Energy metabolism in osteoprogenitors and osteoblasts: Role of the pentose phosphate pathway

Bioenergetic preferences of osteolineage cells, including osteoprogenitors and osteoblasts (OBs), are a matter of intense debate. Early studies pointed to OB reliance on glucose and aerobic glycolysis while more recent works indicated the importance of glutamine as a mitochondrial fuel. Aiming to clarify this issue, we performed metabolic tracing of ¹³C-labeled glucose and glutamine in human osteolineage cells: bone marrow stromal (a.k.a. mesenchymal stem) cells and bone marrow stromal cell-derived OBs. Glucose tracing showed noncanonical direction of glucose metabolism with high labeling of early glycolytic steps and the pentose phosphate pathway (PPP) but very low labeling of late glycolytic steps and the Krebs cycle. Labeling of Krebs cycle and late steps of glycolysis was primarily from glutamine. These data suggest that in osteolineage cells, glucose is metabolized primarily via the PPP while glutamine is metabolized in the mitochondria, also feeding into the late steps of glycolysis likely via the malate-aspartate shuttle. This metabolic setup did not change after induction of differentiation. To evaluate the importance of this setup for osteolineage cells, we used the inhibitors of either PPP or malate-aspartate shuttle and observed a significant reduction in both cell growth and ability to differentiate. In sum, we observed a distinct metabolic wiring in osteolineage cells with high flux of glucose through the PPP and glutamine flux fueling both mitochondria and late steps of glycolysis. This wiring likely reflects their unique capacity to rapidly proliferate and produce extracellular matrix, e.g., after bone fracture.