PMID- 32729639
OWN - NLM
STAT- MEDLINE
DCOM- 20210728
LR  - 20231110
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 35
IP  - 12
DP  - 2020 Dec
TI  - Lactate Dehydrogenase Inhibition With Oxamate Exerts Bone Anabolic Effect.
PG  - 2432-2443
LID - 10.1002/jbmr.4142 [doi]
AB  - 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. (c) 2020 American Society for Bone and 
      Mineral Research (ASBMR).
CI  - (c) 2020 American Society for Bone and Mineral Research (ASBMR).
FAU - Hollenberg, Alex M
AU  - Hollenberg AM
AD  - Center for Musculoskeletal Research, University of Rochester School of Medicine & 
      Dentistry, Rochester, NY, USA.
FAU - Smith, Charles O
AU  - Smith CO
AD  - Center for Musculoskeletal Research, University of Rochester School of Medicine & 
      Dentistry, Rochester, NY, USA.
FAU - Shum, Laura C
AU  - Shum LC
AD  - Center for Musculoskeletal Research, University of Rochester School of Medicine & 
      Dentistry, Rochester, NY, USA.
FAU - Awad, Hani
AU  - Awad H
AUID- ORCID: 0000-0003-2197-2610
AD  - Center for Musculoskeletal Research, University of Rochester School of Medicine & 
      Dentistry, Rochester, NY, USA.
FAU - Eliseev, Roman A
AU  - Eliseev RA
AUID- ORCID: 0000-0002-6783-7388
AD  - Center for Musculoskeletal Research, University of Rochester School of Medicine & 
      Dentistry, Rochester, NY, USA.
LA  - eng
GR  - R21 AR070928/AR/NIAMS NIH HHS/United States
GR  - P30 AR069655/AR/NIAMS NIH HHS/United States
GR  - R01 AR070613/AR/NIAMS NIH HHS/United States
GR  - R21 AR07928/AR/NIAMS NIH HHS/United States
GR  - P30 AR069655- 5278/AR/NIAMS NIH HHS/United States
GR  - R01 AR072601/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200919
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Anabolic Agents)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
SB  - IM
MH  - *Anabolic Agents
MH  - Animals
MH  - Glycolysis
MH  - *L-Lactate Dehydrogenase/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxidative Phosphorylation
PMC - PMC7736558
MID - NIHMS1646626
OTO - NOTNLM
OT  - BONE
OT  - GLYCOLYSIS
OT  - LACTATE DEHYDROGENASE
OT  - MITOCHONDRIA
OT  - OSTEOBLAST
OT  - OXAMATE
EDAT- 2020/07/31 06:00
MHDA- 2021/07/29 06:00
PMCR- 2020/12/15
CRDT- 2020/07/31 06:00
PHST- 2020/04/07 00:00 [received]
PHST- 2020/07/14 00:00 [revised]
PHST- 2020/07/18 00:00 [accepted]
PHST- 2020/07/31 06:00 [pubmed]
PHST- 2021/07/29 06:00 [medline]
PHST- 2020/07/31 06:00 [entrez]
PHST- 2020/12/15 00:00 [pmc-release]
AID - 10.1002/jbmr.4142 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2020 Dec;35(12):2432-2443. doi: 10.1002/jbmr.4142. Epub 2020 
      Sep 19.