Kashin–Beck disease (KBD) is a disabling endemic osteoarthropathy of China, Siberia, and Korea in which death of chondrocytes (the cartilage-forming cells) in the deep zones of epiphyseal and joint cartilage of children produces growth-plate damage, shortened deformed joints, and secondary osteoarthritis. The review that established the epidemiological basis of this question (Wang et al., 2020) concluded from surveillance and multivariate epidemiology that KBD is food-sourced — driven by fungal contamination of staple grain (mycotoxins such as T-2 toxin), selenium deficiency, and low protein intake — while the causal mechanism remains unresolved: the subsequent mechanistic literature documents that the biological interaction of these combined exposures still requires experimental and mechanistic elucidation (Yu et al., 2022; Deng et al., 2024; Liu et al., 2024). The question remains open: four etiological hypotheses still coexist, and recent studies dissect only individual pathway branches (autophagy via AMPK/mTOR/ULK1, ferroptosis via system Xc−/GSH/GPX4, Notch/Hes1-mediated apoptosis), none providing an integrated causal account of how the factor combinations produce the characteristic lesions.

Background

Kashin–Beck disease (KBD) is a chronic, disabling osteoarthropathy (a disease of bone and joint formation) endemic to a narrow belt from northeastern to southwestern China and into Siberia and Korea. It primarily affects children in farming areas: the earliest and most characteristic lesion is death (necrosis) of chondrocytes — the cartilage-forming cells — in the deep zones of the epiphyseal cartilage and the growth plate (the cartilage layer near the ends of growing bones from which bone lengthening proceeds). Focal necrosis there leads to impaired endochondral ossification (the process by which cartilage is replaced by bone during growth), resulting in shortened, deformed joints and early-onset secondary osteoarthritis. The latest Chinese epidemic lasted from the late 1950s to the end of the 1980s; after nationwide preventive measures begun in the 1990s the national incidence fell from 22.1% in 1990 to 0.18% in 2015, yet in 2016 about 22.6 million inhabitants still lived in endemic areas with roughly 575,000 patients (Wang et al., 2020).

The etiology is not settled. Epidemiological multivariate regression supports food-related factors: contamination of stored staple grain by fungi and their mycotoxins — notably T-2 toxin, a trichothecene mycotoxin produced by Fusarium species that contaminates cereals in cold, humid storage; selenium deficiency (selenium is a trace element required for selenoprotein antioxidant enzymes such as glutathione peroxidase, GPX); and low dietary protein intake, in particular low animal-protein intake (Wang et al., 2020). A 2022 review of all KBD animal models records that four etiological hypotheses still coexist — the fulvic-acid hypothesis (organic matter in drinking water; fulvic acid is a humic-water organic compound), the selenium-deficiency (biogeochemical) hypothesis, the T-2 mycotoxin hypothesis, and the compound (multi-factor) etiology hypothesis — and identifies rats treated with T-2 toxin combined with selenium/nutrition deficiency as the most suitable experimental model (Yu et al., 2022).

Recent mechanistic work has dissected individual branches of the response of chondrocytes to these exposures: low selenium and T-2 toxin perturb autophagy (the cellular self-digestion process that degrades damaged organelles) through the AMPK/mTOR/ULK1 signaling pathway (a nutrient- and energy-sensing kinase cascade that initiates autophagy), with autophagy apparently increasing early and becoming deficient late in lesion progression (Deng et al., 2024); T-2 toxin induces ferroptosis (an iron-dependent form of programmed cell death driven by lipid peroxidation) in articular chondrocytes by inhibiting the system Xc−/glutathione/GPX4 antioxidant axis (system Xc− is the transporter that imports cysteine needed to synthesize the antioxidant glutathione, and GPX4 is the glutathione-dependent enzyme that halts lipid peroxidation), and the selenium compound selenomethionine counteracts this damage (Yu et al., 2025); selenium deficiency activates Notch/Hes1 signaling (a cell-fate signaling pathway whose receptors Notch1/Jagged1 and target Hes1 were elevated in KBD patients' blood), promoting chondrocyte apoptosis in a way reversed by selenium supplementation (Zhang et al., 2023); and selenium combined with iodine deficiency further depresses glutathione-peroxidase activity and increases chondrocyte vulnerability to oxidative stress (Liu et al., 2024). Population-level evidence confirms that preventive interventions (grain diversification, selenium and iodine supplementation) have effectively controlled the disease — a 2023 meta-analysis of 34 prevalence studies found a pooled prevalence of 0.06% in China, negatively correlated with time (Xu et al., 2023) — but the epidemiological success does not identify the causal mechanism, and it does not settle why incidence persists in some villages.

Three sibling applied needs are documented here as context rather than as part of the problem core: re-evaluating why prevention remains incomplete in still-active villages; the absence of any specific biochemical or molecular biomarker for early diagnosis or subclinical cartilage injury (current early-diagnosis research is imaging-based, e.g. ultra-high-field MRI detection of early epiphyseal-plate lesions in the rat model; Li et al., 2020); and evidence-based clinical and rehabilitation planning for the large surviving adult caseload. These are distinct public-health and clinical objectives; the scientific question that remains open, and that the animal and laboratory studies are meant to answer, is the causal mechanism itself.

Problem Statement

Identify the causal mechanism — or refute the combined-factor causation — by which the food-sourced environmental factors implicated in endemic Kashin–Beck disease, namely grain mycotoxins (in particular T-2 toxin, a fungal toxin of stored cereals), selenium deficiency, and low protein intake (in particular low animal-protein intake), individually and in combination, produce the disease's characteristic lesions: deep necrosis of chondrocytes (the cartilage-forming cells) in epiphyseal and articular cartilage, growth-plate damage, and impaired endochondral ossification (the replacement of cartilage by bone during growth) in growing children. A complete answer must (i) establish which factor or factor combination is causal, with the dose–response relationship anchored to the best available exposure data from endemic areas; (ii) specify the cellular and molecular pathways (including, but not limited to, apoptosis, ferroptosis, dysregulated autophagy, oxidative-stress and inflammatory signaling) through which the causal exposures act and interact biologically, using appropriate evidence such as the recommended combined-exposure animal model (rat T-2 toxin plus selenium/nutrition deficiency; Yu et al., 2022) and human cartilage or biomarker data; and (iii) be consistent with the documented epidemiology, including the endemic geographic distribution and the decline of incidence after grain-diversification and selenium/iodine supplementation. A refutation of the combined-factor hypothesis is completed in one of two ways. The first is evidence supporting one of the other coexisting etiological hypotheses (fulvic-acid water poisoning, selenium deficiency alone, or T-2 mycotoxin food poisoning; Yu et al., 2022); conditions (i)–(iii) are then read with that alternative hypothesis as the subject, condition (iii) requiring an account of the endemic geographic distribution and of the decline of incidence after grain-diversification and selenium/iodine supplementation. The second is a demonstration that the food-factor combination is not causal, which requires showing that the implicated exposures, individually and in combination, fail to produce the characteristic lesions at exposures documented in endemic areas, and requires no named alternative hypothesis and no restatement of conditions (i)–(iii).

References

  1. Kewei Wang, Jun Yu, Hui Liu, Yunqi Liu, Ning Liu, Yanhong Cao, Xufeng Zhang, Dianjun Sun. "Endemic Kashin–Beck disease: A food-sourced osteoarthropathy." Seminars in Arthritis and Rheumatism 50(2):366–372, 2020. DOI: 10.1016/j.semarthrit.2019.07.014. https://doi.org/10.1016/j.semarthrit.2019.07.014
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