Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes as these pathologies are characterized by a shift from oxidative to glycolytic metabolism. We have previously reported such glycolytic shift in aged bone as a major contributor to bone loss in mice. We and others also demonstrated the importance of oxidative phosphorylation (OxPhos) for osteoblast differentiation. It is therefore reasonable to propose that stimulation of OxPhos will have bone anabolic effect. One strategy widely used in cancer research to stimulate OxPhos is inhibition of glycolysis. In this work, we aimed to evaluate the safety and efficacy of pharmacological inhibition of glycolysis to stimulate OxPhos and promote osteoblast bone-forming function and bone anabolism. We tested a range of glycolytic inhibitors including 2-deoxyglucose, dichloroacetate, 3-bromopyruvate, and oxamate. Of all the studied inhibitors, only lactate dehydrogenase (LDH) inhibitor, oxamate, did not show any toxicity in either undifferentiated osteoprogenitors or osteoinduced cells in vitro. Oxamate stimulated both OxPhos and osteoblast differentiation in osteoprogenitors. In vivo, oxamate improved bone mineral density, cortical bone architecture, and bone biomechanical strength in both young and aged C57BL/6J male mice. Oxamate also increased bone formation by osteoblasts without affecting bone resorption. In sum, our work provided a proof of concept for the use of anti-glycolytic strategies in bone and identified a small molecule LDH inhibitor, oxamate, as a safe and efficient bone anabolic agent.
www.ncbi.nlm.nih.gov
Oxamate is a salt of oxamic acid. Oxamate is a competitive inhibitor of the enzyme lactate dehydrogenase. Oxamate is a possible pyruvate analog that has the ability to halt lactate production by inhibiting lactate dehydrogenase (LDH), effectively stopping the conversation process of pyruvate to lactate.
Oxamic acid is the monoamide of oxalic acid. Oxamic acid inhibits Lactate dehydrogenase. The active site of lactate dehydrogenase (LDH) is closed off once oxamic acid attaches to the LDH-NADH complex, effectively inhibiting it.
Oxalate is a conjugate base of oxalic acid. Oxalate also is a competitive inhibitor of lactate dehydrogenase (LDH). LDH catalyses the conversion of pyruvate to lactic acid oxidizing the coenzyme NADH to NAD+ and H+ concurrently.
LACTATE DEHYDROGENASE INHIBITION WITH OXAMATE EXERTS BONE ANABOLIC EFFECT
Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes as these pathologies are characterized by a shift from oxidative to glycolytic metabolism. We have previously reported such glycolytic shift in aged bone as a ...
www.ncbi.nlm.nih.gov
Oxamate is a salt of oxamic acid. Oxamate is a competitive inhibitor of the enzyme lactate dehydrogenase. Oxamate is a possible pyruvate analog that has the ability to halt lactate production by inhibiting lactate dehydrogenase (LDH), effectively stopping the conversation process of pyruvate to lactate.
Oxamic acid is the monoamide of oxalic acid. Oxamic acid inhibits Lactate dehydrogenase. The active site of lactate dehydrogenase (LDH) is closed off once oxamic acid attaches to the LDH-NADH complex, effectively inhibiting it.
Oxalate is a conjugate base of oxalic acid. Oxalate also is a competitive inhibitor of lactate dehydrogenase (LDH). LDH catalyses the conversion of pyruvate to lactic acid oxidizing the coenzyme NADH to NAD+ and H+ concurrently.
