Decreased Expression of CHST-12, CHST-13, and UST in the Proximal Interphalangeal Joint Cartilage of School-Age Children with Kashin–Beck Disease: an Endemic Osteoarthritis in China Caused by Selenium Deficiency

  • Yijie Guo
  • Yuan Zhou
  • Siqi Yan
  • Chengjuan Qu
  • Liyun Wang
  • Xiong Guo
  • Jing HanEmail author


The objective of this study is to investigate changes in the expression of enzymes involved in chondroitin sulfate (CS) sulfation in distal articular surface of proximal interphalangeal joint isolated from school-age children patients with Kashin–Beck disease (KBD), using normal children as controls. Articular cartilage samples were collected from four normal and four KBD children (7–12 years old), and these children were assigned to control and KBD groups. Hematoxylin and eosin (H&E), toluidine blue (TB), and immunohistochemical (IHC) stainings were utilized to evaluate changes in joint pathology and expression of enzymes involved in CS sulfation, including carbohydrate sulfotransferase 12 (CHST-12), carbohydrate sulfotransferase 13 (CHST-13), and uronyl 2-O-sulfotransferase (UST). The correspondence results were examined by semi-quantitative analysis. Compared with the control group, the KBD group showed the following: a significant decrease of total chondrocytes in superficial, middle, and deep layers and deposition of sulfated glycosaminoglycans in extracellular matrix of KBD cartilage were observed; positive staining chondrocytes of CHST-12, CHST-13, and UST were significantly less in superficial zone of KBD cartilage; and CHST-13 positive staining chondrocytes was reduced in deep zone of KBD cartilage. In contrast, the positive staining rates of CHST-12, CHST-13, and UST in KBD were significantly higher than those in the control group. The decreased expression of these enzymes and the physiologic compensatory reaction may be the signs of early-stage KBD. The alterations of CS structure modifying sulfotransferases in finger articular cartilage might play an important role in the onset and pathogenesis of school-age KBD children.


Kashin–Beck disease Selenium deficiency Child cartilage Chondroitin sulfate Sulfation Sulfotransferases 



We thank senior technician Zengtie Zhang and Jian Lei from the Public Health Department of Xian Jiaotong University for his support and cooperation in the collection of cartilage specimens and staining.


This study was supported by the National Natural Science Foundation of China (81402639, 81872567) and Shenzhen Science and Technology Project (JCYJ20170816100755047).

Compliance with Ethical Standards

All human experimental procedures followed the protocols approved by the Medical Research Ethics Committee at Xi’an Jiaotong University and were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All the KBD and normal donors or their guardians had provided a written informed consent for the study participation and publication of their individual clinical details and images

Conflict of Interest

The authors declare that they have no conflicts of interest. The authors’ affiliations are shown on the cover page. The authors have sole responsibility for the writing and content of the paper.


