Inflammation induced epigenetic activation of bivalent genes in osteoarthritic cartilage

Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation, which includes a switch from an articular to a growth-plate chondrocyte phenotype. Epigenetics serves as a new therapeutic target but histone modification changes in OA remain elusive. Here, we investigated the profiles of four histone modifications in normal and OA chondrocytes. The repressive mark H3K27me3 was significantly lost in OA, associated with up-regulated gene expression. Surprisingly, many of these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. These bivalent genes are deemed to be activated during the hypertrophy of growth plate chondrocytes. Furthermore, inflammation induced the expression of demethylase KDM6B and decreased H3K27me3 level in OA chondrocytes, which was rescued by the KDM6B inhibitor GSK-J4. Altogether, our results suggest an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contribute to a promising epigenetic therapy for OA. The Paper ExplainedO_ST_ABSProblemC_ST_ABSOsteoarthritis (OA) affects as much as 40% of the elderly population, representing the largest cause of age-related disability. The high susceptibility to OA suggests an intrinsic and systemic characteristic in articular chondrocytes that makes cartilage prone to degeneration. ResultsEpigenetic bivalent genes, which are occupied with both H3K27me3 and H3K4me3, are considered to poise expression of developmental genes. Surprisingly, we reported bivalency for hypertrophy related genes in normal articular chondrocytes. These bivalent genes need to be activated in growth plate chondrocytes for extracellular matrix degradation and ossification, but are left as a "bomb" for degeneration in articular chondrocytes. We further found that inflammation induced KDM6B remove H3K27me3 to activate hypertrophy related genes that promote OA. ImpactOur results suggest an inherited epigenetic signature that makes articular chondrocytes prone to hypertrophy and ossification and contribute to a promising epigenetic therapy for OA.