title: A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression.
abstract: OBJECTIVE
  Osteoclasts, the unique bone-resorbing polykaryons, are responsible for many bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Hence, the regulation of osteoclast formation is considered a potential therapeutic approach for these diseases. In this study, we investigated the effect of a novel small compound, C(25)H(32)N(4)O(4)S(2) (NecroX-7) on osteoclast formation.
  
  
  METHODS
  We analyzed the effects of NecoX-7 on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in vitro and LPS-induced bone loss in vivo.
  
  
  RESULTS
  We observed that NecroX-7 suppressed osteoclast formation from primary bone marrow macrophages (BMMs) in a dose-dependent manner. NecroX-7 significantly inhibited the NF-κB signaling pathway without affecting the activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK in response to RANKL. In addition, NecroX-7 strongly attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are crucial transcription factors for osteoclast differentiation. Mirroring the down-regulation of c-Fos and NFATc1, the expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was also reduced by the addition of NecroX-7. Furthermore, confirming the in vitro anti-osteoclastogenic effect, NecroX-7 inhibited lipopolysaccharide (LPS)-induced bone loss in vivo.
  
  
  CONCLUSIONS
  Our data imply that NecroX-7 is useful as a therapeutic drug for the treatment of bone resorption-associated diseases.
authors.affiliation: Skeletal Diseases Genome Research Center, Kyungpook National University and Hospital, Daegu 700-412, Republic of Korea. biohjk@hanmail.net
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Yoon
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Soon Ha
authors.initials: SH
authors.lastname: Kim
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D009930:Organic Chemicals; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C556282:necrox-7