Deoxynivalenol (DON), a Fusarium trichothecene mycotoxin contaminating cereals, activates Wnt/β-catenin signaling in human chondrocytes and thereby drives cytotoxicity and cartilage matrix catabolism — effects that selenium supplementation suppresses in vitro, a finding proposed to explain how two major environmental risk factors of Kashin-Beck disease (mycotoxin exposure and selenium deficiency) interact. What remains unresolved is the mechanistic identity of both limbs of this axis: the proximal molecular step by which DON elevates Wnt-3a and β-catenin in chondrocytes, and the molecular target(s) and biochemical mode of action through which selenium blunts this activation. Whether the in vitro axis holds in vivo is also untested — no animal DON/selenium/cartilage-intervention model exists — and remains open background context for the mechanism question. A 2026 study identified deficiency of selenoprotein S (an endoplasmic-reticulum membrane protein of the selenium-dependent enzyme family) as a Wnt/β-catenin-activating condition in chondrocytes, supplying a candidate selenium-side regulator, but no study has tested it — or any other target — in the DON co-exposure setting.

Background

Kashin-Beck disease (KBD) is a chronic, degenerative osteoarthropathy endemic to selenium-poor regions of China and parts of Russia and North Korea, in which articular cartilage undergoes focal necrosis, chondrocyte death, and matrix breakdown. Two environmental factors dominate the proposed etiology: contamination of staple grains by trichothecene mycotoxins — chiefly deoxynivalenol (DON, also called vomitoxin) and T-2 toxin, secondary metabolites of Fusarium fungi that inhibit eukaryotic protein synthesis and thereby trigger ribotoxic stress responses (intracellular signaling cascades initiated by translational arrest at the ribosome) — and dietary selenium deficiency. Selenium is incorporated as selenocysteine, a selenium-containing analog of the amino acid cysteine, into ~25 human selenoproteins, including the antioxidant glutathione peroxidases and other redox-active enzymes, which carry most of the element's biological function. The canonical Wnt/β-catenin signaling pathway is a central regulator of chondrocyte maturation and cartilage homeostasis: in resting cells, cytoplasmic β-catenin is phosphorylated by the destruction complex (Axin, APC, GSK-3β, CK1) and degraded; binding of Wnt ligands such as Wnt-3a to Frizzled/LRP co-receptors stabilizes β-catenin, allowing its nuclear entry and activation of transcription programs that in chondrocytes promote terminal differentiation, apoptosis, and catabolic matrix remodeling. Prior work had established each piece separately: Wnt-3a, β-catenin, and Runx-2 (a transcription factor driving terminal chondrocyte differentiation) are upregulated in KBD cartilage, with selenium intervention partially normalizing associated matrix genes (Zheng et al. 2013); the related trichothecene T-2 toxin injures chondrocytes via Wnt/β-catenin activation (Wang et al. 2017; Chang et al. 2017); DON itself is cytotoxic to human and rat chondrocytes (Lin et al. 2019) and alters expression of selenium-related genes in chondrocytes (Yang et al. 2019). The source study (Wang et al. 2020) supplied the missing connection: in primary human chondrocytes, DON dose-dependently activated Wnt/β-catenin signaling, blocking the pathway reversed DON's cytotoxic and pro-catabolic effects (suppressing collagen II and aggrecan, the core structural macromolecules of cartilage matrix, together with sulphated glycosaminoglycans and TIMP-1, a tissue inhibitor of metalloproteinases, while inducing the matrix-degrading metalloproteinases MMP-1 and MMP-13), and selenium supplementation reduced the DON-induced Wnt/β-catenin activation while abrogating the cytotoxic and pro-catabolic responses. The authors thus proposed a unified DON–Wnt/β-catenin–selenium axis for KBD pathogenesis. Notably, the direction of DON's effect on this pathway is tissue-specific — in intestinal epithelium and enteroids (three-dimensional intestinal epithelial organoid cultures) DON suppresses Wnt/β-catenin (Li et al. 2019) — so its chondrocyte mechanism cannot be extrapolated from other tissues. What the source study left open, and what subsequent literature has not closed, is the mechanistic identity of both limbs (how DON engages the pathway, and where selenium acts); the in vivo validity of the axis likewise remains untested.

