Endocrine Abstracts

Bone development, remodeling and repair are metabolically very demanding processes. Chondrogenic and osteogenic cells are highly anabolic as they have a high proliferation rate and produce a substantial amount of extracellular matrix. Not only hormones and growth factors control these processes, but recent evidence shows that cell metabolism might also regulate skeletal cell properties. Adequate nutrient supply and metabolic pathways are certainly essential to prevent an energy deficit. However, skeletal cell metabolism supports also other cellular functions beyond bioenergetics as it is also required for biosynthesis, redox homeostasis and epigenetic regulation of gene expression. We could show that a low lipid supply because of poor vascularization induces skeletal stem and progenitor cells (SSPCs) to differentiate into chondrocytes. The chondrogenic transcription factor SOX9 on its turn promotes glutamine metabolism in chondrocytes. Glutamine metabolism is necessary for optimal expression of genes characterizing chondrocyte identity and it supports biosynthesis and redox homeostasis. On the other hand, SSPCs are highly metabolic flexible as they can proliferate when oxidative phosphorylation is blocked, a characteristic tumor cells do not have. SSPCs can maintain their NAD+ levels by increasing glycolysis side pathways, rewiring the TCA cycle and by using fumarate as electron acceptor in the oxidative phosphorylation instead of oxygen. This normal proliferation rate did not exhaust their SSPC properties and even resulted in more bone being formed when these SSPCs were implanted ectopically in mice. Thus, SSPCs have a high plasticity to metabolically adapt to metabolic stressors and they can change cell fate when the supply of certain nutrients is limited.