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

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.

Caffeine enhances osteoclast differentiation from bone marrow hematopoietic cells and reduces bone mineral density in growing rats

“…Some studies indicated that the viability of osteoblasts was significantly decreased at concentrations >0.5 mM caffeine, 9 and the formations of osteoblast and mineralization were significantly decreased in the presence of 10 mM caffeine. 8 These findings indicated that high concentrations of caffeine may possess the cytotoxicity to osteoblasts and its precursor cells.…”

Effects of Coffee Intake and Intraperitoneal Caffeine on Bone Repair Process - A Histologic and Histometric Study

“…Possibly in CAF group there was greater plasma concentration of caffeine compared to the CO group, consequently higher bioavailability during the healing process after tooth extraction. This increased supply in the repair site possibly led to changes in intracellular mediators and thus to a lower viability and activity of osteoblasts to synthesize bone matrix, as evidenced in several studies (8,20,21), and also higher osteoclastic activity (19), which may have provided low maturity of bone trabeculae with the use of pure caffeine (Figs. 1F, I).…”

“…The quality evaluation of bone repair process in the dental socket of animals treated with coffee or caffeine revealed that the newly formed bone trabeculae did not have suitable maturity even on 21 st Many studies have demonstrated that caffeine acts directly on osteoblasts and osteocytes disturbing the process of differentiation (20) multiplication (9), bone matrix production and mineralization (20), even leading to apoptosis of these cells (21). In osteoclasts, it is suggested that the presence of caffeine may increase the differentiation of these cells with the consequent decrease of bone mineral density (19).…”

“…High doses of caffeine have been reported as responsible for the decrease in cell viability of osteoblasts by stimulating intracellular oxidative processes (21). Possibly in CAF group there was greater plasma concentration of caffeine compared to the CO group, consequently higher bioavailability during the healing process after tooth extraction.…”

Salivary extracellular heat shock protein 70 (eHSP70) levels increase after 59 min of intense exercise and correlate with resting salivary secretory immunoglobulin A (SIgA) levels at rest

“…None of the participants had a history of either smoking or taking medications. Subjects were instructed to refrain from alcohol (Taylor et al 2010b), caffeine (Lu et al 2008), smoking (Anbarasi et al 2006), and intense physical activity before and on the test day and until the 4-h post-exercise sampling was completed. On the experimental days, all subjects arrived at the laboratory at either 6:30 or 7:30 am after an overnight fast.…”