The ageing skeleton is highly susceptible to low bone density, osteoporosis and bone fractures, some of the most common ailments affecting our ageing population. This is partly due to a decline in bone cell numbers and a reduced capacity to differentiate into bone, associated with increased fat tissue, a pathological characteristic of the aged skeleton and osteoporosis. The ability of skeletal stem cells or bone marrow derived mesenchymal stem cells (BMSC) to form osteoblasts or adipocytes are regulated by epigenetic factors. We have shown that lineage determination is under the control of epigenetic regulation and that the histone 3 lysine 27 methyltransferase, Ezh2 and the demethylase counterpart, KDM6A regulate human BMSC differentiation.
Ezh2 inhibits osteogenesis and promotes adipogenesis whilst KDM6A performs the opposite function. When Ezh2 is conditionally deleted in BMSC, young mice display craniosynostosis, increased trabecular bone and bone volume accompanied by a striking increase in bone marrow fat. We have now assessed the skeleton of conditional knockout animals in later stages of development and discovered that removal of one allele of Ezh2 leads to an early onset Osteoporotic like phenotype characterized by decreased bone volume, trabecular bone and increased bone marrow fat, a kin to patients with Weaver Syndrome. A decline in CFU-F numbers was evident in aged Ezh2+/- mice and BMSC were more susceptible to senescence with a reduced capacity to repair damaged DNA. Transcription profiling of BMSC from Ezh2+/- BMSC and control BMSC revealed common gene expression changes between Ezh2 het BMSC versus wild type and wild type aged BMSC versus young BMSC. Gene expression changes were evident in multiple aged related pathways involved in DNA damage, ribosome biogenesis, senescence, osteogenesis, chondrogenesis and adipadipogenesis. This is the first time the conditional deletion of Ezh2 in skeletal tissues has been shown to result in ageing.