Problem Statement

The problem, as left open by Wang et al. (2020), is to establish the molecular mechanism of selenium's suppression of DON-induced Wnt/β-catenin activation in chondrocytes, as one linked objective with two components. (1) Proximal mechanism of the mycotoxin limb: identify the molecular step at which deoxynivalenol (DON) acts to increase Wnt-3a and β-catenin protein in human chondrocytes — whether DON induces Wnt-3a ligand expression, activates receptors, interferes with the β-catenin destruction complex, alters protein stability of pathway components, or engages upstream stress signaling (e.g., ribotoxic stress, MAPK (mitogen-activated protein kinase) signaling, oxidative stress, inflammatory cytokines) that secondarily activates the pathway — established with causal evidence rather than correlation alone. (2) Mechanism of the selenium limb: identify the molecular target(s) and biochemical mode of action by which selenium supplementation reduces DON-induced Wnt/β-catenin activation in chondrocytes — distinguishing direct action on pathway proteins, modulation of redox-sensitive regulators (including specific selenoproteins, of which selenoprotein S is a current candidate suggested by adjacent work), from effects on DON uptake or metabolism in chondrocytes. The in vivo validity of the axis — whether selenium supplementation at exposure ranges and chronicity relevant to endemic human exposure prevents or reverses DON-induced cartilage degeneration in animal models, with Wnt/β-catenin mediation demonstrated in vivo — is untested background context.

