Du Hao, Zhang Yao, Yu Xi, You Xuanhe, Wu Diwei, Du Ze, Cai Yongrui, Luo Zhenyu, Lu Hanpeng, Liao Zhixin, Ding Bi-Sen, Zhao Ya, Wang Yan, Xiao Ke, Yang Fan, Gan Fangji, Ning Ning, Zeng Jiancheng, Shi Peiliang, Zhou Zongke, Huang Shishu
Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Sci China Life Sci. 2025 Feb 17. doi: 10.1007/s11427-024-2676-y.
Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.
骨关节炎（OA）是最常见的关节疾病，伴有关节软骨退化。它包括从关节软骨细胞表型向生长板软骨细胞表型的转变。在此，我们研究了组蛋白修饰谱，发现骨关节炎中H3K27me3显著缺失，这导致了疾病相关基因的表达。令人惊讶的是，这些基因在正常软骨细胞中同时被H3K27me3和H3K4me3占据，呈现出一种平衡的二价状态。此外，我们观察到生长板软骨细胞中类似的二价基因去抑制。最后，一种KDM6B抑制剂GSK-J4在大鼠骨关节炎模型中预防了H3K27me3缺失和软骨损伤。我们的结果揭示了发育基因上一种遗传的二价表观遗传特征，这种特征使关节软骨细胞易于肥大，并为骨关节炎提供了一种有前景的表观遗传治疗方法。
