Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.
Animals
Bone Marrow Cells
/ drug effects
Bone Resorption
/ metabolism
Cell Differentiation
/ physiology
Female
Glycolysis
/ physiology
Macrophages
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases
/ metabolism
NF-kappa B
/ metabolism
Osteoclasts
/ drug effects
Osteogenesis
/ drug effects
Ovariectomy
/ methods
Phosphofructokinase-2
/ antagonists & inhibitors
Pyridines
/ pharmacology
Quinolines
/ pharmacology
RANK Ligand
/ metabolism
Signal Transduction
/ drug effects
Up-Regulation
/ physiology
MAPKs
NF-κB
PFKFB3
glycolysis
osteoclast
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
13
08
2019
revised:
20
11
2019
accepted:
29
11
2019
pubmed:
28
12
2019
medline:
28
4
2021
entrez:
28
12
2019
Statut:
ppublish
Résumé
Osteoclasts are multinucleated cells derived from the monocyte/macrophage cell lineage under the regulation of receptor activator of nuclear factor-κB ligand (RANKL). In previous studies, stimulation by RANKL during osteoclastogenesis was shown to induce a metabolic switch to enhanced glycolytic metabolism. Thus, we hypothesized that blockage of glycolysis might serve as a novel strategy to treat osteoclast-related diseases. In the present study, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential regulator of glycolysis, was up-regulated during osteoclast differentiation. Genetic and pharmacological inhibition of PFKFB3 in bone marrow-derived macrophages suppressed the differentiation and function of osteoclasts. Moreover, intraperitoneal administration of the PFKFB3 inhibitor PFK15 prevented ovariectomy-induced bone loss. In addition, glycolytic activity characterized by lactate accumulation and glucose consumption in growth medium was reduced by PFKFB3 inhibition. Further investigation indicated that the administration of L-lactate partially reversed the repression of osteoclastogenesis caused by PFKFB3 inhibition and abrogated the inhibitory effect of PFK15 on the activation of NF-κB and MAPK pathways. In conclusion, the results of this study suggest that blockage of glycolysis by targeting PFKFB3 represents a potential therapeutic strategy for osteoclast-related disorders.
Identifiants
pubmed: 31880389
doi: 10.1111/jcmm.14912
pmc: PMC7011148
doi:
Substances chimiques
NF-kappa B
0
PFK15
0
Pyridines
0
Quinolines
0
RANK Ligand
0
PFKFB3 protein, mouse
EC 2.7.1.105
Phosphofructokinase-2
EC 2.7.1.105
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2294-2307Informations de copyright
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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