4,8-Dicarboxyl-8,9-iridoid-1-glycoside inhibits apoptosis in human osteoarthritis chondrocytes via enhanced c-MYC-mediated cholesterol metabolism in vitro

• Published in: Arthritis research & therapy 2023-12, Vol.25 (1), p.240-240, Article 240
• Main Authors: Wang, WeiBing, Mai, HaiMin, Xu, Huang, Jing, BaoSheng, Yu, CuiYu, Li, XiaoTing, Chen, DanGui, Huang, Yuan, Shao, MeiMang, Pan, Tao
• Format: Article
• Language: English
• Subjects: Analysis; Antioxidants; Apoptosis; Arthritis; Autophagy; Borojoa; Care and treatment; Cartilage; Cell culture; Cell growth; Cholesterol; Cholesterol metabolism; Cytokines; Diagnosis; Disease; Flow cytometry; Health aspects; Lipids; Metabolism; Osteoarthritis; Physiology, Pathological; Protein-protein interactions; Proteins; Software; Tumor necrosis factor-TNF
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-023-03217-1

Osteoarthritis (OA) is a degenerative disease related to cholesterol metabolism disorders. However, current therapies for OA are insufficient and no convincing disease-modifying OA drugs exist. Therefore, we aimed to elucidate the mechanism by which borojoa iridoid glycoside (BIG) inhibits chondrocyte apoptosis in OA. Borojoa pulp was heated to 70 °C, and the main active substance in borojoa, BIG, was extracted by fractionation at an ultraviolet 254-nm absorption peak. Chondrocytes were identified by immunohistochemistry and visualized by immunofluorescence confocal microscopy. The proliferation of chondrocytes cultured with BIG was determined by MTS assay. The apoptosis of chondrocytes cultured with BIG was tested by Annexin V-FITC/PI, and the cytokine, protein, and cholesterol levels in chondrocytes were detected by ELISA, RT‒qPCR, Western blot, and biochemistry analyses. Protein‒protein interactions were verified by a coimmunoprecipitation (Co-IP) assay. BIG promoted chondrocyte proliferation and reduced apoptosis in vitro. BIG induced an alteration of the total RNA profiles in chondrocytes, and bioinformatic analysis showed that BIG inhibited chondrocyte apoptosis by promoting c-MYC expression; KEGG analysis confirmed that BIG-inhibited apoptosis was enriched in the cell cycle pathway. Flow cell cycle experiments confirmed that BIG promoted chondrocyte proliferation by significantly increasing the S phase cell number. The c-MYC inhibitor 10058-F4 stimulated the increased expression of IL-1β, IL-6, TNF-α, and AGEs and suppressed the cholesterol metabolism, which promoted chondrocyte apoptosis and autophagy. Co-IP analysis showed that BIG promoted the interaction of c-MYC and CH25H, Bcl-2, which suggests that BIG could inhibit chondrocyte apoptosis in part by enhancing c-MYC-mediated cholesterol metabolism. This study confirmed that BIG promotes chondrocyte proliferation and inhibits apoptosis and autophagy, and BIG improving OA is associated with cholesterol metabolism. The results identify a potential mechanism by which BIG enhances c-MYC-mediated CH25H regulation of cholesterol metabolism in vitro and suggest that BIG might be a promising new drug against OA.