Contrasting Effects of HT-2 Toxin Exposure and ZIP6 Knockdown on Chondrocyte Extracellular Matrix Metabolism

Kashin-Beck disease (KBD) is a chronic, endemic osteoarticular disorder associated with T-2 toxin exposure, which is rapidly metabolized to HT-2 toxin in vivo. However, the role of zinc transporter ZIP6 in HT-2 toxin-induced extracellular matrix metabolic disturbance in chondrocytes remains unclear. This study established HT-2 toxin intervention and ZIP6 knockdown chondrocyte models, combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and transcriptome sequencing, to investigate the regulatory mechanisms of ZIP6 in chondrocyte injury. Following HT-2 toxin exposure, altered chondrocyte morphology and reduced cell viability were observed; ZIP6, COL2A1, MTF1, and MTF2 expression were significantly downregulated, whereas MMP1, MMP13, and COL10A1 were upregulated. ZIP6 knockdown significantly upregulated COL2A1, MTF1, and MTF2, downregulated MMP1 and COL10A1, but did not alter MMP13 expression. Differentially expressed genes following ZIP6 knockdown were predominantly enriched in FoxO, cAMP, and TNF signaling pathways. qRT-PCR validation confirmed consistent expression changes in FOXO4, TNFSF10, COLEC10, UCA1, and LRRC17 with transcriptome sequencing results. Collectively, HT-2 toxin suppresses ZIP6, MTF1, and MTF2 expression, disrupting chondrocyte extracellular matrix metabolism; conversely, ZIP6 knockdown ameliorates matrix metabolic abnormalities through modulation of relevant signaling pathways. These findings reveal differential regulatory effects of HT-2 toxin and ZIP6 on cartilage matrix metabolism, providing experimental evidence for elucidating molecular mechanisms underlying cartilage injury-related diseases.