  1. 1.
    Allander E (1994) An analysis of research and public health activities based on a bibliography 1849-1992. Scand J Rheumatol 23:1–36CrossRefGoogle Scholar
  2. 2.
    Xiong G (2001) Diagnostic, clinical and radiological characteristics of Kashin-Beck disease in Shaanxi Province, PR China. Int Orthop 25:147–150CrossRefGoogle Scholar
  3. 3.
    Duan C, Xiong G, Zhang XD et al (2010) Comparative analysis of gene expression profiles between primary knee osteoarthritis and an osteoarthritis endemic to northwestern China, Kashin-Beck disease. Arthritis Rheum 62:771–780CrossRefGoogle Scholar
  4. 4.
    Hinsenkamp M (2001) Kashin-Beck disease. Int Orthop 25:133CrossRefGoogle Scholar
  5. 5.
    Fang H, Guo X, Farooq U, Xia C, Dong R (2012) Development and validation of a quality of life instrument for Kashin-Beck disease: an endemic osteoarthritis in China. Osteoarthr Cartil 20:630–637CrossRefGoogle Scholar
  6. 6.
    Guo X, Ma WJ, Zhang F, Ren FL, Qu CJ, Lammi MJ (2014) Recent advances in the research of an endemic osteochondropathy in China: Kashin-Beck disease. Osteoarthr Cartil 22:1774–1783CrossRefGoogle Scholar
  7. 7.
    Sun LY, Li Q, Meng FG, Fu Y, Zhao ZJ, Wang LH (2012) T-2 toxin contamination in grains and selenium concentration in drinking water and grains in Kaschin-Beck disease endemic areas of Qinghai Province. Biol Trace Elem Res 150:371–375CrossRefGoogle Scholar
  8. 8.
    Zhang B, Yang L, Wang W, Li Y, Li H (2011) Environmental selenium in the Kaschin-Beck disease area, Tibetan Plateau, China. Environ Geochem Health 33:495–501CrossRefGoogle Scholar
  9. 9.
    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-1β, and TNF-α in Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency. Rheumatol Int 34:995–1004CrossRefGoogle Scholar
  10. 10.
    Wang W, Xiong G, Chen J et al (2008) Morphology and phenotype expression of types I, II, III, and X collagen and MMP-13 of chondrocytes cultured from articular cartilage of Kashin-Beck disease. J Rheumatol 35:696–702PubMedGoogle Scholar
  11. 11.
    Luo M, Chen J, Li S, Sun H, Zhang Z, Fu Q, Li J, Wang J, Hughes CE, Caterson B, Cao J (2014) Changes in the metabolism of chondroitin sulfate glycosaminoglycans in articular cartilage from patients with Kashin-Beck disease. Osteoarthr Cartil 22:986–995CrossRefGoogle Scholar
  12. 12.
    Du B, Zhou J, Zhou J (2018) Selenium status of children in Kashin-Beck disease endemic areas in Shaanxi, China: assessment with mercury. Environ Geochem Health 40:903–913CrossRefGoogle Scholar
  13. 13.
    Han J, Yu FF, Chang ZP, Yang B, Qu CJ, Zhou TT, Liu RY, Guo X (2015) Changing grains for the prevention and treatment of Kashin-Beck disease in children: a meta-analysis. Biomed Environ Sci 28:308–311PubMedGoogle Scholar
  14. 14.
    Moreno-Reyes R, Suetens C, Mathieu F, Begaux F, Zhu D, Rivera MT, Boelaert M, Nève J, Perlmutter N, Vanderpas J (1998) Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 339:1112–1120CrossRefGoogle Scholar
  15. 15.
    Klüppel M (2010) The roles of chondroitin-4-sulfotransferase-1 in development and disease. Prog Mol Biol Transl Sci 93:113–132CrossRefGoogle Scholar
  16. 16.
    Hubbell JA (2003) Materials as morphogenetic guides in tissue engineering. Curr Opin Biotechnol 14:551–558CrossRefGoogle Scholar
  17. 17.
    Gualeni B, Facchini M, De Leonardis F et al (2010) Defective proteoglycan sulfation of the growth plate zones causes reduced chondrocyte proliferation via an altered Indian hedgehog signalling. Matrix Biol 29:453–460CrossRefGoogle Scholar
  18. 18.
    Wang L, Guo X, Yi J, Qu C, Lei J, Guo Q, Han J (2018) The effects of long-term low selenium diet on the expression of CHST-3, CHST-12 and UST in knee cartilage of growing rats. J Trace Elem Med Biol 50:123–129CrossRefGoogle Scholar
  19. 19.
    Han J, Li D, Qu C, Wang D, Wang L, Guo X, Lammi MJ (2017) Altered expression of chondroitin sulfate structure modifying sulfotransferases in the articular cartilage from adult osteoarthritis and Kashin-Beck disease. Osteoarthr Cartil 25:1372–1375CrossRefGoogle Scholar
  20. 20.
