title: Dextromethorphan inhibits osteoclast differentiation by suppressing RANKL-induced nuclear factor-κB activation.
abstract: Dextromethorphan (DXM), a commonly used antitussive, is a dextrorotatory morphinan. Here, we report that DXM inhibits the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption by abrogating the activation of NF-κB signalling in vitro. Oral administration of DXM ameliorates ovariectomy (OVX)-induced osteoporosis in vivo.
  
  
  BACKGROUND
  DXM was reported to possess anti-inflammatory properties through inhibition of the release of pro-inflammatory factors. However, the potential role and action mechanism of DXM on osteoclasts and osteoblasts remain unclear. In this study, in vitro and in vivo studies were performed to investigate the potential effects of DXM on osteoclastogenesis and OVX-induced bone loss.
  
  
  METHODS
  Osteoclastogenesis was examined by the TRAP staining, pit resorption, TNF-α release, and CCR2 and CALCR gene expression. Osteoblast differentiation was analyzed by calcium deposition. Osteogenic and adipogenic genes were measured by real-time PCR. Signaling pathways were explored using Western blot. ICR mice were used in an OVX-induced osteoporosis model. Tibiae were measured by µCT and serum markers were examined with ELISA kits.
  
  
  RESULTS
  DXM inhibited RANKL-induced osteoclastogenesis. DXM mainly inhibited osteoclastogenesis via abrogation of IKK-IκBα-NF-κB pathways. However, a higher dosage of DXM antagonized the differentiation of osteoblasts via the inhibition of osteogenic signals and increase of adipogenic signals. Oral administration of DXM (20 mg/kg/day) partially reduced trabecular bone loss in ovariectomized mice.
  
  
  CONCLUSIONS
  DXM inhibits osteoclast differentiation and activity by affecting NF-κB signaling. Therefore, DXM at suitable doses may have new therapeutic applications for the treatment of diseases associated with excessive osteoclastic activity.
authors: Department of Orthopedics, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd., New Taipei City 220, Taiwan, Republic of China.
authors: Karl
authors: K
authors: Wu
authors: Tzu-Hung
authors: TH
authors: Lin
authors: Houng-Chi
authors: HC
authors: Liou
authors: Dai-Hua
authors: DH
authors: Lu
authors: Yi-Ru
authors: YR
authors: Chen
authors: Wen-Mei
authors: WM
authors: Fu
authors: Rong-Sen
authors: RS
authors: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001862:Bone Resorption / Q000209:etiology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003915:Dextromethorphan / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D003915:Dextromethorphan
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