T-2 toxin enhances catabolic activity of hypertrophic chondrocytes through ROS-NF-κB-HIF-2α pathway.

T-2 toxin (T-2), one of the most important and toxic trichothecene mycotoxins, can cause many medical problems, such as diarrhea, nervous disorders, immunodepression and death, and is also believed as an etiological factor of Kashin-Beck disease, an endemic osteochondropathy prevailing in North China. However, the molecular mechanisms underlying T-2 effects on tissue damage remain elusive. We differentiated ATDC5 chondrogenic cells into hypertrophic chondrocytes, and found that T-2 reduced the expression of anabolic genes, and increased the expression of catabolic genes. To uncover the mechanism that T-2 influenced metabolic homeostasis of hypertrophic chondrocytes, we observed that T-2 increased the production of reactive oxygen species (ROS) and the degradation of IκB-α, and up-regulated the expression of hypoxia-induced factor-2α (HIF-2α). Bay11-7085 (an inhibitor of NF-κB pathway) inhibited the up-regulation of HIF-2α, and N-acetyl-l-cysteine (a ROS scavenger) inhibited both the decrease of IκB-α and the up-regulation of HIF-2α. Our results demonstrate that ROS-NF-κB-HIF-2α pathway participates in the effects of T-2 on hypertrophic chondrocytes, and HIF-2α plays an important role as a key mediator in this process.