Vitamin D Receptor–Dependent 1α,25(OH)2 Vitamin D3–Induced Anti-Apoptotic PI3K/AKT Signaling in Osteoblasts

Oxford University Press (OUP) - Tập 23 Số 8 - Trang 1238-1248 - 2008
Xiaoyu Zhang1, Laura P. Zanello1
1Department of Biochemistry, University of California, Riverside, California, USA

Tóm tắt

Abstract Osteoblast apoptosis plays a crucial role in bone remodeling. Physiological doses of 1α,25(OH)2-vitamin D3 (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.

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Oxford University Press (OUP)

Tập 23 Số 8

1238-1248

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