Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Abstract

The mechanism of environmental factors in Kashin–Beck disease (KBD) remains unknown. We aimed to identify single nucleotide polymorphisms (SNPs) and protein alterations of selenium- and T-2 toxin–responsive genes to provide new evidence of chondrocytic damage in KBD. This study sampled the cubital venous blood of 258 subjects including 129 sex-matched KBD patients and 129 healthy controls for SNP detection. We applied an additive model, a dominant model, and a recessive model to identify significant SNPs. We then used the Comparative Toxicogenomics Database (CTD) to select selenium- and T-2 toxin–responsive genes with the candidate SNP loci. Finally, immunohistochemistry was applied to verify the protein expression of candidate genes in knee cartilage obtained from 15 subjects including 5 KBD, 5 osteoarthritis (OA), and 5 healthy controls. Forty-nine SNPs were genotyped in the current study. The C allele of rs6494629 was less frequent in KBD than in the controls (OR = 0.63, p = 0.011). Based on the CTD database, PPARG, ADAM12, IL6, SMAD3, and TIMP2 were identified to interact with selenium, sodium selenite, and T-2 toxin. KBD was found to be significantly associated with rs12629751 of PPARG (additive model: OR = 0.46, p = 0.012; dominant model: OR = 0.45, p = 0.049; recessive model: OR = 0.18, p = 0.018), rs1871054 of ADAM12 (dominant model: OR = 2.19, p = 0.022), rs1800796 of IL6 (dominant model: OR = 0.30, p = 0.003), rs6494629 of SMAD3 (additive model: OR = 0.65, p = 0.019; dominant model: OR = 0.52, p = 0.012), and rs4789936 of TIMP2 (recessive model: OR = 5.90, p = 0.024). Immunohistochemistry verified significantly upregulated PPARG, ADAM12, SMAD3, and TIMP2 in KBD compared with OA and normal controls (p < 0.05). Genetic polymorphisms of PPARG, ADAM12, SMAD3, and TIMP2 may contribute to the risk of KBD. These genes could promote the pathogenesis of KBD by disturbing ECM homeostasis.

Effects of T-2 toxin on growth performance, feather quality, tibia development and blood parameters in Yangzhou goslings

“…For instance, T-2 toxin is implicated in tibial dyschondroplasia ( TD ), which is characterized by the accumulation of immature, poorly differentiated, unmineralized, and avascular cartilage owing to intoxication and growth retardation of long bones in chickens ( Nascimento et al, 2001 ; He et al, 2012 ). Furthermore, T-2 toxin participates in the pathological process of human Kashin-Beck disease ( KBD ) with chondrocyte damage to bone formation and morphogenesis (proliferation, differentiation, migration, and apoptosis) and imbalanced extracellular matrix ( ECM ) homeostasis (inhibition of synthesis and increase in degradation) ( Li et al, 2016 ; Chang et al, 2017 ; Ning et al, 2021 ). Similarly, compared to the control, 2.0 mg/kg of T-2 toxin significantly inhibited the growth and development of tibia in goslings, reducing their length and weight.…”

“…T-2 toxin also reduces DNA synthesis in chondrocytes because of a basic depression of protein, DNA, and RNA ( Wright Jr et al, 1987 ; Sokolović et al, 2008 ; He et al, 2012 ). Furthermore, T-2 toxin facilitates growth retardation and anomalous structural lesions of the TGP, with some unusual apoptotic and necrotic areas interfering with normal proliferation, differentiation, migration, mineralization of chondrocytes and synthesis, degradation of ECM, and the specific molecular expression mechanism ( Ning et al, 2021 ). In addition, inflammatory cytokines (mainly interleukin 1β) potently induce matrix degrading enzyme MMP expression in chondrocytes, inhibit the expression of matrix components, and evoke cell apoptosis, affecting chondrocyte growth under T-2 toxin exposure ( Chang et al, 2017 ).…”

Differential expression of cyclins CCNB1 and CCNG1 is involved in the chondrocyte damage of kashin-beck disease

“…The significantly upregulated expression of CCNG1 in the deep zone of articular cartilage in KBD patients suggests that CCNG1 may accelerate the chondrocyte necrosis of deep cartilage induced by damage factors. Our previous research found that low selenium status and T-2 toxin exposure can affect the gene and protein expression levels of PPARG, and its SNP rs12629751 is associated with KBD ( Ning et al, 2021 ). PPARG ligands influence the activities of CCNG1, CDK1, GADD45β, CCNA1 and ATM proteins, which are involved in the LPS-triggered expression of genes controlling the DNA damage response ( Mierzejewski et al, 2022 ).…”

Elucidation of the Key Therapeutic Targets and Potential Mechanisms of Marmesine against Knee Osteoarthritis via Network Pharmacological Analysis and Molecular Docking

“…Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear receptor and involved in insulin sensitivity and energy metabolism. A recent study demonstrated that genetic polymorphisms of PPARG might promote the risk of the Kashin-Beck disease via disturbing ECM homeostasis [ 39 ]. Mitogen-activated protein kinase 1 (MAPK1) is a subfamily of the MAPK family that regulated a variety of cellular activities.…”