title: 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.
  
  
  RESULTS
  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 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
  Our data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Ke
authors.initials: K
authors.lastname: Ke
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Ali Muhammad
authors.initials: AM
authors.lastname: Safder
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Ok-Joo
authors.initials: OJ
authors.lastname: Sul
authors.affiliation: Department of Pathology, Ulsan University Hospital, Ulsan 682-714, Korea.
authors.forename: Jae-Hee
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Hye-Seon
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy / Q000009:adverse effects*; D018384:Oxidative Stress / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000077407:Cilostazol