Vitamin D receptor-dependent 1 alpha,25(OH)2 vitamin D3-induced anti-apoptotic PI3K/AKT signaling in osteoblasts.
J Bone Miner Res
; 23(8): 1238-48, 2008 Aug.
Article
en En
| MEDLINE
| ID: mdl-18410228
Osteoblast apoptosis plays a crucial role in bone remodeling. Physiological doses of 1 alpha,25(OH)(2)-vitamin D(3) (1,25D) protect osteoblasts against apoptosis by means of mechanisms only partially understood. We studied activation of an Akt survival cascade downstream of 1,25D nongenomic stimulation of phosphatidylinositide-3'-kinase (PI3K) in osteoblastic cells. We measured a dose- and time-dependent 1,25D induction of Akt phosphorylation (p-Akt) in cultured osteoblastic cells. Maximal response was achieved with 10 nM 1,25D after 5 min. We found that staurosporine (STSP)-induced apoptosis was significantly reduced in 1,25D-pretreated osteoblasts. 1,25D prosurvival effects were abolished when cells were preincubated with inhibitors of PI3K activation. By means of siRNA silencing, we proved that 1,25D induction of p-Akt requires a classic vitamin D receptor (VDR) in osteoblasts. Furthermore, non-osteoblastic CV-1 cells transfected with an enhanced green fluorescent protein (EGFP)-VDR construct responded to 1,25D treatment with a rapid p-Akt response associated with increased cell survival not detected in native, nontransfected cells. We measured increased levels of p-Akt substrates p-Bad and p-FKHR and significantly reduced activity of caspases 8 and 3/7 after 1,25D treatment. In addition, 1,25D-induced protection against apoptosis was abolished when osteoblasts were preincubated with pertussis toxin. We conclude that anti-apoptotic effects of 1,25D in osteoblasts occur through nongenomic activation of a VDR/PI3K/Akt survival pathway that includes phosphorylation of multiple p-Akt substrates and reduction of caspase activities.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteoblastos
/
Calcitriol
/
Transducción de Señal
/
Apoptosis
/
Receptores de Calcitriol
/
Fosfatidilinositol 3-Quinasas
/
Proteínas Proto-Oncogénicas c-akt
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Bone Miner Res
Asunto de la revista:
METABOLISMO
/
ORTOPEDIA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos