Sestrin2 inhibits RANKL-induced osteoclastogenesis through AMPK activation and ROS inhibition.
Free Radic Biol Med
; 211: 77-88, 2024 02 01.
Article
em En
| MEDLINE
| ID: mdl-38101586
ABSTRACT
Sestrins are stress-responsive proteins with antioxidant properties. They participate in cellular redox balance and protect against oxidative damage. This study investigated the effects of Sestrin2 (Sesn2) on osteoclast differentiation and function. Overexpressing Sesn2 in osteoclast precursor cells significantly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis. This was assessed as reduced expression of various osteoclast markers, including c-Fos, nuclear factor of activated T cells 1 (NFATc1), osteoclast-associated receptor, tartrate-resistant acid phosphatase, and cathepsin K. Conversely, downregulation of Sesn2 produced the opposite effect. Mechanistically, Sesn2 overexpression enhanced AMPK activation and the nuclear translocation of nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2), promoting antioxidant enzymes. Moreover, azithromycin (Azm) induced Sesn2 expression, which suppressed RANKL-induced osteoclast differentiation. Specifically, Azm treatment reduced RANKL-induced production of reactive oxygen species in osteoclasts. Furthermore, intraperitoneal administration of Azm ameliorated RANKL-induced bone loss by reducing osteoclast activity in mice. Taken together, our results suggested that Azm-induced Sesn2 act as a negative regulator of RANKL-induced osteoclast differentiation through the AMPK/NFATc1 signaling pathway. Concisely, targeting Sesn2 can be a potential pharmacological intervention in osteoporosis.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteogênese
/
Ligante RANK
Limite:
Animals
Idioma:
En
Revista:
Free Radic Biol Med
/
Free radic. biol. med
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Free radical biology and medicine
Assunto da revista:
BIOQUIMICA
/
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article