    Qian ZZ, Qian LZ, Wang YZ (1979) A radiographic study on Kashin-Beck’s disease in the skeletal system. The collected works of scientific investigation in Yongshou County. Beijing, China. People’s Health 1982:193–199Google Scholar
  21. 21.
    Li S, Cao J, Caterson B, Hughes CE (2012) Proteoglycan metabolism, cell death and Kashin-Beck disease. Glycoconj J 29:241–248CrossRefGoogle Scholar
  22. 22.
    Sokoloff L (1990) Acquired chondronecrosis. Ann Rheum Dis 49:262–264CrossRefGoogle Scholar
  23. 23.
    Wang S, Guo X, Zuo H et al (2005) Chondrocyte apoptosis and the expression of Bcl-2, Bax, Fas and iNos in articular cartilage in Kashin-Beck disease. J S Med Univ 25:643–646Google Scholar
  24. 24.
    Wang S, Guo X, Ren F, Zhang YG, Zhang ZT, Zhang FJ, Geng D (2006) Comparison of apoptosis of articular chondrocytes in the pathogenesis of Kashin-beck disease and primary osteoarthritis. Acta Acad Med Sin 28:267–270Google Scholar
  25. 25.
    Wang Y, Guo X, Zhang Z et al (2011) Expression of caspase-8 and Bcl-2 in the cartilage loose bodies in patients with Kashin-Beck disease. J S Med Univ 31:1314–1317Google Scholar
  26. 26.
    Li S, Hayes AJ, Caterson B et al (2012) The effect of beta-xylosides on the chondrogenic differentiation of mesenchymal stem cells. Histochem Cell Biol 139:59–74CrossRefGoogle Scholar
  27. 27.
    Mo X (1994) Study on disaccharides and components of glycosaminoglycan in urine from children with Kashin-Beck disease. Chin J Control Endem Dis 9:197–201Google Scholar
  28. 28.
    Wang W, Zhong B, Sun J, Cao J, Tian J, Zhong N, Zhao W, Tian L, Xu P, Guo D, Ju X, Ma W, Li M, Hou W, Lu S (2011) Down-regulated HS6ST2 in osteoarthritis and Kashin-Beck disease inhibits cell viability and influences expression of the genes relevant to aggrecan metabolism of human chondrocytes. Rheumatology (Oxford) 50:2176–2186CrossRefGoogle Scholar
  29. 29.
    Zheng J, Wu C, Ma W, Zhang Y, Hou T, Xu H, Wu S, Yao X, Guo X (2013) Abnormal expression of chondroitin sulphate N-acetylgalactosaminyltransferase 1 and Hapln-1 in cartilage with Kashin-Beck disease and primary osteoarthritis. Int Orthop 37:2051–2059CrossRefGoogle Scholar
  30. 30.
    Yue J, Yang M, Yi S, Dong B, Li W, Yang Z, Lu J, Zhang R, Yong J (2012) Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study. Osteoarthr Cartil 20:622–629CrossRefGoogle Scholar
  31. 31.
    Izumikawa T, Koike T, Kitagawa H (2011) Chondroitin 4-O-sulfotransferase-2 regulates the number of chondroitin sulfate chains initiated by chondroitin N-acetylgalactosaminyltransferase-1. Biochem J 441:697–705CrossRefGoogle Scholar
  32. 32.
    Zhang Y, Dong W, Liu H, Cicuttini F, de Courten M, Yang JB (2010) Effects of chondroitin sulfate and glucosamine in adult patients with Kaschin-Beck disease. Clin Rheumatol 29:357–362CrossRefGoogle Scholar
  33. 33.
    Ohtake S, Kimata K, Habuchi O (2005) Recognition of sulfation pattern of chondroitin sulfate by uronosyl 2-O-sulfotransferase. J Biol Chem 280:39115–39123CrossRefGoogle Scholar
  34. 34.
    Cortes M, Baria AT, Schwartz NB (2009) Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development 136:1697–1706CrossRefGoogle Scholar
  35. 35.
    Liu Y, Yan W, Zhou Q et al (1992) Effect of grain and water from endemic area of Kaschin-Beck disease on cartilage proteoglycans metabolism in rhesus monkey. Chin J Control Endem Dis 7:7–10Google Scholar
  36. 36.
    Zhou Q, Chang S, Bai X et al (1992) Injurious effect of grain and water from endemic areas of Kashin-Beck disease on cartilaginous sulphur metabolism in rhesus monkey. J Jilin Univ 18:12–15Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Key laboratory of Environment and Genes Related to Diseases, Ministry of Education of ChinaXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  2. 2.College of Public Health, Health Science CenterXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  3. 3.Department of Ophthalmology, the First Affiliated Hospital Xi’an Jiaotong UniversityXi’anPeople’s Republic of China
  4. 4.Department of Integrative Medical BiologyUmeå UniversityUmeåSweden
  5. 5.Shenzhen InstituteXi’an Jiaotong UniversityShenzhenPeople’s Republic of China

Personalised recommendations