Histone Demethylases KDM4B and KDM6B Promotes Osteogenic Differentiation of Human MSCs

Human bone marrow mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with multilineage differentiation potentials including osteogenesis and adipogenesis. While significant progress has been made in understanding transcriptional controls of MSC fate, little is known about how MSC differentiation is epigenetically regulated. Here we show that the histone demethylases KDM4B and KDM6B play critical roles in osteogenic commitment of MSCs by removing H3K9me3 and H3K27me3. Depletion of KDM4B or KDM6B significantly reduced osteogenic differentiation and increased adipogenic differentiation. Mechanistically, while KDM6B controlled HOX expression by removing H3K27me3, KDM4B promoted DLX expression by removing H3K9me3. Importantly, H3K27me3- and H3K9me3-positive MSCs of bone marrow were significantly elevated in ovariectomized and aging mice in which adipogenesis was highly active. Since histone demethylases are chemically modifiable, KDM4B and KDM6B may present as therapeutic targets for controlling MSC fate choices and lead to clues for new treatment in metabolic bone diseases such as osteoporosis. [Display omitted] ► BMP 4/7 induces expression of histone demethylases KDM4B and KDM6B in human MSCs ► KDM4B and KDM6B removal of H3K27me3 and H3K9me3 marks is required for osteogenesis ► H3K27me3 and H3K9me3 in MSCs increase in osteoporotic or aging bone marrow of mice ► KDM4B and KDM6B may represent novel therapeutic targets for metabolic bone disease Ye et al. report that mesenchymal stem cells (MSCs) in a model of osteoporosis increase their levels of H3K9me3 and H3K27me3 chromatin marks and that their removal by KDM4B and KDM6B demethylases is required for osteogenic lineage commitment of human MSCs.