendre F, Melin M, Gueret S, Hartmann DJ, Mallein-Gerin F et al (2008) Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem 8:4850–4865CrossRefGoogle Scholar
  28. 28.
    Liu JT, Guo X, Ma WJ, Zhang YG, Xu P, Yao JF, Bai YD (2010) Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin-Beck disease. Osteoarthr Cartil 18:1218–1226. CrossRefPubMedGoogle Scholar
  29. 29.
    Wang SJ, Guo X, Zuo H, Zhang YG, Xu P, Ping ZG, Zhang Z, Geng D (2006) Chondrocyte apoptosis and expression of Bcl-2, Bax, Fas, and iNOS in articular cartilage in patients with Kashin-Beck disease. J Rheumatol 33:615–619PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sen Wang
    • 1
    • 2
  • Guanghui Zhao
    • 3
  • Wanzhen Shao
    • 1
    • 2
  • Huan Liu
    • 1
    • 2
  • Weizhuo Wang
    • 4
  • Cuiyan Wu
    • 1
    • 2
  • Mikko J. Lammi
    • 1
    • 2
    • 5
    • 6
  • Xiong Guo
    • 1
    • 2
    • 6
  1. 1.School of Public HealthHealth Science Center of Xi’an Jiaotong UniversityXi’anChina
  2. 2.Key Laboratory of Trace Elements and Endemic DiseasesNational Health and Family Planning CommissionXi’anChina
  3. 3.Xi’an Honghui HospitalHealth Science Center of Xi’an Jiaotong UniversityXi’anChina
  4. 4.Orthopedic Departmentthe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  5. 5.Department of Integrative Medical BiologyUniversity of UmeåUmeåSweden
  6. 6.Xi’anChina

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