title: 1,25-Dihydroxyvitamin D3 inhibits directly human osteoclastogenesis by down-regulation of the c-Fms and RANK expression.
abstract: OBJECTIVE
  1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a key molecule to maintain calcium homeostasis and bone metabolism. It was recently reported that 1,25(OH)2D3 directly inhibited osteoclast differentiation in mouse bone marrow cells and human bone marrow-derived colony-forming unit granulocyte macrophage (CFU-GM) cells. However, the direct effects of 1,25(OH)2D3 and its affecting mechanisms on the osteoclast differentiation of human osteoclast precursors remain largely unknown. In this study, we examined the direct effects of 1,25(OH)2D3 on the osteoclastogenesis of human peripheral blood (PB) osteoclast precursors.
  
  
  METHODS
  In vitro osteoclastogenesis assays were performed using osteoclast precursors from normal PB. The gene expressions were analyzed using real-time PCR. The cell surface proteins, including c-Fms and RANK, were measured by flow cytometry.
  
  
  RESULTS
  1,25(OH)2D3 strongly inhibited osteoclast differentiation and it suppressed the expression of RANK in the human PB osteoclast precursors. One mechanism of RANK inhibition by 1,25(OH)2D3 is down-regulation of the M-CSF receptor c-Fms, which is required for the expression of RANK. In contrast to the previous reports on mouse osteoclast precursors, 1,25(OH)2D3 did not affect the expression of c-Fos. Parallel to the inhibition of osteoclastogenesis, 1,25(OH)2D3 increased the expression and phosphorylation of CCAAT enhancer-binding protein β (C/EBPβ), which is a recently discovered inhibitor of osteoclastogenesis.
  
  
  CONCLUSIONS
  Our results show that 1,25(OH)2D3 inhibits human osteoclastogenesis by decreasing the RANK+ osteoclast precursors, and we suggest that 1,25(OH)2D3 may be a powerful therapeutic agent for treating inflammation-induced bone disease that shows excessive osteoclast activation.
authors.affiliation: The Hanyang University Hospital for Rheumatic Diseases, Hanyang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Kim
authors.forename: Bitnara
authors.initials: B
authors.lastname: Lee
authors.forename: Eunji
authors.initials: E
authors.lastname: Kwon
authors.forename: Choong Hyeok
authors.initials: CH
authors.lastname: Choi
authors.forename: Il-Hoon
authors.initials: IH
authors.lastname: Sung
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Kim
authors.forename: Jeongwon
authors.initials: J
authors.lastname: Sohn
authors.forename: Jong Dae
authors.initials: JD
authors.lastname: Ji
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D064368:Healthy Volunteers; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics* / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D016760:Proto-Oncogene Proteins c-fos; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor; D002117:Calcitriol