Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.

创伤后骨关节炎（PTOA）是阻碍患者在关节内损伤或手术后恢复的主要原因。目前，还没有有效的治疗方法。在这项研究中，我们表明抑制急性期软骨细胞死亡是减轻 PTOA 发展的有希望的策略。也就是说，我们研究了京都大学物质 (KUS) 121（一种含有缬草素的蛋白质调节剂）对 PTOA 的功效及其治疗机制。在体内，在循环压缩载荷的大鼠 PTOA 模型中，与载体治疗相比，KUS121 的关节内治疗显着改善了改良的 Mankin 评分并减少了受损的软骨体积。此外，KUS121 显着减少了受损膝盖中 TUNEL-、CHOP-、MMP-13- 和 ADAMTS-5 阳性软骨细胞的数量。体外，在单层培养和软骨外植体中，KUS121 从衣霉素诱导的细胞死亡中拯救了人类关节软骨细胞。它还显着下调由衣霉素或 IL-1β 诱导的内质网应激标志物、促炎细胞因子和细胞外基质降解酶的蛋白质或基因表达。总的来说，这些结果表明 KUS121 通过抑制过度的内质网应激来保护软骨细胞免于细胞死亡。因此，KUS121 将是一种新的、有前途的治疗剂，对 PTOA 的进展具有保护作用。衣霉素或 IL-1β 诱导的细胞外基质降解酶。总的来说，这些结果表明 KUS121 通过抑制过度的内质网应激来保护软骨细胞免于细胞死亡。因此，KUS121 将是一种新的、有前途的治疗剂，对 PTOA 的进展具有保护作用。衣霉素或 IL-1β 诱导的细胞外基质降解酶。总的来说，这些结果表明 KUS121 通过抑制过度的内质网应激来保护软骨细胞免于细胞死亡。因此，KUS121 将是一种新的、有前途的治疗剂，对 PTOA 的进展具有保护作用。