Background:
Bone marrow mesenchymal stem cells (BMSCs) are central to skeletal development, regeneration, and age‑related bone loss through their ability to differentiate into osteoblasts or adipocytes. Over the past decade, epigenetic enzymes have emerged as key regulators of BMSC fate, acting as interpreters of intrinsic ageing programs and environmental cues. Recent studies from multiple groups have begun to map dynamic DNA and histone modifications during skeletal ageing and osteoporosis; however, how these epigenetic changes collectively shape lineage commitment and skeletal fragility remains an evolving area of investigation.

Aims:
We aim to summarise recent work, including our own and key discoveries across the field, identifying epigenetic regulators of BMSC lineage determination, skeletal ageing, and osteoporosis, and to examine how metabolic stress modifies these pathways.

Methods:
Using conditional mouse models targeting histone and DNA‑modifying enzymes, including EZH2, KDM6A, and the DNA dioxygenases TET1/2, we investigated skeletal development, ageing, and responses to metabolic stress. Skeletal outcomes were assessed using µCT, histomorphometry, and biomechanical testing. Transcriptomic and metabolomic analyses were integrated with functional assays of osteogenesis, adipogenesis, oxidative stress, and cellular senescence. High‑fat‑diet and hyperglycaemic models were used to assess the impact of metabolic perturbations on BMSC fate.

Results:
Across ageing and osteoporotic contexts, disruption or age‑associated decline of key epigenetic regulators impaired osteoblast differentiation, increased marrow adiposity, and caused trabecular bone loss with reduced skeletal strength. Multi‑omics analyses revealed consistent dysregulation of osteogenic pathways, lipid and energy metabolism, inflammatory signalling, and growth factor pathways, including IGF‑1–mTOR signalling. Metabolic stress further altered the availability of metabolites required for epigenetic enzyme activity, exacerbating DNA and histone modification defects. These findings align with emerging epigenomic maps of skeletal ageing across the field, highlighting convergent epigenetic signatures underlying bone fragility.

Conclusion:
Together, this work establishes epigenetic reprogramming of BMSCs as a central mechanism driving skeletal ageing and osteoporosis, with diet and metabolism acting as important modifiers of chromatin state. By integrating genetic, epigenomic, and metabolic insights, these findings advance a unified framework for understanding age‑related bone loss and identify epigenetic pathways as emerging targets for preserving skeletal health.