Abstract
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.
Highlights
Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries
We first examined whether the messenger RNA of valosin-containing protein (VCP) was ubiquitously expressed in various organs in rat
The number of TdT-mediated dUTP nickend-labelling (TUNEL)-positive chondrocytes in the articular cartilage lesion was significantly lower in the KUS121-treated than in vehicle-treated rats (Fig. 2a,b), indicating the protective effect of KUS121 against apoptosis
Summary
Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants It significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. After a physical damage to the articular cartilage after a traumatic event, acute-stage reactions lead to chondrocyte death followed by matrix damage and induction of proinflammatory cytokines and result in serious and irreversible cartilage d egeneration[7,8,9,10] It would be beneficial for a new therapeutic agent to target the earliest stage of chondrocyte damage, namely chondrocyte death, to inhibit the progression to P TOA7,8,11,12. The aim of this study was to show KUS121 (1) inhibits chondrocyte death following cartilage trauma and reduces subsequent cartilage degeneration in a rodent model of cartilage injury, and (2) inhibits chondrocyte death by the suppression of excessive ER stress and subsequent upregulation of pro-inflammatory cytokines in human chondrocytes
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