Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.
Animals
Bone Resorption
/ metabolism
Cell Differentiation
/ physiology
Chromatography, Liquid
/ methods
Female
Metabolome
/ physiology
Methionine Adenosyltransferase
/ metabolism
Mice
Mice, Inbred C57BL
NF-kappa B
/ metabolism
Osteoclasts
/ metabolism
Osteogenesis
/ physiology
Ovariectomy
/ methods
RANK Ligand
/ metabolism
Reactive Oxygen Species
/ metabolism
Signal Transduction
/ physiology
Tandem Mass Spectrometry
/ methods
MAT2A
RANKL
bone remodeling
osteoclast
osteoporosis
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
31
12
2021
received:
28
07
2021
accepted:
05
01
2022
entrez:
22
1
2022
pubmed:
23
1
2022
medline:
15
2
2022
Statut:
ppublish
Résumé
Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.
Identifiants
pubmed: 35064691
doi: 10.1096/fj.202101205RR
doi:
Substances chimiques
NF-kappa B
0
RANK Ligand
0
Reactive Oxygen Species
0
Mat2a protein, mouse
EC 2.5.1.6
Methionine Adenosyltransferase
EC 2.5.1.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e22167Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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