Inhibition of KDM6B prevents osteoarthritis by blocking growth plate like H3K27me3 loss in bivalent genes

Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation, yet a clear understanding of OA etiology and pathogenesis, in particular epigenetic changes, remain elusive. Here, we investigated the profiles of four classic histone modification marks, H3K4me3, H3K27me3, H3K27ac and H3K9me3, in normal and OA chondrocytes using CUT-Tag. The most significant change genome-wide was the repressive mark H3K27me3, which decreased at promoters and gene bodies in OA compared to normal. Furthermore, the loss of H3K27me3 in OA was associated with up-regulated gene expression. Surprisingly, the loss of H2K27me3 has preference for bivalent genes which were occupied with both H3K27me3 and H3K4me3 in normal chondrocytes. These bivalent genes are deemed to be activated during the proliferation and hypertrophy of growth plate chondrocytes, for example Col1a2 and Adamts2. Furthermore, IL-1b treatment induced the expression of KDM6B, a key H3K27me3 demethylase, and decreased H3K27me3 level in OA chondrocytes. This H3K27me3 loss was rescued by the KDM6B inhibitor GSK-J4. Altogether, our results suggest an inherited epigenetic signature of bivalent promoters on developmental genes makes articular chondrocytes prone to hypertrophy and ossification and contribute to a promising epigenetic therapy for OA.