Abstract
Excessive dexamethasone (Dex) application causes osteoblast cell death, which could lead to osteoporosis or osteonecrosis. AMP-activated protein kinase (AMPK) activation is shown to protect osteoblasts/osteoblastic cells from Dex. In this report, we tested the potential effect of OSU53, a novel AMPK activator, in Dex-treated osteoblastic cells. We show that OSU53 activated AMPK signaling in human OB-6 osteoblastic cells. Further, Dex-induced osteoblastic OB-6 cell death and apoptosis were largely attenuated with pre-treatment with OSU53. OSU53 was more efficient than other known AMPK activators (A-769662 and Compound 13) in protecting OB-6 cells against Dex. AMPK activation is required for OSU53-induced actions in OB-6 cells. AMPKα shRNA knockdown or dominant-negative mutation (dn-AMPKα T172A) almost completely blocked OSU53-induced AMPK activation and OB-6 cell protection against Dex. Further studies showed that OSU53 increased NADPH (nicotinamide adenine dinucleotide phosphate) activity and alleviated Dex-induced oxidative stress in OB-6 cells. Such effects by OSU53 were again almost abolished with AMPKα shRNA or dn-AMPKα in OB-6 cells. Together, these results demonstrate that OSU53 protects osteoblastic cells from Dex possibly via activating AMPK-dependent signaling.
Highlights
Dexamethasone (Dex) and other glucocorticoids (GCs) are common anti-inflammatory and immuno-suppressive medicines [1]
OSU53 is a newly-developed AMPK activator [25], we first tested its effect on AMPK activation in cultured osteoblastic cells
In hFOB1.19 osteoblastic cells, treatment with OSU53 induced significant AMPK and ACC phosphorylations (Data not shown). These results show that OSU53 activates AMPK in human osteoblastic cells
Summary
Dexamethasone (Dex) and other glucocorticoids (GCs) are common anti-inflammatory and immuno-suppressive medicines [1]. Prolonged and/or excessive GC application could lead to osteoporosis [2,3] or even osteonecrosis [4]. Dex is known to induce cytotoxic effects to osteoblasts, which contributes to subsequent bone damages [5,6]. Dex was added to cultured osteoblasts/osteoblastic cells to imitate GC-induced bone damages [5,7,8,9,10]. Groups including ours [10,11] are focusing on the pathological mechanisms of GC-induced osteoblast damages, and on developing possible intervention strategies [9,10,11,12,13,14].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have