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Cilostazol attenuates ovariectomy-induced bone loss by inhibiting osteoclastogenesis.


ABSTRACT:

Background

Cilostazol 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 findings

To test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vitro, using ?CT 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-?B ligand-induced NFAT2 expression and decreased binding of nuclear factor-?B-DNA, finally leading to reduced levels of two transcription factors required for OC differentiation.

Conclusions/significance

Our data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.

SUBMITTER: Ke K 

PROVIDER: S-EPMC4436362 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Cilostazol attenuates ovariectomy-induced bone loss by inhibiting osteoclastogenesis.

Ke Ke K   Safder Ali Muhammad AM   Sul Ok-Joo OJ   Suh Jae-Hee JH   Joe Yeonsoo Y   Chung Hun-Taeg HT   Choi Hye-Seon HS  

PloS one 20150518 5


<h4>Background</h4>Cilostazol 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.<h4>Methodology and principal findings</h4>To test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vi  ...[more]

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