Overexpression of DNMT1 leads to hypermethylation of H19 promoter and inhibition of Erk signaling pathway in disuse osteoporosis.
Bone
; 111: 82-91, 2018 06.
Article
en En
| MEDLINE
| ID: mdl-29555308
ABSTRACT
Disuse osteoporosis (DOP) is a common complication of the lack of mechanical loading. The precise mechanism underlying DOP remains unknown, although epigenetic modifications may be a major cause. Recently, cumulative research has revealed that DNA methyltransferase (DNMT) proteins can catalyze the conversion of cytosine to 5-methylcytosine (5mC), altering the epigenetic state of DNA. Here, we report that DNMT1 expression and lncRNA-H19 methylation are upregulated in the femoral tissues of DOP rats, accompanied with inhibited Erk signaling pathway. Overexpression of DNMT1 in UMR-106 cells mimics 5mC enrichment in the H19 promoter, inhibition of Erk signaling and impairment of osteogenesis, which can be rescued by 5'-aza-deoxycytidine (5'-Aza) treatment. Moreover, local intramedullary injection of Dnmt1 siRNA (siDNMT1) in Sprague-Dawley (SD) rats abrogated disuse lncRNA-H19 (H19) downregulation, Erk signaling inhibition, histopathological changes, and bone microstructure declines in the distal femur in vivo. Therefore, our data identify for the first time a new signaling cascade in DOP mechanical unloading causes upregulation of DNMT1 and hypermethylation of H19 promoter, which subsequently leads to downregulation of lncRNA-H19 and inhibition of the ERK signaling, suggesting a new potential therapeutic target.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteoporosis
/
Epigénesis Genética
/
ARN Largo no Codificante
/
ADN (Citosina-5-)-Metiltransferasa 1
Límite:
Animals
Idioma:
En
Revista:
Bone
Asunto de la revista:
METABOLISMO
/
ORTOPEDIA
Año:
2018
Tipo del documento:
Article