References

  1. Wang X, Jin Z, Chen M, Duan D, Lammi MJ, Guo X, Chang Y. 'Inhibiting the aberrant activation of Wnt/β-catenin signaling by selenium supplementation ameliorates deoxynivalenol-induced toxicity and catabolism in chondrocytes.' Journal of Cellular Physiology 235(5):4434-4442 (2020). DOI: 10.1002/jcp.29319. https://doi.org/10.1002/jcp.29319
  2. Shi Y, Ruan X, Zhao W, Wang H, Li L, Li Q, Liu Y, Wang M, Yang P, Zhang M, Chen J. 'Selenoprotein S deficiency activates Wnt/β-catenin signaling causing impaired terminal chondrocyte differentiation in Kashin-Beck disease.' International Immunopharmacology 185:117014 (2026). DOI: 10.1016/j.intimp.2026.117014. https://doi.org/10.1016/j.intimp.2026.117014
  3. Yang L, Zhang J, Li X, Xu C, Wang X, Guo X. 'Expression Profiles of Selenium-Related Genes in Human Chondrocytes Exposed to T-2 Toxin and Deoxynivalenol.' Biological Trace Element Research 190(2):295-302 (2019). DOI: 10.1007/s12011-018-1560-2. https://doi.org/10.1007/s12011-018-1560-2
  4. Lin X, Shao W, Yu F, Xing K, Liu H, Zhang F, Goldring MB, Lammi MJ, Guo X. 'Individual and combined toxicity of T-2 toxin and deoxynivalenol on human C-28/I2 and rat primary chondrocytes.' Journal of Applied Toxicology 39(2):343-353 (2019). DOI: 10.1002/jat.3725. https://doi.org/10.1002/jat.3725
  5. Yang L, Wang S, Zhao G, Wang X, Guo X. 'Comparison of the toxic mechanism of T-2 toxin and deoxynivalenol on human chondrocytes by microarray and bioinformatics analysis.' Toxicology Letters 321:61-68 (2020). DOI: 10.1016/j.toxlet.2019.12.024. https://doi.org/10.1016/j.toxlet.2019.12.024
  6. Wang X, Ning Y, Zhang P, Yang L, Wang Y, Guo X. 'Chondrocytes damage induced by T-2 toxin via Wnt/β-catenin signaling pathway is involved in the pathogenesis of an endemic osteochondropathy, Kashin-Beck disease.' Experimental Cell Research 361(1):141-148 (2017). DOI: 10.1016/j.yexcr.2017.10.012. https://doi.org/10.1016/j.yexcr.2017.10.012
  7. Chang Y, Wang X, Sun Z, Jin Z, Chen M, Wang X, Lammi MJ, Guo X. 'Inflammatory cytokine of IL-1β is involved in T-2 toxin-triggered chondrocyte injury and metabolism imbalance by the activation of Wnt/β-catenin signaling.' Molecular Immunology 91:195-201 (2017). DOI: 10.1016/j.molimm.2017.08.019. https://doi.org/10.1016/j.molimm.2017.08.019
  8. Zheng J, Wu C, Ma W, Zhang Y, Hou T, Xu H, Wu S, Yao X, Guo X. 'Abnormal expression of chondroitin sulphate N-acetylgalactosaminyltransferase 1 and Hapln-1 in cartilage with Kashin-Beck disease and primary osteoarthritis.' International Orthopaedics 37(10):2051-2059 (2013). DOI: 10.1007/s00264-013-1937-y. https://doi.org/10.1007/s00264-013-1937-y
  9. Li XG, Zhu M, Chen MX, Fan HB, Fu HL, Zhou JY, Zhai ZY, Gao CQ, Yan HC, Wang XQ. 'Acute exposure to deoxynivalenol inhibits porcine enteroid activity via suppression of the Wnt/β-catenin pathway.' Toxicology Letters 305:19-31 (2019). DOI: 10.1016/j.toxlet.2019.01.008. https://doi.org/10.1016/j.toxlet.2019.01.008
  10. Hao S, Yao C, Meng P, Jia Y, Liu L, Zhang C. 'Effects of T-2 and deoxynivalenol mycotoxins on mouse spinal bone growth and integrity.' Toxicon 250:108079 (2024). DOI: 10.1016/j.toxicon.2024.108079. https://doi.org/10.1016/j.toxicon.2024.108079
  11. Hao S, Yao C, Meng P, Jia Y, Li L, Zhang C, Guo X. 'HT-2 mycotoxin and selenium deficiency: Effects on Femur development and integrity in Young mice.' Toxicon 245:107767 (2024). DOI: 10.1016/j.toxicon.2024.107767. https://doi.org/10.1016/j.toxicon.2024.107767
  12. Fan S, Chen J, Tian H, Yang X, Zhou L, Zhao Q, Qin Y, Zhang J, Tang C. 'Selenium maintains intestinal epithelial cells to activate M2 macrophages against deoxynivalenol injury.' Free Radical Biology and Medicine 219:215-230 (2024). DOI: 10.1016/j.freeradbiomed.2024.04.228. https://doi.org/10.1016/j.freeradbiomed.2024.04.228
  13. Fan S, Lin L, Li P, Tian H, Shen J, Zhou L, Zhao Q, Zhang J, Qin Y, Tang C. 'Selenomethionine protects the liver from dietary deoxynivalenol exposure via Nrf2/PPARγ-GPX4-ferroptosis pathway in mice.' Toxicology 501:153689 (2024). DOI: 10.1016/j.tox.2023.153689. https://doi.org/10.1016/j.tox.2023.153689
  14. Deng H, Liu H, Yang Z, Bao M, Lin X, Han J, Qu C. 'Progress of Selenium Deficiency in the Pathogenesis of Arthropathies and Selenium Supplement for Their Treatment.' Biological Trace Element Research 200(10):4238-4249 (2022). DOI: 10.1007/s12011-021-03022-4. https://doi.org/10.1007/s12011-021-03022-4