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Enhancer of zeste homolog 2 (EZH2) is an important member of the epigenetic regulatory factor polycomb group proteins (PcG) and is abnormally expressed in a wide variety of tumors, including osteosarcoma. Scientists consider EZH2 as an attractive target for the treatment of osteosarcoma and have found many potential EZH inhibitors, such as GlaxoSmithKline 343 (GSK343). It has been reported that GSK343 can be used as an inhibitor in different types of cancer. This study demonstrated that GSK343 not only induced apoptosis by increasing cleaved Casp-3 and poly ADP-ribose polymerase (PARP) expression, but also induced autophagic cell death by inhibiting p62 expression. Apoptosis and autophagic cell death induced by GSK343 were confirmed by the high expression of cleaved caspase-3, LC3-II and transmission electron microscopy. GSK343 inhibited the expression of EZH2 and c-Myc. Additionally, GSK343 inhibited the expression of FUSE binding protein 1 (FBP1), which was identified by its regulatory effects on c-Myc expression. Since c-Myc is a common target of EZH2 and FBP1, and GSK343 inhibited the expression of these proliferation-promoting proteins, a mutual regulatory mechanism between EZH2 and FBP1 was proposed. The knockdown of EZH2 suppressed the expression of FBP1; similarly, the knockdown of FBP1 suppressed the expression of EZH2. These results suggest the mutual regulatory association between EZH2 and FBP1. The knockdown of either EZH2 or FBP1 accelerated the sensitivity of osteosarcoma cells to GSK343. Based on these results, this study clarified that GSK343, an EZH2 inhibitor, may have potential for use in the treatment of osteosarcoma. The underlying mechanisms of the effects of GSK343 are partly mediated by its inhibitory activity against c-Myc and its regulators (EZH2 and FBP1). [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is common in the elderly. Baicalin (BA) is a flavonoid monomer extracted from Scutellaria baicalensis Georgi , which has been reported to have anti-inflammatory, anti-deformation and anti-bacterial effects., Methods: Cultures of micromass and 3D alginate beads, Alcian blue and Safranin O (SO)/fast green staining were used to investigate chondrocyte viability and extracellular matrix (ECM) synthesis in chondrocytes of all groups. The expression of SOX9, Smad3, Aggrecan (ACAN), type II collagen (Col2α), matrix metallopetidase 9 (MMP9), MMP13 and ADAMTS5 in chondrocytes of all groups were detected by western blot or qRT-PCR., Results: The present study demonstrates that BA neutralized the IL-1β-induced downregulation of chondrocyte viability and ECM secretion, including ACAN and Col2α. The downregulation of SOX9, and the upregulation of MMP9, MMP13 and ADAMTS5 induced by IL-1β were reversed by BA treatment. Moreover, BA increased the nuclear translocation of Smad3 and SOX9 in chondrocytes cultured by micromass and 3D alginate beads. Interestingly, Smad3 inhibitor SIS3 reversed the promoting effect of BA on chondrocyte viability, ECM secretion, SOX9 and Smad3 nuclear translocation, and the inhibiting effect of BA on MMP9 and ADAMTS5 expressions. BA treatment also attenuated the decrease of Smad3 phosphorylation, SOX9 expression and the damage of cartilage integrity in mice which were induced by destabilization of the medial meniscus (DMM)., Conclusion: BA promotes chondrocyte viability and the cell matrix synthesis through TGF-β/Smad3 pathway in IL-1β-treated chondrocytes and DMM treated mice. BA is a potential therapeutic target for OA., Competing Interests: None., (AJTR Copyright © 2021.)

Background: Bone-tendon junction (BTJ) is a unique structure connecting tendon and bone through a fibrocartilage zone. Owing to its unique structure, the regeneration of BTJ remains a challenge. Here, we study the fibrochondrogenic differentiation of human tendon-derived stem/progenitor cells (TSPCs) both in vitro and in vivo ., Methods: TSPCs were isolated from human patellar tendon tissues and investigated for their multidifferentiation potential. TSPCs were cultured in chondrogenic medium with transforming growth factor beta 3 (TGF-β3) and BMP-2 in vitro  ​and examined for the expression of fibrochondrogenic marker genes by quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. TSPCs pretreated were also seeded in collage II sponge and then transplanted in immunocompromised nude mice to examine if the fibrochondrogenic characteristics were conserved in vivo ., Results: We found that TSPCs were differentiated towards fibrochondrogenic lineage, accompanied by the expression of collagen I, collagen II, SRY-box transcription factor 9 (Sox 9), and tenascin C. Furthermore, after TSPCs were seeded in collagen II sponge and transplanted in immunocompromised nude mice, they expressed fibrochondrogenic genes, including proteoglycan, collagen I, and collagen II., Conclusion: Taken together, this study showed that TSPCs are capable of differentiating towards fibrocartilage-like cells, and the fibrochondrogenic characteristics were conserved even in vivo , and thus might have the potential application for fibrocartilage regeneration in BTJ repair., The Translational Potential of This Article: TSPCs are able to differentiate into fibrocartilage-like cells and thus might well be one potential cell source for fibrocartilage regeneration in a damaged BTJ repair., (© 2019 Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society.)