A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

• Published in: Scientific reports Vol. 10; no. 1; p. 20787
• Main Authors: Saito, Motoo, Nishitani, Kohei, Ikeda, Hanako O., Yoshida, Shigeo, Iwai, Sachiko, Ji, Xiang, Nakahata, Akihiro, Ito, Akira, Nakamura, Shinichiro, Kuriyama, Shinichi, Yoshitomi, Hiroyuki, Murata, Koichi, Aoyama, Tomoki, Ito, Hiromu, Kuroki, Hiroshi, Kakizuka, Akira, Matsuda, Shuichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.11.2020; Nature Publishing Group
• Subjects: 692/4023; 692/4023/1671; Adenosine Triphosphate - metabolism; Aged; Animals; Apoptosis; Apoptosis - drug effects; Arthritis; Cartilage; Cartilage diseases; Cartilage, Articular - drug effects; Cartilage, Articular - injuries; Cartilage, Articular - metabolism; Cell culture; Cell death; Cells, Cultured; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; Collagenase 3; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Disease Progression; Endoplasmic Reticulum Stress - drug effects; Explants; Female; Gene expression; Humanities and Social Sciences; Humans; IL-1β; Inflammation; Male; Mortality; multidisciplinary; Naphthalenes - therapeutic use; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - etiology; Osteoarthritis - metabolism; Pyridines - therapeutic use; Rats; Rats, Wistar; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Sulfonic Acids - therapeutic use; Surgery; Tunicamycin; Tunicamycin - toxicity; Valosin Containing Protein - antagonists & inhibitors; Valosin-containing protein; Wounds and Injuries - complications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-77735-2

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.