Abstract
BackgroundCilostazol has been reported to alleviate the metabolic syndrome induced by increased intracellular adenosine 3’,5’-cyclic monophosphate (cAMP) levels, which is also associated with osteoclast (OC) differentiation. We hypothesized that bone loss might be attenuated via an action on OC by cilostazol.Methodology and Principal FindingsTo test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vitro, using μCT and tartrate-resistant acid phosphatase staining, respectively. Cilostazol prevented from OVX-induced bone loss and decreased oxidative stress in vivo. It also decreased the number and activity of OC in vitro. The effect of cilostazol on reactive oxygen species (ROS) occurred via protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor 1, two major effectors of cAMP. Knockdown of NADPH oxidase using siRNA of p47phox attenuated the inhibitory effect of cilostazol on OC formation, suggesting that decreased OC formation by cilostazol was partly due to impaired ROS generation. Cilostazol enhanced phosphorylation of nuclear factor of activated T cells, cytoplasmic 1 (NFAT2) at PKA phosphorylation sites, preventing its nuclear translocation to result in reduced receptor activator of nuclear factor-κB ligand-induced NFAT2 expression and decreased binding of nuclear factor-κB-DNA, finally leading to reduced levels of two transcription factors required for OC differentiation.Conclusions/SignificanceOur data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.
Highlights
Postmenopausal osteoporosis is a prominent symptom of loss of ovarian function, which is characterized by decreased estrogen and increased follicle-stimulating hormone (FSH)
Cilostazol did not significantly affect the in vivo bone formation markers, serum alkaline phosphatase (ALP) and osteocalcin (Table 1), both were elevated in OVX mice, indicating that cilostazol may exert bone protection through its action on OC, not on osteoblasts
In our present studies we have shown that cilostazol induces the elevation of intracellular cAMP in OC and protects from bone loss and oxidative stress induced by OVX in mice, suggesting a protective role of cAMP in maintaining bone mass
Summary
Postmenopausal osteoporosis is a prominent symptom of loss of ovarian function, which is characterized by decreased estrogen and increased follicle-stimulating hormone (FSH). FSH enhances the differentiation and function of osteoclasts (OC) via lowering adenosine 3’,5’-cyclic monophosphate (cAMP) in OC [2]. Recent studies have broadened its application as it has anti-inflammatory [6] and antiatherogenic actions [7] It attenuates atherosclerosis by inhibiting NF-κB activation and so reducing levels of superoxide and tumor necrosis factor (TNF)-α with a significant elevation of cAMP expression in the mice fed cilostazol-supplemented high fat diet [7]. An ability of cilostazol to scavenge hydroxyl and peroxyl radicals has been demonstrated in endothelial cells [8] These studies suggest that cilostazol has an anti-oxidative and anti-inflammatory activity by up-regulating cAMP. Cilostazol has been reported to alleviate the metabolic syndrome induced by increased intracellular adenosine 3’,5’-cyclic monophosphate (cAMP) levels, which is associated with osteoclast (OC) differentiation. We hypothesized that bone loss might be attenuated via an action on OC by cilostazol
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
