GSKJ-4

Meniscus injuries are challenging to treat due to the tissue heterogeneity and limited treatment efficacy. Understanding meniscus cell migration, crucial for healing, remains incomplete, especially its zonal dependency. This study explores how epigenetic mechanisms affect meniscus cell migration under inflammation, focusing on healing implications. Distinct histone modifications and chromatin dynamics between inner and outer cells were observed during migration, emphasizing the need to consider these differences in repair strategies. Furthermore, tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine, slows inner meniscus cell migration, while outer cells remain unaffected, indicating a zonal response. Interestingly, TNF-α differentially alters histone modifications, particularly H3K27me3, between the cell types. Transcriptome analysis showed significant gene expression changes with inner cells more affected than outer cells. Gene cluster analysis revealed different responses in chromatin remodeling, extracellular matrix assembly, and wound healing between zones. We further identified potential therapeutic targets by using epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), which restored inner meniscus cell migration under inflammatory conditions, highlighting their potential in treating meniscus tears. This highlights their potential utility in treating meniscus tear injuries. Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insight into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis.

Gilteritinib treats acute myeloid leukemia (AML) with the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Dysregulation of histone modification affects the genesis and progression of AML. Strategies targeting key histone regulators have not been applied to the treatment of AML. Lysine demethylase 6B (KDM6B) is dysregulated in a variety of cancers and regulates the expression of oncogenes, which has potential in anticancer therapy. We explored whether GSK-J4 (an inhibitor of the demethylase KDM6B) has an anti-leukemic effect in the gilteritinib treatment of FLT3-ITD⁺ AML and the effect of gilteritinib combined with GSK-J4 in leukemia. In our study, we evaluated the anti-leukemic effect of GSK-J4 in gilteritinib therapy through in vitro and in vivo experiments. The results revealed that the combined treatment of gilteritinib and GSK-J4 has greater anti-proliferation and pro-apoptosis effects than gilteritinib alone. Gilteritinib and GSK-J4 performed synergistically to arrest the cell cycle. Gilteritinib mainly induces cell cycle phase arrest at the S or G0/G1, and GSK-J4 inhibits the cell cycle progression in the S phase and reduces cell viability by reducing the expression of key regulatory factors from the G1 phase to the S phase. At the same time, GSK-J4 enhances the expression of apoptosis-related proteins (Bax and cleavage caspase-9). In addition, gilteritinib or GSK-J4 monotherapy increases reactive oxygen species (ROS) production, and the combination has a synergistic effect, accelerating leukemic cell death. Our study provides proof that the combined therapy of gilteritinib and GSK-J4 has a synergistic antileukemic effect on FLT3-ITD⁺ AML.