JMJD3 and UTX as key targets for gene-modified mesenchymal stem cell therapy in cartilage tissue engineering

Histone methylation plays a critical role in cartilage development, making it an appealing target for improving cartilage engineering protocols. In this study, we evaluated the roles of JMJD3 (KDM6B) and UTX (KDM6A), both demethylases of histone H3 at lysine 27 (H3K27), in chondrogenesis and their application in gene-modified mesenchymal stem cell therapy for cartilage tissue engineering. Our findings revealed that JMJD3 is specifically upregulated during chondrogenesis in human bone-marrow-derived mesenchymal stem cells and is crucial for this differentiation process. In contrast, UTX was found to be dispensable for chondrogenesis. Nevertheless, both JMJD3 and UTX share the ability to demethylate similar gene loci, thereby promoting the expression of chondrogenic signature genes, which suggests functional redundancy. Notably, the genes encoding these H3K27me3 demethylases emerge as strong candidates for enhancing gene-modified mesenchymal stem cell therapy for cartilage tissue engineering, as their overexpression during chondrogenesis significantly increased the formation of thicker cartilage disks enriched with type II collagen. These findings emphasize the potential of transient JMJD3 transduction, along with a lesser emphasis on UTX, as effective strategies for improving gene-modified mesenchymal stem cell therapy in cartilage tissue engineering.