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Lactate Dehydrogenase Inhibition With Oxamate Exerts Bone Anabolic Effect. | LitMetric

AI Article Synopsis

  • Cellular bioenergetics targets aging, cancer, and diabetes by shifting from oxidative to glycolytic metabolism, which contributes to conditions like bone loss in aged mice.
  • The study tested various glycolytic inhibitors to stimulate oxidative phosphorylation (OxPhos) and promote bone formation, with oxamate being the only non-toxic option that enhanced both OxPhos and osteoblast differentiation.
  • In vivo experiments showed oxamate improved bone density, structure, and strength in young and aged mice while increasing bone formation without raising resorption levels.

Article Abstract

Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes because 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 showed 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 a 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. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736558PMC
http://dx.doi.org/10.1002/jbmr.4142DOI Listing

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