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Int. J. Mol. Sci. 2008, 9(5), 698-718; doi:10.3390/ijms9050698
Article

Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts

,  and *
Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, Taiwan 32023
* Author to whom correspondence should be addressed.
Received: 8 November 2007 / Revised: 25 February 2008 / Accepted: 5 May 2008 / Published: 8 May 2008
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)

Abstract

Caffeine consumption is a risk factor for osteoporosis, but the precise regulatory mechanisms are currently unknown. Here, we show that cell viability decreases in osteoblasts treated with caffeine in a dose-dependent manner. This cell death is attributed primarily to apoptosis and to a smaller extent, necrosis. Moreover, caffeine directly stimulates intracellular oxidative stress. Our data support caffeine-induced apoptosis in osteoblasts via a mitochondria-dependent pathway. The apoptotic biochemical changes were effectively prevented upon pretreatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the caffeine-induced apoptotic cascade. Additionally, p21-activated protein kinase 2 (PAK2) and c-Jun N-terminal kinase (JNK) were activated in caffeine-treated osteoblasts. Experiments further found that PAK2 activity is required for caffeine-induced JNK activation and apoptosis. Importantly, our data also show that caffeine triggers cell death via inactivation of the survival signal, including the ERK- and Akt-mediated anti-apoptotic pathways. Finally, exposure of rats to dietary water containing 10~20 μM caffeine led to bone mineral density loss. These results demonstrate for the first time that caffeine triggers apoptosis in osteoblasts via activation of mitochondria-dependent cell death signaling and inactivation of the survival signal, and causes bone mineral density loss in vivo.
Keywords: caffeine; ROS; apoptosis; necrosis; osteoporosis caffeine; ROS; apoptosis; necrosis; osteoporosis
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Lu, P.-Z.; Lai, C.-Y.; Chan, W.-H. Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts. Int. J. Mol. Sci. 2008, 9, 698-718.

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