Downregulation of HSP47 Triggers ER Stress-mediated Apoptosis of Hypertrophic Chondrocytes Contributing to T-2 toxin-induced Cartilage Damage

T-2 toxin contamination in food and feed is a growing global concern, with its toxic effects on developing cartilage remaining poorly understood. In this study, we constructed an animal model using 4-week-old male Sprague-Dawley rats, which were administered T-2 toxin (200 ng/g body weight per day) by gavage for one month. Histological analysis showed a significant reduction in hypertrophic chondrocytes and increased caspase-3 expression and TUNEL staining in the deep cartilage zone of T-2 toxin-treated rats. T-2 toxin exposure significantly decreased the expression of heat shock protein 47 (HSP47) and elevated ER stress-mediated apoptosis markers (BiP, caspase-12, and CHOP) in the cartilage of T-2 toxin-treated rats. In an in vitro hypertrophic ATDC5 chondrocyte model, T-2 toxin exposure (10, 25, 50 ng/mL) reduced cell viability and HSP47 expression, while increasing the expression of BiP, caspase-12, and CHOP. Treatment with the ER stress inhibitor Salubrinal suppressed the upregulation of caspase-3 activity, BiP, caspase-12, and CHOP while partially restoring HSP47 expression in T-2 toxin-treated hypertrophic ATDC5 chondrocytes. Furthermore, Hsp47 knockdown in hypertrophic ATDC5 chondrocytes increased the apoptosis ratio, caspase-3 activity, and the expression of BiP, caspase-12, and CHOP. In children with Kashin-Beck disease, a human condition associated with T-2 toxin exposure, reduced HSP47 expression and increased BiP and CHOP expression were observed in the deep zone of articular cartilage. These findings demonstrated that T-2 toxin-induced cartilage damage primarily involves hypertrophic chondrocyte apoptosis in the deep zone. Downregulation of HSP47 leads to ER stress-mediated apoptosis in T-2 toxin-induced cartilage damage. Inhibition of ER stress offers a potential therapeutic approach for mitigating T-2 toxin-induced cartilage damage.