Sunday, May 18, 2025
5/18/2025
Energy Metabolism in Osteoblasts and Bone Health - Energy Metabolism in Osteoblasts and Bone Health Energy metabolism is an important regulator of cell fate and tissue homeostasis while its dysregulation is a hallmark of aging in various tissues, including bone. Data on energy metabolism in osteoblasts (OB) are contra- dictory, claiming OB reliance either on aerobic glycolysis or mitochondrial oxidative phosphorylation (OxPhos). With regards to bioenergetic substrates, glutamine and fatty acids were recently shown to be as important for OBs as glucose; and they are metabolized mostly in mitochondria. Our new exciting data suggest an explanation to the above controversies and can reconcile the opposing views on OB metabolism. First, we confirmed that in OBs, glucose metabolites do not reach the mitochondrial Krebs cycle but mostly flow into the pentose phosphate pathway (PPP) and little into pyruvate and lactate. Actively proliferating and synthetic OBs likely benefit from this setup as PPP provides NADPH for redox reactions, nucleotides, etc. Second, we found that OB mitochondria actively metabolize glutamine, supplying not only the Krebs cycle but also cytosolic pyruvate and lactate due to the malate-aspartate shuttle (MAS) activity and ensuing cytosolic reactions. This suggests a regulatory role of mitochondria in the glycolytic process and PPP in OBs. Third, we found that in aged bone, there is mitochondrial dysfunction and increased glucose metabolism to lactate and away from the PPP, and signs of oxidative stress. Systemic inhibition of glucose flux to lactate using lactate dehydrogenase (LDH-A) inhibitor, oxamate, reverses the glycolytic shift and ‘rejuvenates’ bone in aged mice. Our hypothesis is that in OBs, glucose preferential flux into the PPP and glutamine-dependent mitochondrial activity supporting glycolysis and the PPP, is required for bone maintenance and can be restored in aging by targeting LDH-A. This will be tested by characterizing the role of PPP in OBs using loss-of-function (LOF) of G6PD, a key PPP enzyme (Aim 1); confirming the role of mitochondria in supporting glycolysis and the PPP in OBs using inhibition of glutaminolysis or MAS (Aim 2); and confirming LDH-A as a therapeutic target to reverse bone metabolic changes and aging using LDH-A LOF in OBs (Aim 3). Altogether, this is expected to significantly enhance our understanding of how cell energy metab- olism determines OB differentiation and function, explain existing controversies in the field, and suggest new therapies for bone aging.
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